bluuebunny/crossref_metadata_2025_split huggingface dataset:
Splenic Marginal Zone Lymphoma (SMZL): Clinical Course after Splenectomy. A Single Institution Experience
Authors: Gaykazyan Susanna S , Janakiraman Nalini , Kuriakose Philip , Maeda Koichi , Hammour Tareq 
Published: April 2020

Abstract
SMZL is an indolent B-cell malignancy accounting for 1–2% of chronic lymphoid leukemia found on bone marrow examination and up to 25% of low-grade B-cell neoplasms in splenectomy patients. Aggressive transformation of SMZL rarely occurs. It usually presents as an incidental finding or with symptoms of splenomegaly and anemia. There is still no reliable clinical or biological scoring system for prognostic stratification. We reviewed pathology reports of 41 splenectomized patients at HFHS from 1994 to 2007 and identified 14 patients with splenic marginal zone lymphoma (SMZL). The reasons for splenectomy were symptoms of splenomegaly in all 14 patients, anemia in 13 patients, thrombocytopenia in 12 patients, AIHA in 4 patients, splenic laceration in one patient. We report here the demographics, clinical course and pathology review of these patients. The median age of patients was 77.8 years. There were 7 male and 7 female patients. ECOG performance status was 0–1 in 12(86%), and 2 in 2(14%). Of the 14 patients, 8(57%) were at Ann Arbor stage IV, 1(7%) was at stage III, 4(29%) were at stage II, and 1(7%) at stage I. LDH was above normal in 9(64%) patients B-symptoms were observed in 1(7%).
Bone marrow involvement was documented in 8(57%) of the patients. Anemia in 13(93%), thrombocytopenia in 12(86%), AIHA in 4(29%). IPI score was 1–2 in 5(36%), and score 3–4 in 9(64%) of the patients. Median weight of the spleen was 1235 gm. Bone marrow cytogenetics were abnormal in 4(29%) cases. Following splenectomy, cytopenias resolved completely or partially (CR/PR) in 13(93%) patients. Bacterial infections were observed in 4(29%) patients and 2(14%) died of infectious complications. Progressive disease requiring additional systemic therapy was documented in 5(36%) patients. Total of 5(36%) patients died. One secondary to NSLC, 1(7%) of urothelial carcinoma, 1(7%) secondary to hypercalcemia, 2(14%) due to bacterial sepsis. Patients were followed up to 139 months (with median follow-up time of 42 months). The estimated median overall survival (OS) for this group was 116.5 months (9.7 years), the median progression-free survival (PFS) was 91 months (7.6 years). The Kaplan Meier method was used to calculate these estimates. A simple median was calculated for the sample median. In summary, we report the course of 14 patients with SMZL who underwent splenectomy for symptomatic disease. Only 5(36%) required systemic therapy following splenectomy. No death was attributed to progressive SMZL. Overall course was indolent even after splenectomy. Estimated OS was 116.5 months (9.7 years), PFS - 91 month (7.6 years).
HLA-Identical Umbilical Cord Blood Transplantation from a Sibling Donor in Juvenile myelomonocytic Leukemia
Authors: de Vries Andrica , Bredius Robbert , Lankester Arjan , Bierings Marc , Trebo Monika , Stary Jan , Zecca Marco , Locatelli Franco , Niemeyer Charlotte , Van Den Heuvel Marry 
Published: April 2020

Abstract
Background: Juvenile myelomonocytic leukemia (JMML) is a rare malignant myeloid disorder in childhood, for which stem cell transplantation is currently the only curative treatment option. Although unrelated donor umbilical cord blood transplantations (UCBTs) have been described, series of HLA-identical sibling donor UCBTs in JMML are not available.
Methods: From the European Working Group on Childhood MDS (EWOG MDS) registry the 5 JMML patients who underwent a fully HLA matched sibling UCBT are described.
