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Here, the case of a female patient in her late 60s, who presented to hospital for a scheduled health check relating to a history of myelofibrosis for the previous 9 years, is described. She recently experienced weight loss and abdominal distention. Physical examination revealed no abnormality or tenderness. Laboratory examination showed decreased blood cells, platelets and haemoglobin, and normal renal function. Ultrasound and computed tomography scans revealed a massively enlarged spleen and displaced and compressed left kidney with abnormal features, but normal right kidney. The patient declined surgery and her myelofibrosis was treated with ruxolitinib, with a recommendation of annual follow-up observation. Despite many recorded cases of left renal displacement caused by splenomegaly, it is very rare for the left kidney to be pushed across the midline to the right side by an enlarged spleen. This article explores the causes and management of this uncommon condition and provides a review of previous literature reports with the aim of enhancing the understanding of unusual renal displacement due to massive splenomegaly, and its potential treatment options., Competing Interests: Declaration of conflicting interestThe authors declare that there is no conflict of interest.

Purpose: The evolution of splenomegaly in patients with liver cirrhosis remains largely unknown. In this study, we followed the changes in splenic volume and established the natural course of splenomegaly. We developed an electronic circuit that simulated splenoportal circulation and identified the underlying hemodynamic mechanisms., Materials and Methods: This retrospective observational study included 93 patients with cirrhosis. Splenic volumes were measured in imaging studies at 6-month intervals and normalized by the ratio of each patient's maximum volume during follow-up (%Vmax). An electronic simulation model was constructed using software and realized on a breadboard., Results: Overall, the %Vmax increased from 0.77 ​± ​0.21 to a maximum of 1.00 ​± ​0.00 (p ​< ​0.001) during a median follow-up of 23 (3-162) months and then decreased to 0.84 ​± ​0.18 (p ​< ​0.001) during the next 9 (3-132) months. No interventional radiology procedure was performed to improve hepatic fibrosis and portal hypertension. The evolution of %Vmax showed single-peaked symmetry. An electronic simulation model showed that the upslope of the evolution curve was dependent on the increased intrahepatic vascular resistance and portal hypertension, whereas the downslope was dependent on the decreased portosystemic shunt (PSS) resistance., Conclusions: Splenomegaly in cirrhotic patients aggravated over a period of 23 months and then regressed spontaneously to its initial volume. Electronic simulation of splenoportal circulation showed that splenic enlargement was due to the advancement of liver cirrhosis and portal hypertension, whereas its regression was due to the development of a PSS., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Splenomegaly can exacerbate liver cirrhosis and portal hypertension. We have previously demonstrated that cyclooxygenase-2 (COX-2) inhibitor can attenuate cirrhotic splenomegaly. However, the mechanism of cirrhotic splenomegaly remains unclear, thus becoming the focus of the present study., Materials and Methods: Thioacetamide (TAA) intraperitoneal injection was used to induce cirrhotic splenomegaly. Rats were randomized into the control, TAA and TAA + celecoxib groups. Histological analysis and high-throughput RNA sequencing of the spleen were conducted. Splenic collagen III, α-SMA, Ki-67, and VEGF were quantified., Results: A total of 1461 differentially expressed genes (DEGs) were identified in the spleens of the TAA group compared to the control group. The immune response and immune cell activation might be the major signaling pathways involved in the pathogenesis of cirrhotic splenomegaly. With its immunoregulatory effect, celecoxib presents to ameliorate cirrhotic splenomegaly and liver cirrhosis. Furthermore, 304 coexisting DEGs were obtained between TAA vs. control and TAA + celecoxib vs. TAA. Gene ontology (GO) and KEGG analyses collectively indicated that celecoxib may attenuate cirrhotic splenomegaly through the suppression of splenic immune cell proliferation, inflammation, immune regulation, and fibrogenesis. The impacts on these factors were subsequently validated by the decreased splenic Ki-67-positive cells, macrophages, fibrotic areas, and mRNA levels of collagen III and α-SMA., Conclusions: Celecoxib attenuates cirrhotic splenomegaly by inhibiting splenic immune cell proliferation, inflammation, and fibrogenesis. The current study sheds light on the therapeutic strategy of liver cirrhosis by targeting splenic abnormalities and provides COX-2 inhibitors as a novel medical treatment for cirrhotic splenomegaly.

The large conjugated π bond in the molecular structure of carbon nanotubes (CNTs) interacts with the benzene ring structure in di (n-butyl) phthalates (DBP) through a π - π bond. Compounds of CNTs and DBP form easily, becoming another environmental pollutant of concern. We explore whether CNTs entering animals slow down the degradation of the DBP adsorbed in the CNT cavity, thereby prolonging the "hormonal activity" of DBP. In our study, male BALb/c mice were used as experimental subjects divided into four groups: the control group; the multi-walled carbon nanotubes (MWCNTs) exposure group (10mg/kg/d); the DBP exposure group (2.15 mg/kg/d); and the compound exposure group (MWCNTs + DBP). After 30 days of exposure, the mice were sacrificed and their spleens used for immunotoxicology study. The results showed that the exposure groups exhibited splenomegaly and suffered severe oxidative damage to the spleen. In the compound exposure group: levels of IgA and IgG in the serum of the mice changed, and were significantly different from levels in both the MWCNTs and DBP exposure groups (p <0.05); the pathological sections of the spleen showed that the boundary between the white pulp area (WP) and the red pulp area (RP) was blurred, that the cell arrangement was loose, and that more red blood cells were retained in the spleen. Proteomics mass spectrometry analysis showed that compared with the control group, 70 proteins were up-regulated and 27 proteins were down-regulated in the MWCNTs group, 36 proteins were up-regulated and 23 proteins were down-regulated in the DBP group, 87 proteins were up-regulated and 21 proteins were down-regulated in the compound exposure group. The results of GO enrichment analysis and KEGG enrichment analysis of the differentially expressed proteins showed that the compound exposure harmed the spleen antigen recognition, processing, and presentation, inhibited the activation and proliferation of B cells and T cells, and hindered the adaptive immune responses. Our results showed that MWCNTs and DBP compounds can damage the spleen, and impair the innate and adaptive immune functions of the body., (Copyright © 2021 Elsevier B.V. All rights reserved.)

We present a 75-year old Korean female patient harboring novel hemizygous variant mutation in glucosidase beta acid (GBA) gene, who was diagnosed with splenic marginal zone cell lymphoma and Gaucher disease (GD) concurrently. Our case is significant in that (1) it delivers the message that GD can occur at any age regardless of ethnicity and (2) we report a novel variant of pathogenic GBA mutation, and the fact that the patient harbored hemizygous mutation., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Non-palpable, volumetric splenomegaly at diagnosis was evaluated using computed tomography in patients with essential thrombocythemia (ET) and prefibrotic/early primary myelofibrosis (pre-PMF) based on 2016 World Health Organization guidelines. Each patient's spleen volume was adjusted for their age and body surface area. The degree of splenomegaly was classified as no, borderline volumetric, overt volumetric, or palpable splenomegaly. Seventy-six patients with ET (median age, 62.5 years) and 19 patients with pre-PMF (median age, 65 years) were followed up for a median of 2.4 years (range 0.1-17.6 years) and 4.2 years (range 0.2-19.6 years), respectively. Spleen volume was significantly greater in pre-PMF patients than in ET patients (377.9 ± 92.2 cm 3 vs. 224.9 ± 115.2 cm 3 , P < 0.001). No, borderline volumetric, overt volumetric, and palpable splenomegaly were found in 42 (55.3%), 24 (31.6%), 10 (13.2%), and 0 (0%) patients with ET, respectively, and in 0 (0%), 8 (42.1%), 19 (52.6%), and 1 (5.2%) patient with pre-PMF, respectively (P < 0.001). Volumetric splenomegaly did not affect thrombosis-free survival in patients with ET or those with pre-PMF. This study indicates that all patients with pre-PMF present with splenomegaly, whereas half of the patients with ET have a normal-sized spleen at diagnosis.

