Evaluation of the risk factors for venous thromboembolism post splenectomy - A ten year retrospective cohort study in St James's hospital.

BACKGROUND: Splenectomy is a surgical intervention for a variety of indications; benign and malignant. Complications of this procedure include Venous thromboembolism (VTE) and infection. The incidence of VTE post-surgery has been reported between 0.8%-3% depending on the type of surgery. A higher incidence of abdominal VTE was reported post splenectomy (6-11%). However, there is limited literature regarding the risk factors for post splenectomy VTE and the optimal strategy for thromboprophylaxis. OBJECTIVE: The primary objective of the study was to evaluate the incidence of VTE post splenectomy and to identify the pre-operative, intra-operative and post-operative risk factors. The secondary objective was to assess the local compliance with post-splenectomy prophylactic antibiotics and vaccination protocols. METHODS: We conducted a retrospective observational study. All patients who had a splenectomy in St James's Hospital between January 2007 and June 2017 were included and reviewed. Statistical analysis was carried out using SPSS statistical package. RESULTS: 85 patients were involved in the study. The main indications for splenectomy were benign haematology, malignant haematology, solid tumours, traumatic and spontaneous rupture. 6/85 patients developed VTE (7.06%).High BMI ≥ 30 was associated with increased risk of VTE (p = 0.007), while the use of post-operative prophylactic anticoagulation was associated with reduced risk (p = 0.005). Other factors including age >50 years, female gender, presence of active malignancy and splenomegaly were associated with increased VTE risk with no statistical significance. All VTE's occurred in elective versus emergency splenectomy. Laparoscopic splenectomy was associated with higher risk of VTE than open splenectomy. 97% of patients were prescribed prophylactic antibiotics on discharge, but only 88% had received recommended vaccinations. CONCLUSION: Venous thromboembolism is common post splenectomy. Our data showed that BMI ≥30 was associated with a statistically significant increased risk of VTE, while the use of prophylactic anticoagulation was associated with reduced risk. Further prospective studies with larger samples are warranted and a splenectomy care plan may be helpful.

Cyclosporine A and IFNγ licencing enhances human mesenchymal stromal cell potency in a humanised mouse model of acute graft versus host disease.

Immunosuppressive ability in human MSC donors has been shown to be variable and may be a limiting factor in MSC therapeutic efficacy in vivo. The importance of cytokine activation of mesenchymal stromal cells (MSCs) to facilitate their immunosuppressive function is well established. This study sought to further understand the interactions between MSCs and the commonly used calcineurin inhibitor cyclosporine A (CsA). The existing literature regarding approaches that use MSCs and cyclosporine are conflicting regarding the effect of CsA on MSC potency and function. Here, we clearly demonstrate that when added at the same time as MSCs, CsA negatively affects MSC suppression of T cell proliferation. However, licencing MSCs with IFNγ before addition of CsA protects MSCs from this negative effect. Notably, adding CsA to MSCs after IFNγ pre-stimulation enhances MSC production of IDO. Mechanistically, we identified that CsA reduces SOCS1 expression to facilitate enhanced IDO production in IFNγ pre-stimulated MSCs. Importantly, CsA exposure to IFNγ pre-stimulated MSC before administration, significantly enhanced the potency of MSCs in a human relevant humanised mouse model of acute Graft versus Host Disease. In summary, this study identified a novel licencing strategy to enhance MSC potency in vitro and in vivo.

Hairy Cell Leukemia Masquerading as Pancytopenia in Pregnancy.

Thrombocytopenia is one of the most common hematological abnormalities observed during pregnancy, and in rare cases, this may be the first indicator of an underlying hematological malignancy. Hairy cell leukemia (HCL) is an uncommon B-cell lymphoproliferative disorder of which thrombocytopenia is a recurrent presenting feature. A case of pancytopenia presenting in pregnancy is described in which the thrombocytopenia persisted postpartum coincidental with a vesicular, pustular rash characterised as Sweet's syndrome. Hematological, histological, immunophenotypic, and molecular investigations confirmed the presence of HCL. The patient was treated with cladribine resulting in resolution of Sweet's syndrome, hematological remission from HCL, and achievement of a normal platelet count. This case highlights the need to maintain a wide differential diagnosis for presentations of pancytopenia or thrombocytopenia in pregnancy and the requirement for follow-up investigation of unusual cases with a lack of response to steroids or immunoglobulin.

Myelodysplastic Syndrome/Acute Myeloid Leukemia Arising in Idiopathic Erythrocytosis.