Results: The median age at diagnosis was 18 months (range 15–30 months). In one case no mutation analysis was performed, in one case a PTPN11 mutation was found. In the other cases no mutation in RAS or PTPN11 was found. None of the patients had clinical signs of NF1. The conditioning consisted of busulfan, cyclophosphamide and melphalan in four cases and of cyclophosphamide, etoposide and total body irradiation in one case. All patients engrafted slowly. In 3 patients mild acute graft versus host was noticed (grade 1 and 2), no chronic graft versus host was reported. Two patients relapsed after the initianal transplantation and underwent a second transplant with marrow of the initianal donor. One of them is in second complete remission and the other died after a second relapse. One patient developed increased donor chimerism from day 42 without any clinical sign of relapse. She was treated with DLI, 6 mercaptopurine and 13-cis retinoic acid respectively. She is still in complete remission 5 years after transplantation.
Conclusion: This EWOG serie illustrates that, although this needs to be confirmed in larger series, relatively immunologically naive HLA-matched sibling UCBT is feasible in selected cases of JMML.
Autologous Peripheral Blood Stem Cell Transplantation for POEMS Syndrome
Authors: Ohwada Chikako , Nakaseko Chiaki , Takeda Yusuke , Abe Daijiro , Takeuchi Masahiro , Sakaida Emiko , Masuda Shinichi , Shimizu Naomi , Cho Ryuko , Nishimura Miki , Kanai Kazuaki , Misawa Sonoko , Kuwabara Satoshi 
Published: April 2020

Abstract
Background: POEMS syndrome is a rare plasma cell disorder characterized by polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes associated with multiorgan involvement and monoclonal plasma cell dyscrasia. The pathogenesis of POEMS syndrome is not well understood, but overproduction of vascular endothelial growth factor (VEGF) probably secreted by plasma cells is considered to be responsible. High-dose melphalan (Mel) with autologous stem cell transplantation (ASCT) has been recently considered to be an effective strategy, but its treatment related mortality is considered to be high. Here, we report the results of ASCT for POEMS syndrome.
Methods: Between January 2004 and June 2008, twelve patients with POEMS syndrome underwent ASCT at Chiba University Hospital and were retrospectively analyzed in the study. Conditioning treatment for ASCT was Mel 200 mg/m2, while Mel dose was reduced to 140 mg/m2 if a patient had poor performance status (PS).
Results: Ten out of twelve patients were male and their median age was 48 years (range 34–61). Median time from first symptom and diagnosis to ASCT was 21 and 10 months, respectively. Seven patients received induction therapy before preparation of ASCT, thalidomide-dexamethasone in four, intravenous Mel in two, and bevacizumab followed by thalidomide in one patient. Peripheral blood stem cells were mobilized by cyclophosphamide/G-CSF in nine cases and G-CSF alone in three. Median serum VEGF level before ASCT was 2835 pg/ml (range; 334–5300). Median number of infused CD34+ cells was 2.3 × 106/kg (range; 2.1–4.3 × 106/kg). Eleven patients were conditioned with Mel 200 mg/m2, while one patient with poor PS (Karnofsky score 30%) received Mel 140 mg/m2. Median time to neutrophil recovery (&gt;500/mm3) was 13 days post transplant (range 9–17 days). Only two patients developed respiratory distress during neutrophil engraftment period. Both cases were successfully treated with corticosteroid therapy, none of them required intubation. During a median follow up period of 16.5 months (range 2–54), there was no transplant related death. Neurologic improvement was significantly observed in all patients and median post transplantation serum VEGF level was decreased to 330 pg/ml (range 87–3250). Only one patient experienced relapse of polyneuropathy at 43 months post transplant following reincrease of serum VEGF level.
Conclusions: ASCT is an effective therapy for POEMS syndrome. Despite previous published reports arousing potential risk of life-threatening engraftment syndrome, treatment related mortality and periengraftment pulmonary complications were significantly low in our patient series. We speculate that stabilization of serum VEGF level by induction therapy before ASCT could play a potential role for reducing the risk of peritransplant complications.