The authors are reporting a case of autoimmune lymphoproliferative syndrome in a newborn who presented with massive hepatosplenomegaly, thrombocytopenia, and anemia at birth. Antenatal ultrasound revealed a fetus with hepatosplenomegaly. The infant was treated with steroids and sirolimus and is doing well at 4 years of age. This is the first case report of autoimmune lymphoproliferative syndrome presenting as hepatosplenomegaly during fetal life., Competing Interests: The authors declare no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

OBJECTIVE. Splenomegaly and thrombocytopenia are common complications in patients with cirrhosis. The present study aimed to evaluate changes in splenic volumes and platelet counts after TIPS insertion. MATERIALS AND METHODS. A total of 104 patients who had a diagnosis of portal hypertension and had undergone TIPS placement between November 2015 and August 2019 were enrolled in this retrospective cohort study. We retrospectively calculated splenic volumes before TIPS placement and at 1-2 and 6-12 months after TIPS placement and monitored the platelet count at 1, 3, 6, and 12 months after TIPS placement. RESULTS. The mean (± SD) portal pressure gradient before TIPS placement was 28.3 ± 4.6 mm Hg; after TIPS placement, it was 11.3 ± 4.5 mm Hg ( p < .001). The mean splenic volume of all 104 patients before TIPS placement was 868 ± 409 cm 3 , and at 1-2 months after TIPS placement, it was 710 ± 336 cm 3 ( p < .001). Among the 43 patients for whom splenic volume data were available at both 1-2 and 6-12 months after TIPS placement, the mean splenic volume decreased from 845 ± 342 cm 3 to 691 ± 301 cm 3 and then to 674 ± 333 cm 3 , respectively. Correspondingly, the number of patients with severe thrombocytopenia decreased from 25 patients (35.7%) before the TIPS procedure to 16 patients (22.9%) in the 1-2 months after TIPS placement and then to 11 patients (15.7%) in the 6-12 months after TIPS implantation. The increase in the platelet count was significantly correlated with decreasing splenic volume ( r 2 = 0.3735; p < .001). CONCLUSION. In most patients, TIPS placement resulted in a significant decrease in splenic volume and a significant increase in the platelet count during the same period.

By the advent of the effective therapies for many coagulation diseases and hereditary spherocytosis (HS), patient's survival has been improved significantly; however, if patients are diagnosed late or left untreated, both diseases could ominously be life threatening. Concurrent occurring of factor VII (FVII) deficiency and HS is extremely rare and there is no literature report that explain this condition, thus far. In this study, we confronted a 9-year-old female patient diagnosed with HS and enlarged spleen as a result of this blood disorder. Given to her sever signs and symptoms of splenomegaly, she was candidate for emergent splenectomy. However, assessment of coagulation tests revealed a prolonged prothrombin time, suggesting the moderate FVII deficiency. With a multidisciplinary consultation, we decided to performed total splenectomy with prophylaxis administration of totally 6 doses of active recombinant FVII, initiated 1 hour before surgery and followed until 30 hours postoperation. As a result of cautious undertaken in Mofid Children's Hospital, the patient did not experience any hemostatic defect. Patient is now 14-year-old, generally well-being under regular surveillance of FVII deficiency., Competing Interests: The authors declare no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

A 20-year-old man from Simanjiro district in northern Tanzania presented with a 3-year history of splenomegaly, fatigue, cachexia, skin maculae, and recent onset of watery diarrhea at Kilimanjaro Christian Medical Centre (KCMC) in Northern Tanzania. Due to laboratory findings of pancytopenia, diagnostic workup included bone marrow aspiration cytology and biopsy. Although the rapid test (IT LEISH, rK39 RDT) was negative, blood smear showed amastigote forms of leishmaniasis in macrophages. Repeat bone marrow aspiration and PCR eventually confirmed visceral leishmaniasis (VL). The patient denied travel to known endemic areas of VL. Treatment was initiated with Amphotericin B, but the patient died on the fourth day of treatment from respiratory insufficiency. An autopsy revealed massive organ manifestations of VL. This is the first reported autochthonous case of VL in Tanzania. Clark and colleagues detected the vector Phlebotomus martini in Northern Tanzania in 2013, in a region bordering the district of our patient. The negative rapid test draws attention to the fact that sensitivity and specificity were found to be low in East African VL patients as displayed earlier by a Kenyan study. Therefore, tissue samples (spleen or bone marrow) remain necessary for diagnosis. The variety of symptoms in this presented case was remarkable, including the occurrence of post-kala-azar dermal leishmaniasis (PKDL) and VL at the same time. This has been described in East African VL cases before as well as the occurrence of chronic diarrhea. An elongated undiagnosed period likely led to a mixed clinical picture that included hepato-splenomegaly, PKDL, cachexia, and diarrhea., Competing Interests: The authors have declared that no competing interests exist.

Objectives: Splenomegaly and hypersplenism caused by liver failure increase the mortality and morbidity of patients even after liver transplantation if they do not regress. We evaluated the relation of splenic volume change and transplanted liver function., Material and Methods: A total of 59 of 207 pediatric patients who had liver transplantation between 2013 and 2018 in our institute were evaluated. The relation of spleen volume changes (splenic volume to standard splenic volume ratio [SV/SSV]) were measured at 0, 1, 6, 12, 24, and 36 months of follow-up by constructing electronic three-dimensional structure of the spleen at dynamic computed tomography (CT), and the course of liver functions were evaluated., Results: The SV/SSV ratio decreases in the first postoperative 6 months. After 6 months, SV increases and SV/SSV increases gradually. In a normal functioning graft, SV/SSV significantly decreased in all time points (P < .001). In patients with adverse events, SV/SSV started to increase after 6 months. In patients with fulminant hepatic failure, SV/SSV started to increase after postoperative 6 months. Adverse events in patients with fulminant hepatic failure were more than the patients with chronic liver disease (58% vs 28%). There was an inverse correlation between SV/SSV and thrombocyte levels (P < .001)., Conclusions: SV/SSV seems to be correlated to the adverse events (ie, rejection). Together with thrombocyte levels, it can be used as a noninvasive test for follow-up of transplant patients in terms of adverse events in graft function., (Copyright © 2020 Elsevier Inc. All rights reserved.)

In this paper we characterize the function of Xylosyltransferase 2 (XylT2) in different tissues to investigate the role XylT2 has in the proteoglycan (PG) biochemistry of multiple organs. The results show that in all organs examined there is a widespread and significant decrease in total XylT activity in Xylt2 knock out mice (Xylt2-/-). This decrease results in increased organ weight differences in lung, heart, and spleen. These findings, in addition to our previous findings of increased liver and kidney weight with loss of serum XylT activity, suggest systemic changes in organ function due to loss of XylT2 activity. The Xylt2-/- mice have splenomegaly due to enlargement of the red pulp area and enhanced pulmonary response to bacterial liposaccharide. Tissue glycosaminoglycan composition changes are also found. These results demonstrate a role of XylT2 activity in multiple organs and their PG content. Because the residual XylT activity in the Xylt2-/- is due to xylosyltransferase 1 (XylT1), these studies indicate that both XylT1 and XylT2 have important roles in PG biosynthesis and organ homeostasis.

