Myelofibrosis (MF) is a chronic myeloproliferative neoplasm characterized by progressive cytopenias, splenomegaly, and constitutional symptoms. The hallmark of MF pathophysiology is constitutive activation of JAK/STAT signaling, which, in the majority of cases, is associated with an acquired mutation in one of three driver mutations, JAK2, CALR, or MPL. Our growing understanding of the molecular biology of MPNs has resulted in regulatory approval of four JAK inhibitors (JAKi), which have demonstrated efficacy in improving symptom burden and reducing spleen size. Despite clear benefits of JAKi therapy, including evidence of improved survival, these therapeutic interventions have not established an ability to modify disease in terms of resolution of bone marrow fibrosis or molecular remissions. Therefore, recent emphasis has been on the development of novel therapies with informed targets outside of the JAK/STAT signaling pathway. Moreover, combination approaches utilizing JAK and non-JAK targeting agents underscore the potential for disease modification along with deeper and more durable clinical responses. Emerging combination strategies and their clinical development will be reviewed here, including investigations that pair JAKi therapy with BCL-2 family inhibitors, BET inhibitors, restored p53 cell death signals, telomerase inhibitors, PIM1 kinase inhibitors, and mutant CALR targeted therapies. While several combination clinical trials suggest improved spleen and symptom responses and the possibility of disease modification, toxicity profiles and optimal sequencing remain areas of active investigation.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, highly aggressive hematologic malignancy characterized by frequent involvement of the skin and bone marrow. Central nervous system (CNS) infiltration is uncommon and may be clinically occult, thereby posing diagnostic challenges. We report the case of a 74 year-old man who initially presented with progressively enlarging cutaneous masses on the trunk. Histopathological examination of skin biopsy demonstrated BPDCN with a characteristic immunophenotype, and subsequent bone marrow studies confirmed extensive marrow involvement. The patient was treated with a combination of azacitidine and low-dose cytarabine to achieve sustained hematologic remission with marked regression of skin lesions and splenomegaly, despite intermittent treatment-related myelosuppression. After several months of stable disease, he was readmitted with new-onset paroxysmal occipital headache and blurred vision. Peripheral blood counts, bone marrow evaluation, and systemic imaging were unremarkable, and brain and orbital magnetic resonance imaging showed no abnormalities. Cerebrospinal fluid (CSF) analysis revealed marked pleocytosis with abundant atypical cells. Flow cytometry identified BPDCN cells accounting for 97.6% of nucleated cells, establishing the diagnosis of CNS involvement. Intrathecal methotrexate combined with cytarabine led to the rapid resolution of neurologic and visual symptoms. This case study demonstrates that BPDCN may lead to isolated CNS involvement despite ongoing systemic remission, highlighting the importance of cerebrospinal fluid evaluation in patients with unexplained neurologic manifestations.

Acid sphingomyelinase deficiency (ASMD) is a rare debilitating lysosomal storage disease resulting in multisystemic disease manifestations, significant disease burden, and early mortality for some individuals. Enzyme replacement therapy (ERT) with olipudase alfa (Xenpozyme) is the first disease-specific treatment indicated for noncentral nervous system manifestations of ASMD in children and adults. During the 1-year primary analysis of the ASCEND placebo-controlled trial in 36 adults with ASMD, olipudase alfa treatment reduced sphingomyelin storage and was associated with clinically significant improvements relative to placebo in multiple endpoints. An open-label extension of the ASCEND trial followed 35 of 36 adults during olipudase alfa treatment for up to 5 years. Mean time on olipudase alfa was 4.2 ± 1.0 years; mean compliance was 90% ± 13%. During long-term olipudase alfa treatment, percent predicted diffusing capacity for carbon monoxide (DLCO) increased (mean 50.1% ± 10.8% at baseline vs. 66.5% ± 13.3% at final assessment; mean change from baseline of 35.9% ± 27.5% (p < 0.0001). Mean baseline spleen volume of 11.5 ± 4.6 multiples of normal (MN) decreased to 4.8 ± 2.1 MN at final assessment, mean change from baseline -57.5% ± 10.1% (p < 0.0001) and mean baseline liver volume (1.5 ± 0.4 MN) decreased to 0.95 ± 0.23 MN at final assessment, (mean change from baseline -36.8% ± 11.5%, p < 0.0001). Plasma lyso-sphingomyelin levels decreased by 72% from baseline to final assessment. Overall, improvements in clinical parameters occurred regardless of baseline severity. No new safety issues emerged during the trial extension and 98% of treatment emergent adverse events were mild/moderate. Improvements in visceral ASMD disease with olipudase alfa treatment will significantly impact the disease burden for those with this progressive multiorgan disorder.