Efficacy of Nilotinib (formerly AMN107) in Patients (Pts) with Newly Diagnosed, Previously Untreated Philadelphia Chromosome (Ph)-Positive Chronic Myelogenous Leukemia in Early Chronic Phase (CML-CP)
Authors: Cortes Jorge , O’Brien Susan , Jones Dan , Ferrajoli Alessandra , Konopleva Marina , Borthakur Gautam , Garcia-Manero Guillermo , Letvak Laurie A. , Kantarjian Hagop 
Published: April 2020

Abstract
Background: Nilotinib is an oral tyrosine kinase inhibitor with high selectivity towards Bcr-Abl and approximately 30-fold more potent than imatinib, and is effective in patients with CML after imatinib failure. We initiated a phase II study to evaluate the efficacy of nilotinib as 1st line therapy in pts with newly diagnosed CML-CP.
Aims: To investigate the efficacy and safety of nilotinib as initial therapy for patients with CML-CP.
Methods: The primary objective was to estimate the proportion of pts attaining major molecular response (MMR) at 12 months (mo). Pts with untreated CML-CP (or with &lt;1 months of therapy with imatinib) were eligible and received nilotinib 400mg twice daily. A cohort of patients with previously untreated CML in accelerated phase (AP) was also included.
Results: Forty-nine pts have been treated for a median of 13 months (mo). The median age was 47 years (yrs) (range, 21 to 81); 69% are Sokal low risk. Eight (16%) had received imatinib for &lt;1 months. Overall, 46/48 (96%) of evaluable CP pts achieved a complete cytogenetic response [CCyR]. The rate of CCyR at 3, 6 and 12 mo for pts in CP compares favorably to those observed in historical controls treated with imatinib 400mg or 800 mg daily:
Percent with CCyR (No. evaluable) Months on therapy Nilotinib Imatinib 400mg Imatinib 800mg P value 3 93 (45) 37 (49) 62 (202) &lt; 0.0001 6 100 (36) 54 (48) 82 (199) &lt; 0.0001 12 96 (27) 65 (48) 86 (197) 0.0003 18 92 (12) 68 (38) 89 (179) 0.0042 24 91 (11) 70 (40) 88 (173) 0.0151
MMR was observed in 45% at 6 mo and 52% at 12 mo. Two of 44 (5%) evaluable pts have achieved confirmed complete molecular response, and 3 others unconfirmed (ie, only achieved on their last assessment). Grade 3–4 hematologic toxicity (transient) included thrombocytopenia in 10%, neutropenia in 12%, and anemia in 2%. Grade 3–4 non-hematologic adverse events (regardless of causality) included elevation of bilirubin in 8% and lipase in 6%. 19 (36%) pts had transient treatment interruptions and 17 (32%) had dose reductions. The actual median dose is 800mg daily. Three pts have come off study: 1 pt’s choice and 2 because of toxicity (1 liver, 1 pericardial effusion). One of them (liver toxicity) transformed to blast phase shortly after coming off study. Estimated 24 month EFS (event = loss of CHR, loss of MCyR, AP/BP, death, or off because of toxicity) is 95%.
Conclusion: Nilotinib 400 mg twice daily induces a CCyR in nearly all patients as early as 3 months after the start of therapy with a favorable toxicity profile. Accrual is ongoing.
A Novel Mutation (Q694X) in the ITGB3 Gene Causing Glanzmann’s Thrombasthenia from the Sultanate of Oman
Authors: Albalushi Talal , AlZadjali Shoaib , AlHaddabi Hamood , Dennison J. David , Alkindi Salam , Muralitharan Shanmugaonkar , Arinami Tadao , Pathare Anil 
Published: April 2020

Abstract
Background : Glanzmann Thrombasthenia (GT) results from mutations in the genes ITGA2B and ITGB3, located on chromosome 17q21–23 which encodes the platelet glycoprotein αIIbβ3 complex, namely GPIIb (αIIb) and GPIIIa (β3), the fibrinogen receptors on platelets, which play an important role in platelet aggregation. Patients with GT can require frequent hospitalization and can be a burden on the nation’s health resources. The possibility that GT could be cured by gene replacement therapy makes it essential to study the molecular basis of the GT patients in a particular family or kindred.
