Neutrophil-specific expression of JAK2-V617F or CALRmut induces distinct inflammatory profiles in myeloproliferative neoplasia.

BACKGROUND: Neutrophils play a crucial role in inflammation and in the increased thrombotic risk in myeloproliferative neoplasms (MPNs). We have investigated how neutrophil-specific expression of JAK2-V617F or CALRdel re-programs the functions of neutrophils. METHODS: Ly6G-Cre JAK2-V617F and Ly6G-Cre CALRdel mice were generated. MPN parameters as blood counts, splenomegaly and bone marrow histology were compared to wild-type mice. Megakaryocyte differentiation was investigated using lineage-negative bone marrow cells upon in vitro incubation with TPO/IL-1ß. Cytokine concentrations in serum of mice were determined by Mouse Cytokine Array. IL-1α expression in various hematopoietic cell populations was determined by intracellular FACS analysis. RNA-seq to analyse gene expression of inflammatory cytokines was performed in isolated neutrophils from JAK2-V617F and CALR-mutated mice and patients. Bioenergetics of neutrophils were recorded on a Seahorse extracellular flux analyzer. Cell motility of neutrophils was monitored in vitro (time lapse microscopy), and in vivo (two-photon microscopy) upon creating an inflammatory environment. Cell adhesion to integrins, E-selectin and P-selection was investigated in-vitro. Statistical analysis was carried out using GraphPad Prism. Data are shown as mean ± SEM. Unpaired, two-tailed t-tests were applied. RESULTS: Strikingly, neutrophil-specific expression of JAK2-V617F, but not CALRdel, was sufficient to induce pro-inflammatory cytokines including IL-1 in serum of mice. RNA-seq analysis in neutrophils from JAK2-V617F mice and patients revealed a distinct inflammatory chemokine signature which was not expressed in CALR-mutant neutrophils. In addition, IL-1 response genes were significantly enriched in neutrophils of JAK2-V617F patients as compared to CALR-mutant patients. Thus, JAK2-V617F positive neutrophils, but not CALR-mutant neutrophils, are pathogenic drivers of inflammation in MPN. In line with this, expression of JAK2-V617F or CALRdel elicited a significant difference in the metabolic phenotype of neutrophils, suggesting a stronger inflammatory activity of JAK2-V617F cells. Furthermore, JAK2-V617F, but not CALRdel, induced a VLA4 integrin-mediated adhesive phenotype in neutrophils. This resulted in reduced neutrophil migration in vitro and in an inflamed vessel. This mechanism may contribute to the increased thrombotic risk of JAK2-V617F patients compared to CALR-mutant individuals. CONCLUSIONS: Taken together, our findings highlight genotype-specific differences in MPN-neutrophils that have implications for the differential pathophysiology of JAK2-V617F versus CALR-mutant disease.

Melanuria in a patient with BRAF-mutant metastatic melanoma of unknown primary: Insights on the pathophysiology, differential diagnosis, prognosis, and treatment.

Melanuria is the dark brown discoloration of the urine and an uncommon manifestation in patients with melanoma. It is an ominous sign, usually indicating widespread disease. In this article, through an illustrative case, we discuss the pathophysiological, clinical, and prognostic characteristics of melanuria in melanoma. Moreover, we aim to provide the available data for the prompt diagnosis and treatment of patients presenting with melanuria. We present the case of a 47-year-old man presenting with melanuria and diffure melanosis cutis, who was eventually diagnosed with a BRAF-mutated metastatic melanoma of unknown primary. The patient was started on a BRAF and MEK inhibitor, but he had a rapid disease progression and succumbed to the disease. There is only a limited number of case reports of melanoma patients with melanuria receiving targeted therapies or immune checkpoint inhibitors. In these reports, variable treatment responses have been described. In view of the increasing significance of targeted therapies and immunotherapy for melanoma, more cases are needed to improve our understanding on the prognostic significance of melanuria in the era of novel therapies for melanoma.

A case report of a fulminant Aeromonas hydrophila soft tissue infection in a patient with acute lymphoblastic leukemia harboring a rare translocation.

INTRODUCTION: Aeromonads are gram-negative opportunistic bacteria, mainly found in aquatic environments. Hematologic patients are particularly at risk of Aeromonas soft tissue infections and septicemia, especially during chemotherapy-induced neutropenia. CASE DESCRIPTION: A 46-year-old man was diagnosed with acute lymphoblastic leukemia characterized by the rare t(12;17)(p13;q21)/TAF15-ZNF384 aberration. On day 22 of chemotherapy, he developed febrile neutropenia followed by necrotizing fasciitis in his upper right extremity. Despite appropriate antibiotic therapy and prompt surgical intervention, he died within 36 h after the appearance of a fever. A multi-sensitive Aeromonas hydrophila was isolated from all cultural sites. DISCUSSION AND CONCLUSIONS: In a previous paper we characterized the patient's aberration with cytogenetic and FISH analysis. Here, we provide details regarding the patient's rapidly progressing infection and underline the importance of maintaining high clinical suspicion of Aeromonas infections in acute leukemia. Given the unusually rapid progression of an infection caused by a rare non-resistant pathogen, and after considering data on the implication of metalloproteinase function in immune system regulation, a correlation between risk of severe infection and TAF15-ZNF384 aberrated acute lymphoblastic leukemia cannot be ruled out.