Hypersensitivity reactions and immune dysregulation have been reported with the use of quaternary ammonium compound disinfectants (QACs). We hypothesized that QAC exposure would exacerbate autoimmunity associated with systemic lupus erythematosus (lupus). Surprisingly, however, we found that compared to QAC-free mice, ambient exposure of lupus-prone mice to QACs led to smaller spleens with no change in circulating autoantibodies or the severity of glomerulonephritis. This suggests that QACs may have immunosuppressive effects on lupus. Using a microfluidic device, we showed that ambient exposure to QACs reduced directional migration of bone marrow-derived neutrophils toward an inflammatory chemoattractant ex vivo . Consistent with this, we found decreased infiltration of neutrophils into the spleen. While bone marrow-derived neutrophils appeared to exhibit a pro-inflammatory profile, upregulated expression of PD-L1 was observed on neutrophils that infiltrated the spleen, which in turn interacted with PD-1 on T cells and modulated their fate. Specifically, QAC exposure hindered activation of splenic T cells and increased apoptosis of effector T-cell populations. Collectively, these results suggest that ambient QAC exposure decreases lupus-associated splenomegaly likely through neutrophil-mediated toning of T-cell activation and/or apoptosis. However, our findings also indicate that even ambient exposure could alter immune cell phenotypes, functions, and their fate. Further investigations on how QACs affect immunity under steady-state conditions are warranted., (Copyright © 2020 Abdelhamid, Cabana-Puig, Mu, Moarefian, Swartwout, Eden, Das, Seguin, Xu, Lowen, Lavani, Hrubec, Jones and Luo.)

Enteropathogenic and enterohemorrhagic Escherichia coli are important enteric pathogens that induce hemorrhagic colitis or even fatal hemolytic uremic syndrome. Emerging evidence shows that some bio-actives derived from fruits and vegetables may serve as alternatives to antibiotics for overcoming multidrug resistant E. coli infections. In this study, the Citrobacter rodentium (Cr) infection model was utilized to mimic E. coli -induced acute intestinal inflammation, and the effects of a cruciferous vegetable-derived cancer protective compound, indole-3-carbinol (I3C), on the immune responses of Cr-susceptible C3H/HeN mice were investigated. Dietary I3C significantly inhibited the loss of body weight and the increase in spleen size in Cr infected mice. In addition, I3C treatment reduced the inflammatory response to Cr infection by maintaining anti-inflammatory cytokine IL-22 mRNA levels while reducing expression of other pro-inflammatory cytokines including IL17A, IL6, IL1β, TNF-α, and IFN-γ. Moreover, the serum cytokine levels of IL17, TNF-α, IL12p70, and G-CSF also were down-regulated by I3C in Cr-infected mice. Additionally, dietary I3C specifically enhanced the Cr-specific IgG response to Cr infection. In general, dietary I3C reduced the Cr-induced pro-inflammatory response in susceptible C3H/HeN mice and alleviated the physiological changes and tissue damage induced by Cr infection but not Cr colonization.

Purpose: Haematological toxicities occur in patients receiving oxaliplatin. Mild anaemia (grade 1-2) is a common side effect and approximately 90% of recipients develop measurable spleen enlargement. Although generally asymptomatic, oxaliplatin-induced splenomegaly is independently associated with complications following liver resection for colorectal liver metastasis and separately with poorer patient outcomes. Here, we investigated oxaliplatin-induced haematological toxicities and splenomegaly in mice treated with escalating dosages comparable to those prescribed to colorectal cancer patients., Methods: Blood was analysed, and smears assessed using Wright-Giemsa staining. Paw coloration was quantified as a marker of anaemia. Spleen weight and morphology were assessed for abnormalities relating to splenomegaly and a flow cytometry and multiplex cytokine array assessment was performed on splenocytes. The liver was assessed for sinusoidal obstructive syndrome., Results: Blood analysis showed dose dependent decreases in white and red blood cell counts, and significant changes in haematological indices. Front and hind paws exhibited dose dependent and dramatic discoloration indicative of anaemia. Spleen weight was significantly increased indicating splenomegaly, and red pulp tissue exhibited substantial dysplasia. Cytokines and chemokines within the spleen were significantly affected with temporal upregulation of IL-6, IL-1α and G-CSF and downregulation of IL-1β, IL-12p40, MIP-1β, IL-2 and RANTES. Flow cytometric analysis demonstrated alterations in splenocyte populations, including a significant reduction in CD45+ cells. Histological staining of the liver showed no evidence of sinusoidal obstructive syndrome but there were signs suggestive of extramedullary haematopoiesis., Conclusion: Chronic oxaliplatin treatment dose dependently induced haematological toxicity and splenomegaly characterised by numerous physiological and morphological changes, which occurred independently of sinusoidal obstructive syndrome., Competing Interests: The authors have declared that no competing interests exist.

Background: Acid sphingomyelinase deficiency (ASMD) also known as Niemann-Pick disease, is a rare lysosomal storage disorder with a diverse disease spectrum that includes slowly progressive, chronic visceral (type B) and neurovisceral forms (intermediate type A/B), in addition to infantile, rapidly progressive fatal neurovisceral disease (type A)., Purpose and Methods: We review the published evidence on the relevance of splenomegaly and reduced lung diffusion capacity to the clinical burden of chronic forms of ASMD. Targeted literature searches were conducted to identify relevant ASMD and non-ASMD studies for associations between diffusing capacity of the lungs for carbon monoxide (DL CO ) and splenomegaly, with clinical parameters and outcome measures., Results: Respiratory disease and organomegaly are primary and independent contributors to mortality, disease burden, and morbidity for patients with chronic ASMD. The degree of splenomegaly correlates with short stature, atherogenic lipid profile, and degree of abnormality of hematologic parameters, and thus may be considered a surrogate marker for bleeding risk, abnormal lipid profiles and possibly, liver fibrosis. Progressive lung disease is a prevalent clinical feature of chronic ASMD, contributing to a decreased quality of life (QoL) and an increased disease burden. In addition, respiratory-related complications are a major cause of mortality in ASMD., Conclusions: The reviewed evidence from ASMD natural history and observational studies supports the use of lung function and spleen volume as clinically meaningful endpoints in ASMD trials that translate into important measures of disease burden for patients., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: With increasing frequency, patients with idiopathic splenomegaly are referred to surgeons for splenectomy. We evaluated the diagnostic utility of splenectomy and feasibility of a minimally invasive approach in the face of idiopathic splenomegaly., Methods: We retrospectively reviewed 68 patients who underwent splenectomy for idiopathic splenomegaly. The primary endpoint was the rate of definitive diagnosis based on final surgical pathology of the removed spleen., Results: Preoperative workup included a bone marrow biopsy and peripheral blood smear in 93% and 100% of patients, respectively, with none having lymphadenopathy warranting biopsy. Splenectomy provided a definitive diagnosis for 44 (64.7%) patients. Of these, 34 (50%) patients had an underlying malignancy, of which more than half were splenic marginal zone lymphoma. There were 33 (48.5%) laparoscopic, 23 (33.8%) open, 10 (14.7%) laparoscopic converted to open, and two (2.9%) laparoscopic hand-assist cases. Conversion to open was due to splenic size [median craniocaudal length 21.8 cm (cm)] in eight and staple line bleeding at the splenic hilum in two patients. Overall, the laparoscopic approach was completed in patients with a smaller splenic size compared to open (median craniocaudal length 15.2 vs. 26.0 cm, p < 0.0001). The open group had one (1.5%) intra-operative mortality due to uncontrollable hemorrhage. Thirty-day complication rates were similar for laparoscopic and open approaches (p = 0.10)., Conclusion: Splenectomy is an effective diagnostic modality in determining a pathologic cause for splenomegaly in this patient population. Laparoscopic splenectomy can be performed safely in appropriate cases with craniocaudal splenic size having the largest influence on surgical approach.