The term "idiopathic erythrocytosis (IE)" is applied to those cases where a causal clinical or pathological event cannot be elucidated and likely reflects a spectrum of underlying medical and molecular abnormalities. The clinical course of a patient with IE is described manifesting as a persistent erythrocytosis with a low serum erythropoietin level, mild eosinophilia, and with evidence of a thrombotic event. The patient subsequently developed a myelodysplasic syndrome (MDS) and acute myeloid leukemia (AML), an event not observed in erythrocytosis patients other than those with polycythemia vera (PV). Application of a next-generation sequencing (NGS) approach targeted for myeloid malignancies confirmed wild-type JAK2 exons 12-15 and identified a common SH2B3 W262R single-nucleotide polymorphism associated with the development of hematological features of myeloproliferative neoplasms (MPNs). Further NGS analysis detected a CBL L380P mutated clone expanding in parallel with the development of MDS and subsequent AML. Despite the absence of JAK2, MPL exon 10, or CALR exon 9 mutations, a similarity with the disease course of PV/MPN was evident. A clonal link between the erythrocytosis and AML could be neither confirmed nor excluded. Future molecular identification of the mechanisms underlying IE is likely to provide a more refined therapeutic approach.

CALR mutation profile in Irish patients with myeloproliferative neoplasms.

Insertion and/or deletion mutations of the CALR gene have recently been demonstrated to be the second most common driver mutations in the myeloproliferative neoplasms (MPNs) of essential thrombocythemia (ET) and primary myelofibrosis (PMF). Given the diagnostic and emerging prognostic significance of these mutations, in addition to the geographical heterogeneity reported, the incidence of CALR mutations was determined in an Irish cohort of patients with MPNs with a view to incorporate this analysis into a prospective screening program. A series of 202 patients with known or suspected ET and PMF were screened for the presence of CALR mutations. CALR mutations were detected in 58 patients. Type 1 and Type 1-like deletion mutations were the most common (n=40) followed by Type 2 and Type 2-like insertion mutations (n=17). The CALR mutation profile in Irish ET and PMF patients appears similar to that in other European populations. Establishment of this mutational profile allows the introduction of a rational, molecular diagnostic algorithm in cases of suspected ET and PMF that will improve clinical management.

Role of motor processes in extrinsically encoding mental transformations.

Previous research has shown that imagined perspective rotations elicit spatial and low-level cortical motor areas of the brain when participants rely on knowledge of their physical body, or body percept (Wraga, Flynn, Boyle, & Evans, 2010). The current study used functional magnetic resonance imaging (fMRI) to investigate whether recruitment of the body percept would activate low-level cortical motor areas of the brain within other classes of mental transformations. Participants performed imagined object and perspective rotations of three-dimensional Shephard-Metzler (1971) stimuli. For each task, participants used button presses serving as virtual pointers to locate a prescribed portion of the stimuli with respect to their "right" and "left." We found low-level cortical motor activation (M1) for both mental transformations; however, the degree to which such activation related to participants' performance differed, as well as the recruitment of additional nonmotoric strategies. The results are discussed in terms of recent hypotheses regarding the role of the body percept in extrinsically encoded mental transformations.

Effects of a body-oriented response measure on the neural substrate of imagined perspective rotations.

Previous behavioral studies suggest that response measures related to the body, such as pointing, serve to anchor participants to their physical body during mental rotation tasks in which their perspective must be shifted elsewhere. This study investigated whether such measures engage spatial and low-level cortical motor areas of the brain more readily than non-body-related measures. We directly compared activation found in two imagined perspective rotation tasks, using responses that varied in the degree to which they emphasized the human body. In the body minimize condition, participants imagined rotating themselves around an object and judged whether a prescribed part of the object would be visible from the imagined viewpoint. In the body maximize condition, participants imagined rotating around the object and then located the prescribed object part with respect to their bodies. A direct comparison of neural activation in both conditions revealed distinct yet overlapping neural regions. The body maximize condition yielded activation in low-level cortical motor areas such as premotor cortex and primary motor cortex, as well as bilateral spatial processing areas. The body minimize condition yielded activation in nonmotoric egocentric processing regions. However, both conditions showed activation in the parietal-occipital region that is thought to be involved in egocentric transformations. These findings are discussed in the context of recent hypotheses regarding the role of the body percept in imagined egocentric transformations.

Passive tactile feedback facilitates mental rotation of handheld objects.

Mental rotation of objects improves when passive tactile information for the rotating object accompanies the imagined rotation (Wraga, Creem, & Proffitt, 2000). We examined this phenomenon further using a within-subjects paradigm involving handheld objects. In Experiment 1, participants imagined rotating an unseen object placed on their upturned palms. The participants were faster at mental rotation when the object was rotated on their palm than when the object remained stationary. Experiment 2 tested whether the performance advantage would endure when the participants received tactile information for only the start- and endpoints of the rotation event. This manipulation did not improve performance, relative to a stationary control. Experiment 3 revealed that ambiguous tactile information, continuous with the rotation event but independent of object shape, actually degraded performance, relative to a stationary control. In Experiment 4, we found that continuous tactile rotation discrepant from imagined object movement also hindered performance, as compared with continuous tactile information aligned with imagined object movement. The findings suggest a tight coupling between tactile information specifying continuous object rotation and the corresponding internal representation of the rotating object.