Objectives : Our aim was to identify the underlying mutations responsible for GT in Omani patients in order to establish a strategy for genetic counseling and carrier detection to prevent the occurrence of the homozygous state by prenatal diagnosis.
Methods: GT was diagnosed in a 17 year old Omani female at the Sultan Qaboos University Hospital. The diagnosis of GT was based on clinical features, platelet aggregometry and biochemical studies. Platelet surface expression of GPIIb/IIIa was also studied by flowcytometry. Molecular studies performed at Medical Genetics Department, Tsukuba University, Japan, include DNA sequencing of all exons and exon-intron junctions of ITGA2B and ITGB3 of the two genes by the ABI 3100 Genetic Analyzer®. [Applied Biosystems, Foster City, CA, USA]. Genomic DNA was also analyzed by Illumina Human-1 Bead Chip Illumina® (Illumina Inc., San Diego, CA, USA) to exclude the whole region of the two genes that could produce an apparent homozygous state.
Results : We have identified a novel nonsense causative mutation (Q694X) by sequencing the ITGB3 gene. [Figure 1a & b]. In addition, sequencing ITGB3 gene also revealed 2 SNPs (rs 3809863; IVS14+9C/T, rs 3809865; 3383T/A). The Micro-Array assay using Illumina Human-1 Bead chip excluded the possibility of deletion of these genes in chromosome 17 in this patient.
Summary/Conclusion: A stop codon was found in exon 13 of ITGB3 gene causing the translated protein to be abnormally shortened. It is hypothesized that the altered form of ITGB3 gene is both extremely unstable and rapidly degraded after its biosynthesis, leading to a loss of function of the protein. Further RNA expression studies, transfection tests and cDNA sequencing are ongoing to elucidate the molecular mechanisms responsible for GT.
Fig. 1 a] Structure of αIIbβ3 complex. The blue box indicates the position of the nonsense mutation in ITGB3 gene, which is clearly before the transmembrane (Red Box) AA sequence. 1 b] Electropherogram showing a nonsense mutation in exon 13 of ITGB3. Fig. 1. a] Structure of αIIbβ3 complex. The blue box indicates the position of the nonsense mutation in ITGB3 gene, which is clearly before the transmembrane (Red Box) AA sequence. 1 b] Electropherogram showing a nonsense mutation in exon 13 of ITGB3.
Selective Serotonin Reuptake Inhibitors Influence Agonist-Induced Platelet Aggregation. Preliminary Results from Comorbidity of Depression and Cardiovascular Disease Study
Authors: Iqbal Omer , Adiguzel Cafer , Fareed Jawed , Hoppensteadt Debra , Litinas Evangalos , Zhu He , Halaris Angelos 
Published: April 2020

Abstract
Selective serotonin reuptake inhibitors (SSRI) are a first-line treatment option for depressive illnesses, anxiety and obsessive-compulsive disorders with a favorable risk benefit ratio and side effects. They selectively inhibit neuronal reuptake of serotonin and result in depleted serotonin stores in the dense bodies of platelets. It is hypothesized that depressive illnesses cause platelet activation and endothelial dysfunction, which could be modulated by the use of SSRIs. In order to validate this hypothesis an institutional-based co morbidity of depression and cardiovascular study is undertaken. Patients with depression (n=25) and healthy control (n=25) are recruited in this study. Males and females between the ages of 20 and 65 years meeting the DSM-IV criteria for major depressive disorder served as the inclusion criteria for the study. The exclusion criteria included patients with heart disease, diabetes, lipid disorders, history of smoking, pregnant and lactating women, psychosis, schizoaffective illnesses and presence of other Axis I diagnosis with the exception of generalized anxiety disorder. Blood samples were collected at baseline and then 4 and 8 weeks following treatment with Escitaloprim, an SSRI. Preliminary results from the agonist-induced platelet aggregation showed varying degrees of inhibition of collagen, ADP, arachidonic acid and epinephrine-induced platelet aggregation as shown in the table below.