Sickle cell disease (SCD) is a monogenic red blood cell (RBC) disorder with high morbidity and mortality. Here, we report, for the first time, the impact of SCD on the bone marrow (BM) vascular niche, which is critical for hematopoiesis. In SCD mice, we find a disorganized and structurally abnormal BM vascular network of increased numbers of highly tortuous arterioles occupying the majority of the BM cavity, as well as fragmented sinusoidal vessels filled with aggregates of erythroid and myeloid cells. By in vivo imaging, sickle and control RBCs have significantly slow intravascular flow speeds in sickle cell BM but not in control BM. In sickle cell BM, we find increased reactive oxygen species production in expanded erythroblast populations and elevated levels of HIF-1α. The SCD BM exudate exhibits increased levels of proangiogenic growth factors and soluble vascular cell adhesion molecule-1. Transplantation of SCD mouse BM cells into wild-type mice recapitulates the SCD vascular phenotype. Our data provide a model of SCD BM, in which slow RBC flow and vaso-occlusions further diminish local oxygen availability in the physiologic hypoxic BM cavity. These events trigger a milieu that is conducive to aberrant vessel growth. The distorted neovascular network is completely reversed by a 6-week blood transfusion regimen targeting hemoglobin S to <30%, highlighting the plasticity of the vascular niche. A better insight into the BM microenvironments in SCD might provide opportunities to optimize approaches toward efficient and long-term hematopoietic engraftment in the context of curative therapies., (© 2020 by The American Society of Hematology.)

Splenomegaly is a key clinical manifestation of myelofibrosis, and splenectomy is currently indicated in patients with drug refractory, symptomatic splenomegaly or with the aim of improving refractory cytopenias. Transformation to acute myeloid leukemia occurs in up to 20% of patients with myelofibrosis, while cases of myeloid sarcoma have been reported very unfrequently. In this manuscript, we report the case of a 60-year-old man with a history of primary myelofibrosis who underwent splenectomy because of drug-refractory massive splenomegaly, systemic symptoms and anemia. At the opening of the peritoneal cavity, the spleen resulted massively enlarged and tenaciously entrapped by a pervasive neoplastic-like tissue. The extensive involvement of the abdomen fatally complicated the surgical procedure. At postmortem examination, the spleen showed a diffuse infiltration of immature cells that were also found in the peritoneum, bowel, liver, lungs and myocardium. After immunohistochemical, cytogenetic, flow cytometric and molecular characterization of neoplastic population, a diagnosis of disseminated myeloid sarcoma of the spleen was made. This case report highlights a very unusual case of myeloid sarcoma originating from the spleen in a patient with myelofibrosis who had no evidence of bone marrow or peripheral blood involvement by leukemic cells. Molecular characterization showed that leukemic cells originated from the founding clone of the chronic phase. The sarcoma could not be suspected based on clinical findings and was diagnosed only at the time of surgical procedure and autopsy. This case suggests that leukemic transformation of myelofibrosis can originate outside the bone marrow and, presumably rarely, present as a granulocytic sarcoma.

Latent infection of Epstein-Barr virus (EBV) is associated with a poor prognosis in patients with B cell malignancy. We examined whether dasatinib, a multi kinase inhibitor, which is broadly used for chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia is effective on EBV-positive B cell malignancies, using lymphoblastoid cell lines (LCLs) in vitro and in vivo. As a result, in vitro experiments showed that dasatinib induced cell death of the EBV-LCLs which was not accompanied with a lytic reactivation of EBVs. To evaluate the effectiveness in EBV latency type III represented by immunodeficiency lymphoma, LCL-inoculated immunodeficient NOD/shi-scid/Il2rg nul (NOG) mice were treated with dasatinib. However, in vivo experiments revealed that dasatinib treatment exacerbated tumor cell infiltration into the spleen of LCL-inoculated NOG mice, whereas tumor size at the inoculated site was not affected by the treatment. These results suggest that dasatinib exacerbates the pathogenesis at least in some situations although the drug is effective in vitro. Hence, we should carefully examine a possibility of dasatinib repositioning for EBV + B cell malignancies.

Systemic lupus erythematosus (SLE) is characterized by high levels of autoantibodies and multiorgan tissue damage. The pathogenesis of splenomegaly in SLE remains unknown. In this study, the role of immunoglobulin G (IgG) generation and deposition in the inflammation of the spleen and associated dysfunction in SLE was investigated. In the lupus mice, we observed the development of spontaneous splenomegaly, and we found that lupus serum IgG is an important pathological factor involved in the initiation of inflammation and further germinal center (GC) and plasma cell formation. We discovered that macrophages of the splenic marginal zone are dispensable for the GC response induced by lupus IgG, but red pulp macrophages are important for GC responses. Furthermore, we found that pathogenic lupus IgG promotes inflammation and GC formation through the macrophage-mediated secretion of TNF-α. Syk inhibitor treatment suppressed the changes in the histopathology of the spleen induced by lupus IgG. This study will contribute to the understanding of the pathogenesis of splenomegaly in lupus and promote the development of an effective therapeutic strategy for SLE., (Copyright © 2020 Zhang, Xiang, Zaman, Dong, He and Deng.)

Myeloid-related protein 14 (MRP14) belongs to the S100 calcium-binding protein family and is expressed in neutrophils and inflammatory macrophages. Increase in the number of MRP14+ cells or serum level of MRP14 is associated with various diseases such as autoimmune diseases and infectious diseases, suggesting the involvement of the molecule in pathogenesis of those diseases. In this study, to examine the pathological involvement of MRP14 during cutaneous and visceral leishmaniasis, wild-type (WT) and MRP14 knockout (MRP14KO) mice were infected with Leishmania major and L. donovani. Increase in the number of MRP14+ cells at the infection sites in wild-type mice was commonly found in the skin during L. major infection as well as the spleen and liver during L. donovani infection. In contrast, the influence of MRP14 to the pathology seemed different between the two infections. MRP14 depletion exacerbated the lesion development and ulcer formation in L. major infection. On the other hand, the depletion improved anemia and splenomegaly but not hepatomegaly at 24 weeks of L. donovani infection. These results suggest that, distinct from its protective role in CL, MRP14 is involved in exacerbation of some symptoms during VL., Competing Interests: The authors have declared that no competing interests exist.

Purpose: To find out which single measurement and/or linear regression model correlates well with splenic volume using the orthogonal measurements approach., Methods: The study relied on retrospective analysis of 205 contrast-enhanced abdominal CT examinations carried out in adult patients using a 320-detector CT system. CT volumetry was conducted by a semi-automated, model and threshold based segmentation algorithm that enables voxel-based volume calculation of abdominal organs. The orthogonal measurements were carried out in axial sections by measuring the maximum diameters of spleen projected in sagittal, coronal and transverse planes. In addition, we calculated the diagonal diameter of spleen, which is a derivative of orthogonal measurements. Statistical analysis included calculation of interobserver agreement on orthogonal measurements, followed by model building using linear regression analysis of the measurements., Results: The interobserver agreement between two radiologists was very strong for all orthogonal measurements (r ≥ 0.971). The highest model performance was detected with the diagonal diameter (r2 = 0.956), followed by the superoinferior diameter (r2 = 0.857). Agreement statistics revealed that the regression formula derived from the diagonal diameter outperformed that of superoinferior diameter., Conclusion: The diagonal diameter appears to be the best parameter which correlates with splenic volume, whereas the superoinferior diameter can be an alternative in daily CT reporting practice. The orthogonal measurements approach not only provides a high interobserver agreement, but also the diagonal diameter can be translated into ultrasound studies.