B-cell prolymphocytic leukemia (B-PLL) is a rare B-cell neoplasm that presents splenomegaly, lymphocytosis, minimal or absent lymphoadenopathy, at least 55% of prolymphocytes in peripheral blood and a variable clinical course. Complex/composite karyotype and recurrent structural variants (SVs), including TP53 aberrations (mutations/deletion) and MYC abnormalities (translocation or gain) are genetic features typically seen in B-PLL. We applied the genome-wide technology of optical genome mapping (OGM) in 3 cases with B-PLL, finding multiple genomic aberrations, including SVs, copy number variations (CNVs) and aneuploidies. MYC aberrations were not observed in our cases, whereas all B-PLL showed concomitant deletion 17p and TP53 mutations. TP53-disrupted B-PLL cells showed additional genomic alterations that affect genes implicated in extrinsic and intrinsic apoptotic pathways i.e., TNFRSF10, FAS, MDM2, BCL2, and BCL2L11 and genes involved in cell-cycle regulation i.e., IKBKB, CDK2, CDK4, and RB1, suggesting that a convergent multifactorial pathogenetic mechanism may be involved in B-PLL. Applying the OGM technology on cytogenetically complex rare hematological neoplasia may be useful to improve the genetic definition and differential diagnosis of B PLL/SBLPN and related splenic B cell neoplasms.

Inflammatory bowel disease (IBD)-including Crohn's disease, ulcerative colitis, and indeterminate colitis-is a chronic immune-mediated condition that primarily affects the intestinal mucosa but often presents with extraintestinal digestive manifestations, which are important yet frequently underrecognized sources of morbidity. These heterogeneous manifestations reflect diverse genetic, microbial, immunologic, and environmental influences, highlighting the value of a personalized medicine approach. Hepatobiliary involvement affects IBD adults patients and is even more common in children, ranging from mild liver enzyme elevations to severe complications such as liver failure, with autoimmune disorders, cholelithiasis, portal vein thrombosis, and non-alcoholic fatty liver disease as key considerations. Pancreatic manifestations may include autoimmune or acute pancreatitis, often linked to gallstones, thiopurine exposure, or duodenal Crohn's disease, while splenic abnormalities, such as granulomatous lesions, splenomegaly, or functional hyposplenism, reflect systemic immune dysregulation. Oral findings-including aphthous ulcers, periodontitis, pyostomatitis vegetans, and granulomatous cheilitis-can serve as early, patient-specific indicators of disease activity. Personalized approaches, encompassing investigations tailored to the individual profile and selected targeted therapies, are essential for improving diagnostic accuracy, preventing complications, and optimizing multidisciplinary care in patients with IBD.