Real world data on the prognostic significance of monocytopenia in myelodysplastic syndrome.

Monocytopenia is a common finding in patients with myelodysplastic syndrome (MDS), but although monocytes may exhibit prognostic significance in MDS due to their role in innate immunity, they have not been incorporated in any prognostic scoring system for MDS. In this study, we analyzed national registry data from 1719 adults with MDS. Monocytopenia was present in 29.5% of the patients and was correlated with the presence of excess blasts and higher revised international prognostic scoring system categories. Univariate analysis showed that monocytopenia was prognostic of a lower overall survival [(OS), 32.0 versus 65.0 months, p < 0.001], while it retained its prognostic significance in a multivariate model comprising anemia, neutropenia and thrombocytopenia [hazard ratio (HR) for OS, 1.320, p < 0.001]. Moreover, it was prognostic of a lower leukemia free survival (LFS) both in univariate analysis and in a multivariate model comprising cytopenias, bone marrow blasts, and cytogenetic risk (HR for LFS 1.27, p = 0.031). The findings regarding OS and LFR were exclusive or more pronounced in lower risk patients, respectively. Moreover, monocytopenia could divide the low and intermediate risk groups of IPSS-R in prognostically distinct subgroups. Our results redefine the prognostic role of monocytes in MDS and set the basis for further studies to validate our results and expand our knowledge on the prognostic significance of monocytopenia in MDS.

A case report of Hodgkin lymphoma in a patient treated with ustekinumab for psoriasis.

RATIONALE: Ustekinumab is a biological agent that inhibits interleukin 12 and 23 and has been approved for the treatment of moderate and severe plaque psoriasis. There have been case reports that raise concerns about its oncogenic potential. We are the first authors to report a case of Hodgkin lymphoma in a psoriatic patient receiving ustekinumab. PATIENT CONCERNS: A 22-year-old asymptomatic female patient presented to our department to investigate an enlarged cervical lymph node. Her past history was unremarkable, except for psoriasis since age 13. Two months before presentation the decision to administer Ustekinumab was taken and the patient had already received 3 doses. DIAGNOSES: During workup a Stage IV Hodgkin lymphoma was discovered. INTERVENTIONS: Ustekinumab administration was discontinued. The patient received treatment with the ABVD regimen. OUTCOMES: The patient's disease was refractory to the above-mentioned treatment. Therefore, a more aggressive regimen (BEACOPP escalated) was administered. LESSONS: Growing postmarketing surveillance data and case reports indicate that further research is warranted in order to elucidate a potential association between Ustekinumab and malignancy.

Depression following graft-versus-host disease in a patient with acute lymphoblastic leukaemia: A case report.

There is increasing evidence to suggest an association between depression and inflammation, with patients suffering from immune mediated-disorders exhibiting higher levels of depression. Inflammation in depression is a potential target for the development of novel treatment strategies. The present study presents a clinical case in which a patient with an underlying inflammatory condition acutely developed a severe depressive episode resulting in a sudden, dramatic change in their clinical picture. This case, with no similar case reports being in the literature thus far, at least to the best of our knowledge, highlights the increasing consideration that there may be a causative role between neuro-inflammation and depression. This study reports the case of a 40-year-old male with acute lymphoblastic leukaemia (ALL) and no previous psychiatric history, who developed an acute onset of a severe depressive episode in the context of the immune-mediated graft-versus-host disease (GVHD). GVHD is a complication of allogeneic hematopoietic cell transplantation, which the patient had undergone, for the treatment of his ALL. The rapid onset of depression could be explained by the neuroinflammatory processes occurring in GVHD. This provides a clinical example for the possible role of the immune system in depression, and clinicians should be aware of this association.

An unusual case report of unilateral parotid gland sarcoidosis with spontaneous remission.

RATIONALE: Parotid gland sarcoidosis is a well-recognized, but uncommon disease entity. Parotidectomy is most commonly performed to establish the diagnosis and most patients are treated with corticosteroids. PATIENT CONCERNS: A young female patient presented with right parotid enlargement and developed symptoms of facial nerve palsy during diagnostic investigation. DIAGNOSES: A fine-needle aspiration cytology showed granulomatous inflammation. The diagnosis of sarcoidosis was eventually established based on the demonstration of the characteristic lambda and panda signs by a Gallium-67 scintigraphy. INTERVENTIONS: No specific pharmacologic therapy was initiated. OUTCOMES: The patient's symptoms regressed completely over a period of 3 months. Additionally, she remains asymptomatic 2 years later. LESSONS: This case underlines the importance of not initiating corticosteroids in all patients with parotid gland sarcoidosis and suggests that parotidectomy can be avoided in the presence of characteristic for sarcoidosis imaging findings.