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Histiocytoid Sweet's syndrome (HSS) is a variant of Sweet's syndrome (SS) that clinically resembles SS but differs histologically by infiltrates, predominantly composed of immature cells of the myeloid lineage. Medications such as proteasome inhibitors have been reported to cause HSS but there has been little discussion on the underlying mechanism. Here we report two cases of HSS associated with a proteasome inhibitor. Both patients were on ixazomib for the treatment of multiple myeloma and presented with acute erythematous plaques on the upper half of the body. Pathological findings were consistent with HSS. Similarities between proteasome inhibitor‐induced HSS and Nakajo‐Nishimura syndrome, an inherited inflammatory disease, can be identified both clinically and histologically, suggesting a potential explanation of the mechanism behind proteasome inhibitor‐associated HSS. [ABSTRACT FROM AUTHOR]

We performed retrospective analysis of relapsed/refractory multiple myeloma (RRMM) patients previously exposed to daratumumab treated with ixazomib, lenalidomide, dexamethasone (IRd) regimen in real clinical practice. Our aim was to evaluate efficacy of IRd in these patients and select a subset of patients that would benefit from this treatment the most. In total, we analyzed 43 daratumumab‐exposed RRMM patients treated in our center. Minimal response or better was achieved by 53.5% of patients from the cohort. Median progression free survival (PFS) was 4.56 months (95% CI: 2.56, 8.03) and median overall survival (OS) was 28.92 months (95% CI: 5.4, NR). Duration of response (DOR) was evaluable in 28 patients and reached a median of 21.3 months (95% CI: 6.85, NR). Next, we evaluated hazard ratios (HR) for OS and PFS. There was improved OS in patients that were not‐triple refractory or worse (HR = 0.39, 95%Cl (0.14; 1.10), p = .07) and in patients, that had less than three previous lines of treatment (LOT) (HR = 0.13, 95%Cl (0.03; 0.6) p = .003). Similar to OS, there was improved PFS in patients, that were not triple‐refractory or worse (HR = 0.52, 95%Cl (0.25; 1.10), p = .08). We concluded, that the best survival benefit for RRMM patients pretreated with daratumumab to IRd regimen was observed in patients that were not triple‐refractory and had less than three previous lines of treatment (LOT). The DOR in these patients was 21.3 months (95% CI: 6.85, NR). [ABSTRACT FROM AUTHOR]

Background and Aims: Poor prognosis in lung cancer is associated with tumor-associated macrophages (TAMs) that exhibit M2clike behaviours that support multiple pathways in the tumour microenvironment. The interplay between epigenetic modifications and the ubiquitin-proteasome pathway involves three key mechanisms: regulation of epigenetic enzymes by ubiquitin, interaction between ubiquitin and epigenetic modifiers, and epigenetic silencing of critical genes involved in cellular processes. Therefore, we investigated the effects of ixazomib, a proteasome inhibitor, on gene expression changes in epigenetic chromatin modification enzymes in a co-culture of M2c macrophages and A549 lung cancer cells. Methods: The IC50 concentration of ixazomib was determined to be 2.19 μM using a real-time cell analyser. THP-1 monocytes were polarised into M0 macrophages with 100 ng/mL phorbol 12-myristate 13-acetate (PMA), rested, and then exposed to 1 mM hydrocortisone to become M2c macrophages. A549 cells were seeded in the lower chamber of a co-culture plate. M2c macrophages were then co-cultured with A549 cells for 24 h with or without 2.19 μM ixazomib. After being isolated, mRNA was converted to cDNA and analysed using a gene panel with RT-PCR. Results: The findings showed that 56 genes had exceptionally high expression levels (up to 1848-fold. Ixazomib downregulated these overexpressed genes. Conclusion: Ixazomib effectively modulates the expression of genes involved in epigenetic chromatin modification in the lung cancer microenvironment, indicating its utility in lung cancer therapy. Further studies are needed to explore the combined use of epigenetic drugs and proteasome inhibitors. [ABSTRACT FROM AUTHOR]

The leading cause of cancer‐related death is lung cancer, with metastasis being the most common cause of death. To elucidate the role of macrophages in lung cancer and angiogenesis processes, we established an in vitro co‐culture model of A549 or HUVEC with THP‐1 cells that polarized to M2c macrophages with hydrocortisone. The proteasome inhibitors bortezomib and ixazomib were investigated for their effects on proliferation, invasion, migration, metastasis, and angiogenesis pathways. The effects of bortezomib and ixazomib on gene expression in gene panels, including crucial genes related to angiogenesis and proteasomes, were investigated after the co‐culture model to determine these effects at the molecular level. In conclusion, bortezomib and ixazomib showed antiproliferative effects in both cells, as well as in M2c macrophage co‐culture. M2c macrophages also increased invasion in A549 cells and both invasion and migration in HUVEC. mRNA expression upregulation, specifically in the NFKB and VEGF genes, supported the metastatic and angiogenic effects found in A549 and HUVEC with M2c macrophage co‐culture. Additionally, bortezomib inhibited the VEGFB pathway in HUVEC and NFKB1 in A549 cells. The significant findings obtained as a result of this study will provide information regarding angiogenesis induced by M2 macrophages. [ABSTRACT FROM AUTHOR]