Agonist induced platelet aggregation profile Averaged % aggregation Time Collagen AA ADP Epinephrine Saline Baseline 71.5± 22.4 64.1± 35.1 48.15± 30.9 55.65± 29.2 6.9± 4.5 Week 4 63.4± 19.5 67.1± 25.1 33± 26.7 37.375± 25.8 9.375± 7.8 Week 8 74.7± 21.3 55.71± 36.1 52.4± 31 50.4± 32.3 5± 3.9
While a number of patients showed an inhibition of ADP (2.5μM) and epinephrine (10μg/ml) and collagen (380μg/ml), however, other patients showed an inhibition of collagen-induced platelet aggregation. These results indicate that patients treated with SSRIs may have inhibition of platelet activation and aggregation, which may have an impact in the prevention of atherothrombotic cardiovascular disease. SSRIs might increase the bleeding tendency in some patients by inhibiting platelet aggregation. However, when the SSRIs are given in combination with other drugs patients may have a propensity for bleeding complications due to drug-drug interactions. Further large-scale trials are warranted to validate these results.
Delayed Onset of T Cell-Mediated Xenogeneic Disease in Rag2−/− γc−/− mice after Co- Transplantation of in Vitro Expanded Human CD4+CD25highCD45RA+ Regulatory T Cells
Authors: Boeld Tina J , Obermann Ellen , Andreesen Reinhard , Hoffmann Petra , Edinger Matthias 
Published: April 2020

Abstract
In murine disease models, the adoptive transfer of donor CD4+CD25+ regulatory T cells (Treg) prevents lethal graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation. We recently described methods for the isolation and in vitro expansion of human Treg from adult peripheral blood and found that only CD45RA+ but not CD45RA− CD4+CD25high Treg (RA+ and RA− Treg, respectively) maintain FOXP3 expression as well as suppressive activity after prolonged culture (Hoffmann et al. Blood108:4260; 2006). Here, we compared the immunoregulatory capacity of these two different Treg subpopulations in vivo in a xenogeneic GVHD (xGVHD) model. Transplantation of 20x106 human peripheral blood mononuclear cells (huPBMCs) into immunodeficient BALB/c Rag2−/−γc−/− mice led to engraftment and extensive proliferation of human CD45+ cells (huCD45+), which was accompanied by clinical signs of xGVHD. Histological and flow cytometric evaluation revealed that mainly CD8+ T cells within PBMC caused xGVHD and that main targets were liver, lung and spleen as well as mouse hematopoiesis. When expanded CD45RA+ Treg were co-transplanted at a 1:1 ratio with CD4+ and CD8+ T cells contained in huPBMC, the frequency of huCD45+ cells in peripheral blood (PB) at d14 was reduced to 12 ± 4.9 % (n=15), while animals that received expanded RA− Treg had 30 ± 7.5 % (n=15) and animals without co-transfer of Treg 40 ± 8.3 % (n=14) huCD45+ cells. The expansion of conventional T cells, however, was only delayed but not prevented, as by d21 the percentage of huCD45+ cells in PB increased to 35 ± 9.2 % (n=15) when RA+ Treg were co-transplanted as compared to 40 ± 9.3 % (n=15) with RA− Treg and 50 ± 6.4 % (n=14) without Treg administration. Subsequently, all mice developed clinical signs of xGVHD and 73.3 % of mice co-transplanted with RA+ Treg, 86.7 % co-transplanted with RA− Treg and 78.6 % of mice transplanted with huPBMCs alone died within 100 days. Since Treg mainly inhibited early expansion of huPBMC, we examined the splenic cellularity of xeno-transplanted animals at d10 after cell transfer. While spleens of mice that received only huPBMC contained 20 ± 3x106 huCD45+ cells (n=10), co-transfer of RA− Treg reduced huCD45+ cells to 14 ± 4.8×106 (n=9) whereas animals that received RA+ Treg contained only 5 ± 1.1×106 huCD45+ cells (n=11) at that time. Furthermore, IL-2 and IFN-γ production of conventional T cells re-isolated from the spleen on d10 was reduced 5fold in mice co-transplanted with RA+ Treg as compared to recipients of only huPBMCs or additional RA− Treg. Thus, in vitro expanded human RA+ Treg suppress the proliferation and cytokine production of conventional T cells in early phases of xGVHD, but ultimately do not prevent disease onset and mortality.