BackgroundChronic myeloid leukemia (CML) typically presents with fatigue, weight loss, leukocytosis, and splenomegaly. Major bleeding or spontaneous hematoma as the initial manifestation is rare and poses significant diagnostic and therapeutic challenges. This narrative review summarizes published cases of CML presenting first with bleeding or hematoma.MethodsA PRISMA-style literature search of PubMed, Embase, Scopus, and Web of Science (up to 8 November 2025) identified case reports and series in which bleeding, hemorrhage, or hematoma constituted the initial presentation leading to the diagnosis of CML. Extracted data included demographics, bleeding site, laboratory findings, management and outcomes.ResultsFifty-three patients were identified (median age 45 years; range 10-68), 74% male. Bleeding most commonly involved the central nervous system (40%), followed by soft-tissue/musculoskeletal hematomas (25%), intra-abdominal or visceral bleeding-predominantly splenic (19%)-and ocular/orbital hemorrhage (13%). Most patients had marked leukocytosis (median WBC ≈280 × 10[9]/L; 87% ≥ 100 × 10[9]/L) and frequent anemia (median hemoglobin 8.5 g/dL; 71% < 10 g/dL), with highly variable platelet counts. Defined acquired bleeding disorders were uncommon. Management was medical/supportive in 47% and surgical or interventional in 36%, particularly for CNS and splenic events. At last follow-up, 62% were alive, 21% had died-mainly from intracranial hemorrhage or splenic rupture-and some survivors had permanent sequelae.ConclusionBleeding as the initial presentation of CML, though rare, carries substantial morbidity and mortality, especially with CNS or splenic involvement. Clinicians should consider CML in unexplained major bleeding with marked leukocytosis. Early diagnosis, prompt CML-directed therapy, and site-specific hemorrhage management are crucial.

The present study evaluated the acute and subacute oral toxicities of a chloroform extract from Pseudomonas fluorescens DS17R in Wistar rats to support its safe application as a biocontrol agent. For acute toxicity assessment following OECD Guideline 423, female Wistar rats (n = 3 per step) received single oral doses of 300, 2000, or 5000 mg/kg body weight (bw) and were observed for 14 days. For subacute toxicity, female rats (n = 5 per group) received daily oral doses of 0 (control), 57.5, 115, 230, or 460 mg/kg bw for 28 days, after which hematological, biochemical, and histopathological analyses were performed. Acute toxicity testing revealed no mortality at 300 or 2000 mg/kg bw, but 50% mortality at 5000 mg/kg bw, yielding a median lethal dose (LD50) of 4574 mg/kg bw, classifying the extract as practically nontoxic (OECD Category 5). Subacute 28-day oral exposure induced dose- and time-dependent physiological and biochemical responses. Body weight showed a biphasic pattern, with a significant increase at 57.5 mg/kg bw and reductions at ≥ 115 mg/kg bw, while feed intake was transiently suppressed. Hepatic enlargement was observed at 115-460 mg/kg bw, accompanied by elevated alkaline phosphatase and mild AST increase; histology revealed sinusoidal dilation and leukocyte infiltration. Splenomegaly, lymphopenia at 230 and 460 mg/kg bw, microcytosis, anisocytosis, and thrombocytosis reflected hematopoietic and immune modulation. Renal stress was evidenced by hyponatremia, hypokalemia, hypochloremia, hypercalcemia, and decreased phosphate at doses ≥ 57.5 mg/kg bw, with mild tubular alterations. Lipid remodeling included increased triglycerides and HDL, with decreased LDL at doses ≥ 115 mg/kg bw. Overall, the extract induced adaptive metabolic and redox-mediated responses without irreversible organ damage, supporting its potential safe use as a microbial biocontrol agent under the tested conditions.

To investigate the pathogenicity of Pasteurella multocida (Pm) Type B in large-eared white rabbits, the Pm strain C45-2 (C45-2) was used to infect rabbits. The clinical symptoms and post-mortem pathological changes of the rabbits were observed. Multiple tissues were collected from the deceased rabbits for pathological sectioning and immunohistochemical (IHC) staining. Additionally, quantitative real-time PCR (qPCR) was employed to detect the load of C45-2 in each tissue. The results showed that the minimum lethal dose (MLD) of the C45-2 to rabbits was 5 CFU. After infection, the rabbits exhibited typical Pm infection symptoms, including hemorrhage in multiple tissues and splenomegaly with dark coloration. The results of IHC and qPCR indicated that the C45-2 was more concentrated in the heart, spleen, and intestinal lymph node tissues of the infected rabbits. This study evaluated the pathogenicity of the C45-2 in infected rabbits, providing fundamental support for in-depth research on the pathogenic mechanism and vaccine development of Pm Type B.