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Chronic proinflammatory signaling is a characteristic trait in myeloproliferative neoplasms (MPN), particularly myelofibrosis (MF). Aberrant inflammatory signaling, particularly from NF-κB pathway, exacerbates the progression of MPN. Previously, we identified a critical role of miR-146a, a negative regulator of the TLR/NF-κB axis, in MF development. MPN patients carrying the miR-146a rs2431697-TT genotype, associated with lower miR-146a expression levels, have a higher risk of progression to overt-MF from chronic-phase disease. Using miR-146a -/- (KO) mice, a MF-like model lacking MPN driver mutations, we here investigate whether pacritinib, a dual JAK/NF-κB pathways inhibitor (via JAK2/IRAK1, respectively), prevents the age-associated myelofibrotic phenotype of these mice. Young miR-146a -/- mice were treated either with or without pacritinib, for 3 or 6 months. Notably, pacritinib prevented the splenomegaly, reticulin fibrosis and osteosclerosis observed in untreated KO mice. Pacritinib also avoided the myeloproliferation, loss of splenic architecture, and extramedullary hematopoiesis observed in age-matched untreated KO mice. Pharmacological targeting of IRAK1/JAK2 attenuated the pro-inflammatory environment, preventing the increase of inflammatory cytokines, particularly CXCL1 and TNF-α, without inducing cytopenias but rather the opposite. Compared to age-matched untreated KO mice, treated mice showed higher platelet counts irrespective of treatment duration, and higher erythrocyte counts with the longer treatment. Additionally, pacritinib preventive treatment reduced COL1A1 production in an in vitro model mimicking JAK2-driven fibrosis. These findings highlight that dual inhibition of JAK2/IRAK1 with pacritinib, by delaying or attenuating the myelofibrotic progression, could be a potential modifier of the natural course of MPN., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Francisca Ferrer-Marin reports a relationship with CTI BioPharma Corp, a Sobi company, that includes: funding grants (CFE/BI/72–19). If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Emerging evidence shows the crucial role of inflammation (particularly NF-κB pathway) in the development and progression of myelofibrosis (MF), becoming a promising therapeutic target. Furthermore, tailoring treatment with currently available JAK inhibitors (such as ruxolitinib or fedratinib) does not modify the natural history of the disease and has important limitations, including cytopenias. Since recent studies have highlighted the role of miR-146a, a negative regulator of the NF-κB pathway, in the pathogenesis of MF; here we used miR-146a -/- (KO) mice, a MF-like model lacking driver mutations, to investigate whether pharmacological inhibition of JAK/STAT and/or NF-κB pathways may reverse the myelofibrotic phenotype of these mice. Specifically, we tested the JAK1/2 inhibitor, ruxolitinib; the NF-κB inhibitor via IKKα/β, BMS-345541; both inhibitors in combination; or a dual inhibitor of both pathways (JAK2/IRAK1), pacritinib. Although all treatments decreased spleen size and partially recovered its architecture, only NF-κB inhibition, either using BMS-345541 (alone or in combination) or pacritinib, resulted in a reduction of extramedullary hematopoiesis, bone marrow (BM) fibrosis and osteosclerosis, along with an attenuation of the exacerbated inflammatory state (via IL-1β and TNFα). However, although dual inhibitor improved anemia and reversed thrombocytopenia, the combined therapy worsened anemia by inducing BM hypoplasia. Both therapeutic options reduced NF-κB and JAK/STAT signaling in a context of JAK2V617F-driven clonal hematopoiesis. Additionally, combined treatment reduced both COL1A1 and IL-6 production in an in vitro model mimicking JAK2-driven fibrosis. In conclusion, NF-κB inhibition reduces, in vitro and in vivo, disease burden and BM fibrosis, which could provide benefits in myelofibrosis patients., (© 2024 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