CCR2 Mediates Hematopoietic Stem/Progenitor Cell Trafficking to Peripheral Tissues after Inflammation
Authors: Si Yue , Tsou Chia-Lin , Charo Israel 
Published: April 2020

Abstract
Hematopoietic stem cells (HSCs) are bone-marrow derived, self-renewing pluripotent cells that give rise to terminally differentiated circulating blood cells. HSCs have been implicated in parenchymal tissue repair in the setting of inflammation. In response to the antagonist of the chemokine receptor CXCR4, HSCs and their progenitors migrate from bone marrow to the blood. However, little is known about the signals that mediate their trafficking from the blood into peripheral tissues. Recently, we showed that mice genetically deficient in chemokine receptor CCR2 (CCR2−/− mice) have a marked decrease in the number of circulating “inflammatory” (7/4+, Ly6c+) monocytes, but no decrease in myeloid progenitor cells in the bone marrow (Tsou et al, J Clin Invest, 2007, 902). These data indicated that although CCR2 is not necessary for HSCs to differentiate into mature monocytes, it does play a role in monocyte egress from bone marrow to blood. In the current study, we extend this work and investigate the expression of CCR2 on HSCs, and tested the hypothesis that CCR2 is critical for the recruitment of circulating HSCs to sites of inflammation. We found that CCR2 was expressed on subsets of primitive HSCs and myeloid progenitors and mediated HSC movement in response to inflammation. Using traditional transwell chambers, we found that c-Kit+Lin− cells derived from bone marrow underwent chemotaxis in response to the CCR2 ligands MCP-1 (CCL2) and MCP- 3 (CCL7). To determine whether CCR2 mediates HSC movement in vivo, we treated wildtype mice with thioglycollate to induce aseptic inflammation. HSCs were actively recruited to the peritoneum, as shown by fluorescence-activated cell sorting and functional colony formation assays. In contrast, this response was profoundly impaired in CCR2−/− mice. To determine whether the clonogenic cells recruited to peritoneum were true HSCs, we performed competitive transplantation assays. Thioglycollate was instilled into wildtype CD45.2+ mice, and peritoneal Lin− cells were collected, purified, and infused, together with CD45.1+ bone marrow cells, into lethally irradiated CD45.1+ mice. Four months later, up to 12% of the leukocytes in the peripheral blood of these primary recipient mice were CD45.2+. At the time of sacrifice, bone marrow cells were collected from these mice and injected into lethally irradiated secondary CD45.1+ recipient mice. Two months following the transplantation, up to 9% of the blood leukocytes in these secondary recipient mice were CD45.2+, confirming that long-term repopulating HSCs were recruited to the inflamed peritoneum of the donor mice. These findings suggest a novel role for CCR2 in the recruitment of long-term repopulating HSCs to sites of inflammation and injury. We are currently investigating whether recruited HSCs and their progenitors hasten the resolution of the inflammatory response or promote the repair of injured tissue.