Sweet's syndrome (acute febrile neutrophilic dermatosis) is an infrequent skin disease characterized by sudden onset of fever, leucocytosis and erythematous plaques or nodules infiltrated by neutrophils. There are three main clinical settings in which Sweet's syndrome has been described: classical or idiopathic Sweet's syndrome, malignancy-associated Sweet's syndrome and drug-induced Sweet's syndrome. Classical Sweet's is often preceded by an upper respiratory tract infection and may be associated with inflammatory bowel disease and pregnancy. Approximately 21% of patients have an associated malignancy, most commonly hematological disease. The syndrome may occur as a paraneoplastic accompaniment to established cancer or may be a first sign of malignancy or its recurrence. The incidence is said to be increasing in recent years due to the frequent use of growth factors in cancer patients. Several anticancer agents including all-trans-retinoic acid proteosome inhibitors, hypomethylating agents, tyrosine kinase inhibitors and lenalidomide are potential harbingers of Sweet's syndrome. Unfortunately, little is known about the pathophysiology of Sweet's syndrome and there are no established guidelines for treatment of malignancy-associated Sweet's syndrome. Systemic corticosteroids are the mainstay of treatment. Sweet's syndrome caused by anticancer agents sometimes involves withdrawal or temporary discontinuation of anticancer agents, use of systemic corticosteroids and/or rechallenge with either with the same anticancer agents or different agents. This report provides insights into the pathophysiology, clinical presentation, diagnostic work, differential diagnosis and management of malignancy-associated Sweet's syndrome published in reported cases.

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Non-Hispanic Black (NHB) and Hispanic patients with acute myeloid leukemia (AML) have higher mortality rates than non-Hispanic white (NHW) patients despite more favorable genetics and younger age. A discrete survival analysis was performed on 822 adult AML patients from six urban cancer centers and revealed inferior survival among NHB (HR=1.59, 95% CI: 1.15, 2.22) and Hispanic (HR=1.25, 95% CI: 0.88, 1.79) compared to NHW patients. A multilevel analysis of disparities was then conducted to investigate the contribution of neighborhood measures of structural racism on racial/ethnic differences in survival. Census tract disadvantage and affluence scores were individually calculated. Mediation analysis of hazard of leukemia death between groups was examined across six composite variables: structural racism (census tract disadvantage, affluence and segregation), tumor biology (ELN risk and secondary leukemia), health care access (insurance and clinical trial enrollment), comorbidities, treatment patterns (induction intensity and transplant utilization) and ICU admission during intensive chemotherapy. Strikingly, census tract measures accounted for nearly all of the NHB-NHW and Hispanic-NHW disparity in leukemia death. Treatment patterns, including induction intensity and allogeneic transplant, as well as treatment complications, as assessed by ICU admission during induction chemotherapy, were additional mediators of survival disparities in AML. This is the first study to formally test mediators for observed disparities in AML survival and highlights the need to investigate the mechanisms by which structural racism interacts with known prognostic and treatment factors to influence leukemia outcomes.

The transcriptional output at a genomic locus in eukaryotes is determined, in part, by the pattern of histone modifications that are read and interpreted by key effector proteins. The histone deacetylase activity of the evolutionarily-conserved Rpd3S/Sin3S complex is crucial for suppressing aberrant transcription from cryptic start sites within intragenic regions of actively transcribed genes. Precise targeting of the complex relies on the chromatin binding activities of the MRG15 and Pf1 subunits. Whereas the molecular target of the MRG15 chromodomain (CD) has been suggested to be H3K36me2/3, the precise molecular target of the Pf1 plant homeodomain 1 (PHD1) has remained elusive. Here we show that Pf1 PHD1 binds preferentially to the unmodified extreme N-terminus of histone H3 (H3K4me0) but not to H3K4me2/3, which are enriched in the promoter and 5′ regions of genes. Unlike previously characterized CD and PHD domains that bind to their targets with micromolar affinity, both MRG15 CD and Pf1 PHD1 bind to their targets with >100 μM affinity, offering an explanation for why both MRG15 CD and Pf1 PHD1 domains are required to target the Rpd3S/Sin3S complex to chromatin. Our results also suggest that bivalency, rather than cooperativity, is the operative mechanism by which Pf1 and MRG15 combine to engage H3 in a biologically significant manner. Finally, the studies reveal an unanticipated role of Pf1 PHD1 in engaging the MRG15 MRG domain, albeit in a Pf1 MRG-binding domain (MBD)-dependent manner, implying a key role for the MRG15 MRG-Pf1 MBD interaction in chromatin targeting of the Rpd3S/Sin3S complex.

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