Introduction: Keratoacanthoma is a fast-growing crateriform skin tumor. Approximately 25% of such tumors undergo malignant transformation and develop areas of squamous cell carcinoma (SCC). The presence of laminin-322 has been associated with progression to invasive forms of SCC. The aim of this study was to determine whether or not immunohistochemical staining for laminin-322 would be of value in distinguishing between keratoacanthomas, keratoacanthomas with areas of squamous cell carcinoma, and SCCs., Material and Methods: Seventy-four lesions were selected from the pathology archives of our hospital and divided into 4 groups: 20 keratoacanthomas without SCC, 20 keratoacanthomas with areas of squamous cell carcinoma, 20 invasive SCCs (8 with crateriform morphology) unrelated to keratoacanthoma, and 14 problem lesions (keratoacanthomas with areas suggestive of SCC). All 74 lesions were stained for laminin-322., Results: Laminin-322 staining was strongly positive both in areas of SCC in keratoacanthomas with malignant transformation and in invasive SCCs (mostly at the invasive front of the SCC). However, in benign keratoacanthomas, it was only weakly positive and furthermore it was confined to isolated cells or small groups of cells. The 14 problem lesions were reexamined after laminin-322 staining and 8 were diagnosed as keratoacanthomas with incipient SCC and 6 as keratoacanthomas without SCC., Conclusions: Laminin-322 staining is different in keratoacanthomas and SCCs and would thus be a useful test for differentiating keratoacanthomas from both invasive SCCs and keratoacanthomas with areas of squamous cell carcinoma. It would also be of value in diagnosing keratoacanthomas with areas suggestive of SCC or with incipient SCC., (Copyright © 2011 Elsevier España, S.L. y AEDV. All rights reserved.)

Glycogen-rich clear cell (GRCC) is a rare subtype of breast carcinoma characterized by carcinoma cells containing an optically clear cytoplasm and intracytoplasmic glycogen. We present the case of a 55-year-old woman with a palpable mass in the right breast and clinical signs of locally advanced breast cancer (LABC). The diagnosis of GRCC carcinoma was based on certain histopathological characteristics of the tumor and immunohistochemical analysis. To our knowledge, this is the first case of GRCC LABC with intratumoral calcifications. There is no evidence of recurrence or metastatic disease after 14 months' follow-up.

Introduction: the patients affected by systemic lupus erythematosus (SLE) often suffer gastrointestinal symptoms. The differential diagnosis should contemplate pathology of the gall bladder. We present the case of a patient with hemorrhagic lithiasic cholecystitis and hemobilia., Case Report: 24 year old female diagnosed with SLE under treatment with Sintrom®, Dacortin® and Dolquine® that presented acute lithiasic cholecystitis and hemobilia with a distal calculus. Cholecystectomy and aperture of the ductus choledochus were performed allowing to confirm the hemobilia and to extract the calculus., Discussion: The treatment of cholecystitis in the patients with SLE is controversial due to the fact that most reviewed cases have been solved with cholecystectomy, or in other cases with conservative treatment with corticosteroids. We believe that the presence of cholelithiasis in a patient with SLE with pain on the right hypochondrium and ultrasound confirming the suspicion of cholecystitis demands a surgical treatment since the cause may be vascular, lithiasic or combined. Besides, the possible complications will not respond to pharmaceutical treatment.

Hepatic angiosarcoma is a rare primary tumor of the liver with a mesenchymal origin. Diagnosis is difficult because clinical manifestations and imaging studies are inconclusive. In many cases a diagnosis is obtained during necropsy, not being apparent during the course of disease. It is associated with several risk factors, but these contribute to explaining only a few of all reported cases. When clinical manifestations begin progression is often fast, and possibilities for curative treatment are limited.We report two cases of hepatic angiosarcoma. In the first one, our patient had an insidious initial course, and then suddenly presented with hepatic failure followed by acute respiratory distress. A diagnosis was reached during necropsy. In the second case, we initiated the study of a chronic liver disease using fine-needle aspiration biopsy, which showed findings suggestive of hepatic angiosarcoma. In the following weeks the patient started on a torpid clinic course, and died from multiple organ failure.