Reduced intensity compared with high dose conditioning for allotransplantation in acute myeloid leukemia and myelodysplastic syndrome: a comparative clinical analysis.

We evaluated the efficacy of hematopoietic stem cell transplantation (HSCT) using reduced intensity (RI) vs. myeloablative (MA) conditioning for patients with acute myeloid leukemia (AML) and myelodysplastic syndrome. Thirty two patients (median age 54) who underwent a RI HSCT (2000-2003) were compared with 187 patients (median age 39) who received a MA transplant (1990-2003). Neutrophil engraftment was more rapid in the RI group (median 11.5 vs. 21 days). Platelet recovery was similar and graft failure was infrequent. The incidence of graft-versus-host disease (GVHD) and treatment-related mortality was similar though relapse was more frequent after RI conditioning (RR 2.2 [95% CI = 1.1-4.6] P = 0.03). At 2 years, disease-free survival (DFS) (31% vs. 30%, P > 0.1) and overall survival (33% vs. 35%, P > 0.1) were comparable between RI and MA groups, respectively. We suggest that RI allografts can yield satisfactory DFS both for older as well as younger patients with pre-existing comorbidities, who are ineligible for MA allografts. Advances in GVHD management and new approaches for relapsed or refractory disease are necessary to improve these outcomes.

Donor cell leukemia: insight into cancer stem cells and the stem cell niche.

Donor cell leukemia (DCL) is a rare complication of hematopoietic cell transplantation (HCT). Its incidence has been reported between 0.12% and 5%, although the majority of cases are anecdotal. The mechanisms of leukemogenesis in DCL may be distinct from other types of leukemia. Possible causes of DCL include oncogenic alteration or premature aging of transplanted donor cells in an immunosuppressed person. Although many studies have recently better characterized leukemic stem cells, it is important to also consider that both intrinsic cell factors and external signals from the hematopoietic microenvironment govern the developmental fate of hematopoietic stem cells (HSCs). Therefore, in cases of DCL, alteration of the microenvironment after HCT may increase the likelihood that some progeny of normal HSCs become leukemic. This complex intercommunication between cells, growth factors, and cytokines in the hematopoietic microenvironment are critical to balance HSC self-renewal, proliferation, and differentiation. However, this homeostasis is likely perturbed in the development of DCL, allowing unique insight into the stimuli that regulate normal and potentially abnormal hematopoietic development. In this article, we discuss the possible pathogenesis of DCL, its association with stem cells, and its likely dependence on a less-supportive stem cell niche.

Functional analysis of human hematopoietic stem cell gene expression using zebrafish.

Although several reports have characterized the hematopoietic stem cell (HSC) transcriptome, the roles of HSC-specific genes in hematopoiesis remain elusive. To identify candidate regulators of HSC fate decisions, we compared the transcriptome of human umbilical cord blood and bone marrow (CD34+)(CD33-)(CD38-)Rho(lo)(c-kit+) cells, enriched for hematopoietic stem/progenitor cells with (CD34+)(CD33-)(CD38-)Rho(hi) cells, enriched in committed progenitors. We identified 277 differentially expressed transcripts conserved in these ontogenically distinct cell sources. We next performed a morpholino antisense oligonucleotide (MO)-based functional screen in zebrafish to determine the hematopoietic function of 61 genes that had no previously known function in HSC biology and for which a likely zebrafish ortholog could be identified. MO knock down of 14/61 (23%) of the differentially expressed transcripts resulted in hematopoietic defects in developing zebrafish embryos, as demonstrated by altered levels of circulating blood cells at 30 and 48 h postfertilization and subsequently confirmed by quantitative RT-PCR for erythroid-specific hbae1 and myeloid-specific lcp1 transcripts. Recapitulating the knockdown phenotype using a second MO of independent sequence, absence of the phenotype using a mismatched MO sequence, and rescue of the phenotype by cDNA-based overexpression of the targeted transcript for zebrafish spry4 confirmed the specificity of MO targeting in this system. Further characterization of the spry4-deficient zebrafish embryos demonstrated that hematopoietic defects were not due to more widespread defects in the mesodermal development, and therefore represented primary defects in HSC specification, proliferation, and/or differentiation. Overall, this high-throughput screen for the functional validation of differentially expressed genes using a zebrafish model of hematopoiesis represents a major step toward obtaining meaningful information from global gene profiling of HSCs.