Objective: Anemia and thrombocytopenia are the most frequently reported adverse events of ruxolitinib in patients with MPN-associated myelofibrosis (MPN-MF). Although thalidomide, androgens and prednisone have previously demonstrated improvements in myelofibrosis-associated anemia, it is unclear whether these drugs are effective in patients taking ruxolitinib. Method: We conducted a retrospective cohort study to evaluate the efficacy and tolerability of combination therapy with low dose thalidomide, stanozolol and prednisone (TSP) in patients with IPSS intermediate-2 or high-risk myelofibrosis (MF) who received ruxolitinib treatment. Results: Sixty-five patients with MPN-MF who took ruxolitinib were enrolled in this retrospective study, of which 46 patients also took TSP while 19 did not take TSP (TSP and non-TSP groups). Within the first 24 weeks, the proportion of patients with anemia response and platelet count increase ≥50 × 10 9 /L were 45.7% and 67.4% in the TSP group as compared to 0% and 10.5% in the non-TSP group ( p  < 0.001). The mean hemoglobin level in the non-TSP group reached the nadir after approximately 12-16 weeks of therapy, but gradually increased in the TSP group. Conclusion: In summary, TSP regimen can improve anemia and thrombocytopenia during ruxolitinib treatment in patients with MPN-MF, and the associated adverse events were manageable.

Adjuvants enhance the immune response during vaccination. Among FDA-approved adjuvants, aluminum salts are most commonly used in vaccines. Although aluminum salts enhance humoral immunity, they show a limited effect for cell-mediated immune responses. Thus, further development of adjuvants that induce T-cell-mediated immune response is needed. Toll-like receptors (TLRs) recognizing specific pathogen-associated molecular patterns activate innate immunity, which is crucial to shape adaptive immunity. Using TLR ligands as novel adjuvants in vaccines has therefore attracted substantial attention. Among them a small molecule TLR7 ligand, imiquimod, has been approved for clinical use, but its use is restricted to local administration due to unwanted adverse side effects when used systematically. Since TLR7 is mainly located in the endosomal compartment of immune cells, efficient transport of the ligand into the cells is important for improving the potency of the TLR7 ligand. In this study we examined gold nanoparticles (GNPs) immobilized with α-mannose as carriers for a TLR7 ligand to target immune cells. The small molecule synthetic TLR7 ligand, 2-methoxyethoxy-8-oxo-9-(4-carboxy benzyl)adenine (1V209), and α-mannose were coimmobilized via linker molecules consisting of thioctic acid on the GNP surface (1V209-αMan-GNPs). The in vitro cytokine production activity of 1V209-αMan-GNPs was higher than that of the unconjugated 1V209 derivative in mouse bone marrow-derived dendritic cells and in human peripheral blood mononuclear cells. In the in vivo immunization study, 1V209-αMan-GNPs induced significantly higher titers of IgG2c antibody specific to ovalbumin as an antigen than did unconjugated 1V209, and splenomegaly and weight loss were not observed. These results indicate that 1V209-αMan-GNPs could be useful as safe and effective adjuvants for development of vaccines against infectious diseases and cancer.

MPIG6B has orthologous physiological effects in human and mice, which regulates platelet production and function. For this reason, germline loss-of-function mutations in this gene cause congenital thrombocytopenia that is associated with bone marrow fibrosis, organomegaly and subsequent anemia. This was described in a consanguineous Arabian family with a novel truncation mutation (p.C108*) in chromosome 6, open reading frame 25 gene, also known as MPIG6B. In our case, we identified a homozygous frameshift variation (c.392delC,p.P134Lfs*10) in a ten-month-old boy presenting with signs of pallor, splenomegaly and resistant hemocytopenia. Interestingly, this is a new form of a MPIG6B variation, which could disrupt the effector protein for the key hematopoiesis regulators. This report adds to the growing number of mutations causing complex clinical manifestations associated with pancytopenia and splenomegaly in children., (Published by Elsevier B.V.)

To confirm that neoplastic monocyte-derived collagen- and fibronectin-producing fibrocytes induce bone marrow (BM) fibrosis in primary myelofibrosis (PMF), we injected PMF BM-derived fibrocyte-precursor CD14+/CD34- monocytes into the tail vein of NOD-SCID-γ (NSG) mice. PMF BM-derived CD14+/CD34- monocytes engrafted and induced a PMF-like phenotype with splenomegaly, myeloid hyperplasia with clusters of atypical megakaryocytes, persistence of the JAK2V617F mutation, and BM and spleen fibrosis. As control we used normal human BM-derived CD14+/CD34- monocytes. These monocytes also engrafted and gave rise to normal megakaryocytes that, like PMF CD14+/CD34--derived megakaryocytes, expressed HLA-ABC and human CD42b antigens. Using 2 clonogenic assays we confirmed that PMF and normal BM-derived CD14+/CD34- monocytes give rise to megakaryocyte colony-forming cells, suggesting that a subpopulation BM monocytes harbors megakaryocyte progenitor capacity. Taken together, our data suggest that PMF monocytes induce myelofibrosis-like phenotype in immunodeficient mice and that PMF and normal BM-derived CD14+/CD34- monocytes give rise to megakaryocyte progenitor cells., Competing Interests: The authors have declared that no competing interests exist.

Background and Aim: Idiopathic portal hypertension (IPH) refers to a relatively rare condition characterized by intrahepatic portal hypertension in the absence of underlying disease such as liver cirrhosis., Methods: We retrospectively reviewed 338 patients with IPH that were diagnosed at the pathological consultation center of our hospital., Results: The ratio of male to female patients was 1:1. Mean age at onset was 35.1 ± 16.5 years; male patients on average were 12 years younger than female patients at onset. The median duration from onset to IPH diagnosis was 12 months. In 50 patients, medication use may have been an etiological factor. The most common clinical manifestations were splenomegaly (91.3%) and hypersplenism (68.9%); 57.0% patients presented varicosis, while 25.1% patients had a history of variceal bleeding. Nodular regenerative hyperplasia was found in 22.2% liver biopsies. Among patients for whom laboratory data were available, 65.0%, 50.3%, and 71.4% patients presented leukopenia, anemia, and thrombocytopenia due to hypersplenism. Liver function was mostly in the compensated stage. Female patients showed worse leukopenia and anemia, while male patients were more likely to have abnormal serum transaminase and bilirubin levels. Sixty-seven patients received surgical or interventional treatment., Conclusions: High-quality liver biopsy, detailed clinical information, and expert pathologist are necessary for diagnosis of IPH. IPH can occur concurrently with other liver disease such as hepatitis and drug-induced liver injury. Medication appears to be an important etiological factor for IPH in China. Management approach was largely focused on treatment of portal hypertension and its complications., (© 2018 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Although it is well known that myeloproliferative neoplasms occur in younger patients, few large cohorts of such patients have been reported. Thus, our knowledge about circumstances of diagnosis, outcome and treatment is limited, especially for children and young adults. We therefore performed a systematic review of cases, published since 2005, concerning patients aged below 20 years at the time of diagnosis of essential thrombocythemia or polycythemia vera. We identified 396 cases of essential thrombocythemia and 75 of polycythemia vera. The median age at diagnosis was 9.3 and 12 years, respectively, and females constituted 57.6% and 45% of the groups, respectively. Half of the patients were asymptomatic at diagnosis. The proportion of so-called triple negativity was high: 57% in essential thrombocythemia and 73% in polycythemia vera. The incidence of thrombosis during the follow-up was 9.3% in patients with polycythemia vera and less, 3.8%, in those with essential thrombocythemia. Venous events were predominant (84.2%), with hemorrhagic episodes being rarer (<5%). The risk of evolution also seemed low (2% to myelofibrosis and no reports of acute leukemia), but the median follow-up was only 50 months. Survival curves were not available. Half of the patients received an antithrombotic drug and 40.5% received a cytoreductive drug. All data should be analyzed with care because of the proportion of missing data (10.7% to 74.7%). This review highlights interesting points concerning this population of young patients with myeloproliferative neoplasms, including that such patients were identified as negative for all common driver mutations, but also shows the need for larger contemporary cohorts with longer follow-up to assess the true prognosis of these patients., (Copyright© 2019 Ferrata Storti Foundation.)

Ruxolitinib is the only commercially available JAK1/2 inhibitor approved for the treatment of myelofibrosis-related splenomegaly and symptoms. During treatment, as rare conditions, leukocytosis and/or thrombocytosis could develop and the management of these situations is not well established. We report here 53 myelofibrosis patients that received a combination of hydroxyurea and ruxolitinib because of uncontrolled myeloproliferation. Both drugs were administered outside clinical trials. At 48 weeks, a significant reduction in leucocyte and platelet counts was observed (p = 0.02 and p = 0.04, respectively). Additionally, the spleen volume decreased from a median value of 10 cm below the left costal margin (range, 0-10) to 6 cm (range, 0-15). The rate of spleen response increased from 14% at the start of the combination to 45% after 48 weeks. The safety profile of the combination was consistent with that observed with ruxolitinib single agent. These data require further confirmation in large cohorts of patients prospectively assessed.

Notch signaling plays pivotal roles in both hematopoietic stem/progenitor and their niche cells. Myeloproliferative phenotypes are induced by disruption of Notch signaling in nonhematopoietic bone marrow (BM) cells. Nestin-expressing cells in the BM reportedly represent a component of the hematopoietic stem cell niche. We established mice in which rare Nestin-expressing cells in the BM were marked by green fluorescent protein, and Notch signaling was conditionally disrupted in these cells specifically. We observed impairment of erythropoiesis in the BM accompanying splenomegaly with BM hematopoietic programs in other lineages undisturbed. Transplantation experiments revealed that the microenvironmental rather than the hematopoietic cells were attributable to these phenotypes. We further found that the erythroid-island-forming ability of BM central macrophages was compromised along with the transcriptional upregulation of interleukin-6. Various Inflammatory conditions hamper BM erythropoiesis, which often accompanies extramedullary hematopoiesis. The mouse model demonstrated here may be of relevance to this common pathophysiologic condition. Stem Cells 2019;37:924-936., (©AlphaMed Press 2019.)

Chronic myelogenous leukemia (CML) is a chronic myeloproliferative neoplasm consistently associated with the BCR-ABL1 fusion gene located in the Philadelphia chromosome. The Blast Phase is diagnosed when blasts are ≥20% of the peripheral blood white cell count or of bone marrow nucleated cells or when there is an extramedullary blast proliferation. Megakaryocytic blast crisis as the presenting manifestation of CML is extremely rare and only 7 reported cases were found in the literature. Out of 34 cases of CML-Blast Phase between April 2015 and June 2016, 3 cases showed megakaryocytic differentiation. 2 of these presented in Blast phase as the first manifestation of CML and the third case was a known case of CML-Chronic phase. Flow cytometric immunophenotyping was performed on peripheral blood/bone marrow using 6- color flow cytometer Navios. On CD45 vs SSC two distinct populations of blasts were seen in two cases and single population in the third case. All the 3 cases were positive for CD61, cCD41, cCD61 confirming the megakaryocytic lineage. The clinical features, morphologic and cytogenetic findings help in the identification and distinction of megakaryocytic blast phase of CML from Acute Megakayoblastic Leukemia. The diagnosis of such rare presentation of CML is essential for determining the choice of treatment. Therefore including a megakaryocytic marker in the primary flow cytometry panel is important so that these cases are not under-diagnosed as Acute myeloid leukemia because of expression of CD13 and CD33 only.

Objective: The aim of this study was to evaluate the reproducibility of measurement of spleen stiffness at the time of the initial detection of splenomegaly, whether it is found incidentally or not, in determining the etiology of splenomegaly., Methods: The pathologies that brought about the diffuse splenomegaly were evaluated in 3 main groups as follows: hepatoportal, myeloproliferative, and infectious causes. In addition, 17 healthy control patients were recruited. All patients were examined with acoustic radiation force impulse imaging with VTQ., Results: The difference between the splenic parenchymal elasticity values in the hepatoportal group (3.27 ± 0.36 m/s), in the myeloproliferative disease group (2.98 ± 0.33 m/s), in the infectious disease group (2.44 ± 0.21 m/s), and in the control group (2.08 ± 0.19 m/s) was found to be statistically significant (P = 0.001). The intraclass correlation coefficient for shear wave velocity measurement between hepatoportal causes and myeloproliferative causes was 71.2% (95% confidence interval [CI], 54.9%-87.4%), between hepatoportal causes and infective causes was 99.7% (95% CI, 98.6%-100.0%), and between myeloproliferative causes and infective causes was 83.3% (95% CI, 68.8%-97.9%). In the same patient groups, spleen volumes were measured as 64.08 ± 9.66, 78.18 ± 18.52, and 51.57 ± 7.44 cm, respectively; in the control group, it was 26.75 ± 6.57 cm. The difference between spleen volumes was found to be statistically significant (P = 0.001)., Conclusions: Distinguishing the causes of splenomegaly is important because the disorders require different management strategies. In diseases that cause splenomegaly, tissue content may change according to pathogenesis. Such changes in the spleen are mechanical properties that can be quantified by elastography.

The antibacterial and anticancerous properties of EMTAHDCA have already been reported in our previous study. However, mode of action of EMTAHDCA is still elusive. The present study was aimed to investigate the molecular targets in Escherichia coli and spleen of lymphoma-bearing mice in response to cyanocompound 9-ethyliminomethyl-12 (morpholin-4-ylmethoxy)-5, 8, 13, 16-tetraaza -hexacene-2, 3- dicarboxylic acid (EMTAHDCA) isolated from fresh water cyanobacterium Nostoc sp. MGL001. Differential expressions of proteins were observed in both E. coli and spleen of lymphoma-bearing mice after EMTAHDCA treatment. In continuation of our previous study, the present study revealed that the antibacterial agent, EMTAHDCA causes the drastic reduction in synthesis of proteins related to replication, transcription, translation and transportation in E. coli. Probably the direct or indirect interaction of this compound with these important metabolic processes led to the reduction in growth and cell death. Furthermore, the anticancerous property of the compound EMTAHDCA reflected as down regulation in proteins of cell cycle, cellular metabolism, signalling, transcription and transport together with up regulation of apoptosis, DNA damage and immunoprotection related proteins in spleen of lymphoma-bearing mice. In this study the EMTAHDCA induced modulations in expression of proteins of key metabolic pathways in E. coli and spleen cells of lymphoma bearing mice helped in understanding the mechanism underlying the antibacterial and anti-cancerous property.

Objective: To investigate the ZAP-70 and CD38 expressions and their combined expressions in Sudanese B-CLL patients and their relationships with clinical and hematological characteristics as well as the disease staging at presentation., Results: In the present cross-sectional descriptive study, analysis of ZAP-70 expression showed that 36/110 (32.7%) patients positively expressed ZAP-70 and insignificant higher presentation in intermediate and at advanced stages as well as no correlation was seen with hematological parameters and clinical features compared with negatively ZAP-70, on the other hand, 41/110 (37.3%) were CD38 + and no significant correlation was shown with the stage at presentation, clinical characteristics (except Splenomegaly, P = 0.02) and hematological parameters. However, in combined expressions of both ZAP-70 and CD38 together, 20/110 (18.2%) were concordantly ZAP-70 + /CD38 + , 53/110 (48.2%) concordantly ZAP-70 - /CD38 - and 37/110 (33.6%) either ZAP-70 + or CD38 + , and these three groups showed insignificant correlation with clinical (except Splenomegaly, P = 0.03) and hematological parameters, and the stage at presentation. Our data showed the combined analysis of these two markers, lead to classify our patients into three subgroups (either concordant positive, negative or discordant expressions) with statistically insignificant correlation with clinical presentation (except Splenomegaly), hematological parameters and stage at presentation of B-CLL patients.

Deletion of long arm of chromosome 20 [del(20q)] is the second most frequent recurrent chromosomal abnormality in hematological malignancies. It is detected in 10% of myeloproliferative neoplasms, 4-5% of myelodysplastic syndromes, and 1-2% of acute myeloid leukaemia. Recurrent, non-random occurrence of del(20q) indicates that it is a pathogenic driver in myeloid malignancies. Genetic mapping of patient samples has identified two regions of interest on 20q - the "Common Deleted Region" (CDR) and "Common Retained Region" (CRR), which was often amplified. We proposed that the CDR contained tumor suppressor gene(s) (TSG) and the CRR harbored oncogene(s); loss of a TSG together with over-expression of an oncogene favored development of myeloid malignancies. Protein Tyrosine Phosphatase Receptor T (PTPRT) and Hemopoietic cell kinase (HCK) were identified to be the likely candidate TSG and oncogene respectively. Retroviral transduction of HCK into PTPRT-null murine LKS+ stem and progenitor cells resulted in hyperproliferation in colony forming assays and hyperphosphorylation of intracellular STAT3. Furthermore, over half of the murine recipients of these transduced cells developed erythroid hyperplasia, polycythemia and splenomegaly at 12 months, although no leukemic phenotype was observed. The findings suggested that HCK amplification coupled with PTPRT loss in del(20q) leads to development of a myeloproliferative phenotype.

Background: The benefits of laparoscopic splenectomy (LS) over open splenectomy (OS) for normal-sized spleens have been well documented. However, the role of laparoscopy for moderate and massive splenomegaly is debated., Methods: A retrospective review of patients undergoing elective splenectomy at one institution from 1997 to 2017 was conducted. Moderate and massive splenomegaly was defined as splenic weight of 500-1000 g and greater than 1000 g, respectively. We performed a 1:2 matching of laparoscopic to open splenectomy to control for differences in splenic weight. Differences in perioperative morbidity (infection, thromboembolism, reoperation, readmission), intraoperative factors (blood loss, operative time), length of stay, and mortality were examined., Results: A total of 491 elective splenectomies were identified. 268 cases were for splenic weights greater than 500 g. After a 1:2 matching of LS:OS, we identified 22 LS and 44 matched OS for moderate splenomegaly. The LS group had longer mean operative times (178 vs. 107 min, p < 0.01), with similar length of stay and blood loss. For massive splenomegaly, 26 LS were identified and matched to 52 OS. LS had longer mean operative times (171 vs. 112 min, p < 0.01) and higher readmission rates (27% vs. 6%, p < 0.05). Other factors and outcomes did not differ between LS and OS for moderate or massive splenomegaly. The conversion rate for LS was higher for massive versus moderate splenomegaly, but was not statistically significant (35% vs. 14%, p = 0.09)., Conclusions: LS for moderate and massive splenomegaly is associated with longer operative times. Other perioperative outcomes were comparable to OS, with no demonstrated benefits for LS. Although LS may be a feasible approach to moderate and massive splenomegaly, its benefits require further clarification in this patient population.

Objective: Liver biopsy is the gold standard test for assessment of liver pathology. This study was performed to assess the predictive value of spleen thickness for liver pathology and the role of routine follow-up procedures in significant liver pathology for patients with chronic hepatitis B (CHB) with persistently normal alanine aminotransferase (PNALT) or minimally raised alanine aminotransferase (ALT)., Methods: Patients with CHB who underwent percutaneous liver biopsy were retrospectively reviewed. The relationship of liver pathology with age, ALT, hepatitis B e-antigen, and spleen thickness was statistically analyzed, and the predictive accuracy of spleen thickness was evaluated., Results: In total, 80.65% of patients had significant necroinflammation and/or fibrosis. Nearly 60% of patients had splenomegaly, of which 89.12% had a histopathological grade of ≥G2 and/or S2. Spleen thickness was predictive of liver pathology, and significant histological findings increased as the hepatitis B virus (HBV) DNA level increased., Conclusions: Spleen thickness is an effective predictor of liver pathology in patients with PNALT or minimally raised ALT. Additionally, the prevalence of significant histological findings tended to increase as the HBV DNA level increased. Patients with CHB and splenomegaly and a high HBV DNA level should be treated early with antivirals to improve liver pathology.

Non-cirrhotic portal hypertension - The point of view of the pathologist Abstract. Non-cirrhotic portal hypertension (NCPH) is a heterogeneous group of liver disorders leading to portal hypertension. Many disorders are associated with NCPH. Based on the site of resistance to blood flow, they are classified as pre-hepatic, hepatic, and post-hepatic. Hepatic causes are further subdivided into pre-sinusoidal, sinusoidal and post-sinusoidal. The diagnosis of idiopathic non-cirrhotic portal hypertension (INCPH) can be made if all these disorders have been excluded and consequently no clear liver disease has been identified. INCPH is clinically characterized by features of PHT, moderate to massive splenomegaly, with or without hypersplenism, and preserved liver functions. This review is focused on pathological features of INCPH, which is thought to be caused largely by parenchymal vascular obstruction. INCPH must be considered in every patient presenting with clinical signs of portal hypertension where cirrhosis appears to be absent and the cause of portal hypertension is not clear. In most instances, patients present with bleeding esophageal varices. In order to exclude severe fibrosis or cirrhosis, liver histology remains essential in the diagnosis of INCPH.

The spleen plays an important role in the immune and hematopoietic systems. Splenomegaly is a frequent consequence of portal hypertension, but the underlying molecular and cellular mechanisms remain to be fully elucidated. In this study, we have performed a whole-genome microarray analysis combined with histological examination in enlarged spleens isolated from rats with partial portal vein ligation (PPVL) surgery to provide comprehensive profiles of microRNAs and their target mRNAs with a focus on their potential biological functions. A total of 964 mRNAs and 30 microRNAs showed significant differential expression in the spleens of PPVL rats compared to rats undergoing a sham procedure. Twenty-two down-regulated microRNAs were associated with significantly increased genes highly involved in fibrogenic activity and cell proliferation/migration (e.g., Ctgf, Serpine1, Col1a1). Consistently, histological analyses demonstrated increased splenic fibrosis and cell proliferation in the spleens of PPVL rats. Eight up-regulated microRNAs were associated with suppression of genes that are related to interferon-mediated antiviral activity in innate immune responses (e.g., Irf7, Dhx58). In conclusion, we determined a specific microRNA-mRNA network potentially implicated in the tissue fibrosis and cell proliferation in portal hypertension-induced splenomegaly. Our findings provide new insight into the mechanisms for regulation of spleen structure and function.

Purpose: To evaluate a possible relationship between the size of the spleen and values of circulating blood elements in patients with schistosomatic splenomegaly., Methods: ixty one patients with hepatosplenic schistosomiasis mansoni underwent a clinical exam and peripheral venous blood was collected for a hemogram. The erythrocyte, hemoglobin, hematocrit, leukocyte, and platelet values were determined. All patients underwent abdominal ultrasound to measure the spleen. The hematological test results were compared to the size of the spleen., Results: The size of the spleen varied from 14.0 to 28.4 (19.9 ± 3.7) cm according to the ultrasound image. Thrombocytopenia was observed 58 (95%) patients, leukopenia in 55 (90%) patients, and anemia in 32 (52.4%) patients. Leukopenia was proportional to splenomegaly., Conclusion: Schistosomal splenomegaly leads to leukopenia in direct proportion to the size of the spleen.

Background: Gaucher disease is a rare pan-ethnic disorder which occurs due to an increased accumulation of undegraded glycolipid glucocerebroside inside the cells' lysosomes. A beta-Glucosidase (GBA) gene defect results in glucocerebrosidase enzyme deficiency. Though the disease is mainly diagnosed in childhood, the adult manifestation is often missed or identified late due to the failure to recognize the heterogeneous clinical presentation. The present study includes seven unrelated Indian adult patients (age range: 20-40 years) having splenomegaly, with or without hepatomegaly, cytopenia and bone abnormality., Methods: The biochemical investigation implicated measuring plasma chitotriosidase enzyme activity followed by confirmatory test of β-Glucosidase enzyme activity from the leukocytes. The molecular characterization involved patients' initial screening for the common Gaucher mutation (Leu444Pro). Later, all patients were subjected to whole GBA gene coding region study using bidirectional Sanger sequencing. The population screening for common Gaucher disease mutation (Leu444Pro) was executed in 1200 unrelated and healthy Indian subjects by Restriction Fragment Length Polymorphism-Polymerase Chain Reaction technique. The allele frequency was calculated using Hardy-Weinberg formula., Results: The biochemical analysis revealed a significant reduction in the β-Glucosidase activity in all the patients. Also, an elevated level of plasma Chitotriosidase activity in five patients supported their diagnosis of Gaucher disease. Sanger sequencing established four patients with homozygous variation and three patients with compound heterozygous variation in GBA gene. This study uncovers two missense variants (Ala448Thr and Val17Gly) not previously reported in Gaucher disease patients. Also the known mutations like Leu444Pro, Arg329Cys, Asp315Asn, Ser125Arg, and Arg395Cys were identified in these patients. The homology modeling suggested the destabilization of the protein structure due to novel variants. The Leu444Pro mutation screening in the Indian population spotted two people as a carrier. This emerged the carrier frequency of 1:600 along with wild-type allele frequency 0.97113 and mutant allele frequency 0.02887., Conclusions: The study reports novel and known variants identified in the GBA gene in seven adult patients. The given study is the first report on the carrier frequency of the Leu444Pro mutant allele in an Indian population which will help understanding the burden and susceptibility of Gaucher disease to affect next generation in India.

Allogeneic stem cell transplantation is currently the only curative therapy for primary myelofibrosis (MF), while the JAK2 inhibitor, ruxolitinib. Has been approved only for palliation. Other therapies are desperately needed to reverse life-threatening MF. However, the cell(s) and cytokine(s) that promote MF remain unclear. Several reports have demonstrated that captopril, an inhibitor of angiotensin-converting enzyme that blocks the production of angiotensin II (Ang II), mitigates fibrosis in heart, lung, skin and kidney. Here, we show that captopril can mitigate the development of MF in the Gata1 low mouse model of primary MF. Gata1 low mice were treated with 79 mg/kg/d captopril in the drinking water from 10 to 12 months of age. At 13 months of age, bone marrows were examined for fibrosis, megakaryocytosis and collagen expression; spleens were examined for megakaryocytosis, splenomegaly and collagen expression. Treatment of Gata1 low mice with captopril in the drinking water was associated with normalization of the bone marrow cellularity; reduced reticulin fibres, splenomegaly and megakaryocytosis; and decreased collagen expression. Our findings suggest that treating with the ACE inhibitors captopril has a significant benefit in overcoming pathological changes associated with MF., (© 2018 Virginia Commonwealth University. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Objectives To investigate peripheral cytopenia in patients with splenomegaly due to hepatitis B-related cirrhotic portal hypertension (HBRCPH) by comparing blood cell counts from enlarged spleens with peripheral blood. Methods This prospective study involved patients undergoing splenectomy at the Nangfang Hospital from June 2013 to December 2015. Blood cell counts from peripheral blood were compared with those from splenic blood taken during splenectomies. Results Clinical data were available from 30 patients. White blood cell (WBC), red blood cell (RBC) and platelet counts were statistically significantly lower in peripheral blood compared with splenic blood. After splenectomy, peripheral blood cell counts increased significantly compared with pre-operative levels. Platelet and WBC counts in the lower spleen were significantly higher than those in the porta lienis (middle segment) and upper spleen. Conclusions In patients with splenomegaly due to HBRCPH, the counts of three blood cell lineages were significantly higher in the spleen than in peripheral blood. Splenectomy can aid the return of peripheral blood cell counts to normal levels. The most significant retention of platelets and WBCs occurred in the lower spleen which may be useful information for surgeons performing partial splenectomies.

Purpose: To find CT-texture analysis (CTTA) features for the discrimination of splenomegaly due to diffuse lymphoma involvement and liver cirrhosis versus normal-sized spleens in controls and to assess their potential role for longitudinal lymphoma monitoring., Material and Methods: We had retrospectively identified 74 subjects with diffuse splenic involvement due to lymphoma (n = 29) and liver cirrhosis (n = 30), and healthy controls (n = 15), who underwent contrast-enhanced abdominal CT between August 2013 and October 2017. CTTA evaluation included heterogeneity, intensity, average, deviation, skewness, entropy of co-occurrence, number non-uniformity (NGLDM) and entropy NGLDM. A greater than 50% reduction of spleen volume after chemotherapy was considered proof for splenic involvement., Results: There were significant differences of splenic CTTA-values before and after treatment of patients with lymphoma, including mean of entropy(p < .001), uniformity of average(p < .001), uniformity of deviation(p = .002) and entropy of skewness(p < .001). Significant differences of splenic CTTA-values in subjects with lymphoma vs. healthy controls were found for mean intensity(p < .001), mean average(p < .001), and entropy of deviation(p < .001). No significant differences in splenic CTTA-values were found in subjects with lymphoma that reached complete remission vs. controls. Splenic CTTA values mean intensity(p = .002) and mean average(p = .004) were significantly different between subjects with untreated lymphoma and subjects with liver cirrhosis. At end-of-treatment all lymphomas reached complete remission. Entropy/uniformity of heterogeneity(p < .001), mean intensity(p = .007), mean average (p = .007), uniformity of average(p = .008) and mean/entropy/uniformity of skewness(p = .001) measured at this time differed significantly from baseline., Conclusions: CTTA features in subjects with splenomegaly due to lymphoma and liver cirrhosis differ significantly from those of healthy controls and can be also used for monitoring lymphoma treatment. Quantitative CTTA features may increase the accuracy of diagnosing causes of splenomegaly., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Despite being a cardinal experimental model, the induction of cirrhosis in rats by repeated exposure to carbon tetrachloride (CCl4) has low reproducibility. Here, we compared two models of cirrhosis induced by orogastric administration of CCl4 once (CCl4-1xWk) or twice a week (CCl4-2xWk) for 12 weeks in male Sprague-Dawley rats. Control rats received water instead of CCl4. Both CCl4 protocols similarly attenuated body weight gain (p < 0.01 vs. Control). Although both CCl4 protocols increased hepatic fibrosis, portal hypertension and splenomegaly, the magnitude of these alterations was higher and more consistent in CCl4-2xWk rats. Importantly, two CCl4-1xWk rats did not develop cirrhosis versus a 100% yield of cirrhosis in CCl4-2xWk rats. The CCl4-2xWk protocol consistently induced liver atrophy together with hematological, biochemical and coagulation abnormalities characteristic of advanced cirrhosis that were absent in CCl4-1xWk rats. Ascites occurred in 20% and 80% of rats in theCCl4-1xWk and CCl4-2xWk groups (p < 0.01). All rats showed normal renal function, arterial blood gases and stable systemic hemodynamics. The total dose of CCl4 and mortality rate were similar in both protocols. The CCl4-2xWk protocol, therefore, was highly reproducible and effective for the induction of experimental cirrhosis within a confined time, representing a valuable advance for liver research.