bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical Characteristics of T-Cell Lymphoma Associated Hemophagocytic Syndrome: Comparison of T-Cell Lymphoma with and without Hemophagocytic Syndrome.
Authors: Tong Hongyan , Ren Yanling , Xiao Feng , Mai Wenyuan , Meng Haitao , Qian Wenbin , Jin Jie 
Published: April 2020

Abstract
T-cell lymphoma associated hemophagocytic syndrome (T-LAHS) has been regularly reported in Asia countries and is considered with extremely poor prognosis. The rate of definite diagnosis during early stage is low and the therapeutic outcome has been disappointed. We therefore compared T-cell lymphoma patients with and without hemophagocytic syndrome (HPS) in order to have a better understanding of the clinical characteristics of T-LAHS. One hundred and thirteen patients (66 men and 47 women, age from 12 to 80 years with the median age of 42) with aggressive T-cell lymphoma admitted to our department between January 2000 and December 2005 were included in this study, while 28 of them were with T-LAHS. The patients were divided into LAHS group and no-LAHS group. The clinical data including clinical manifestations and laboratory findings were compared between the two groups by using Chi-square test. The method of Kaplan and Meier was used to analyze overall survival (OS). The results showed that LAHS occured in about 1/4 of all the patients with T-cell lymphoma, which were all aggressive type. The elevated rates of lactate dehydrogenase (LDH) and ferritin were much higher in LAHS group than in no-LAHS group. β2-microglobulin and ovarian cancer antigen (CA125) were also elevated in both groups, but there was no significant difference. The rate of hypo-fibrinogen and liver dysfunction were higher in LAHS group than that in no-LAHS group. The rate of bone marrow infiltration in LAHS group is remarkably higher than that in no-LAHS group (57% vs 32%, p&lt;0.05). The median survival was 40 days (16 days - 22 months) in the LAHS group, and the median survival of 11 patients accepted chemotherapy more than 2 courses was 6 months. By contrast, the 2-year survival for no-LAHS group was 43%. There was significant difference between the two groups. Three patients undergoing plasmapheresis as initial therapy had survived for 3–6 months. These results indicate that high suspicion is required for early diagnosis of T-LAHS. In patients with fever, hepatosplenomegaly and cytopenia, simultaneously with serum markers such as LDH, ferritin, TG, CA125, and β2-microglobulin constantly increasing, T-LAHS should be considered. For patients without extranodal invasion or enlargement of lymph nodes, repeating biopsy of multiple sites of bone marrow may help improving the diagnosis rate. As for treatment, other more intensive regimens were not superior to CHOP regimen. While the overall outcome of treatment is still unsatisfied, plasmapheresis as initial therapy is worth considering.
Thalidomide Combinations Improve Response Rates; Results from the MRC IX Study.
Authors: Morgan Gareth J. , Davies Faith E. , Owen Roger G. , Rawstron Andrew C. , Bell Sue , Cocks Kim , Gregory Walter , Jackson Graham , Drayson Mark T. , Jenner Matthew W. , Child James A. 
Published: April 2020

Abstract
Improving response rates represents an important way to improve PFS and OS in myeloma. In the MRC Myeloma VII study, now with a median follow up of 8 years, we showed the importance of achieving CR. The addition of thalidomide represents a way of increasing response rates. In the MRC Myeloma IX study, which has recruited 1800 patients, in two randomisations embracing younger and older patients, we have compared CTD with MP and CTD + HDM + ASCT with CVAD + HDM + ASCT. In addition to giving insight as to the impact of thalidomide on ORR and CR in both settings, we can assess the effects of HDM + ASCT following CTD induction. We have used a number of techniques to assess response in this study including protein electrophoresis, immunofixation and serum free light chain estimation combined with bone marrow aspiration and trephine assessment. This approach has been supplemented by sensitive multiparameter flow cytometry MRD analysis able to quantitate low levels of residual myeloma plasma cells. In a preliminary analysis, a thalidomide containing combination is associated with improved response rates. Post induction rates are CTD: ORR 95.7%, CR 20.3%; CVAD: ORR 83.4%, CR 11.7% and these differences are maintained at 100 days post HDM, CTD + HDM: ORR 98.7%, CR 58.2%; CVAD + HDM: ORR 95.7, CR 41%, showing that the ORR rate is higher and that the percentage of CR is doubled before HDM and 20% more following the HDM. The depth of CR is also greater in the cases receiving thalidomide. We are updating these results as well as the results from the MP vs CTD comparison and will present these data. There are some discrepancies between each of the disease monitoring approaches and optimally all should be used. At d+100 it is possible to have true CR measured by flow MRD assessment but still have detectable paraprotein. The opposite also occurs: apparent CR by paraprotein estimation with MRD positivity by flow. This has important implications for the definition of remission as well as for the assessment of new treatments and their use. Our findings suggest that thalidomide combinations significantly improve ORR, taking more patients to response levels which render them eligible for HDM + ASCT. CR rates are increased and there is a qualitative difference in the depth of CR obtained. The additive value of HDM + ASCT, even when thalidomide is used initially, is suggested by the further increase in the number of responses above that achieved by CTD alone. We await the follow up of patients entered into this large study to assess whether these increased and enhanced responses translate into improved PFS and OS.
Dose Definition for Intravenous Cyclophosphamide in Combination with Bortezomib/Dexamethasone for Remission Induction in Patients with Newly Diagnosed Multiple Myeloma.
Authors: Kropff Martin , Liebisch Peter , Wand Hannes , Weisel Katja , Gann Claudia-Nanette , Knop Stefan , Einsele Herrmann 
Published: April 2020

Abstract
This study was designed to determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), safety, and efficacy of intravenous cyclophosphamide (CY) in combination with the proteasome inhibitor bortezomib and high-dose dexamethasone (DEX) for remission induction in younger patients with newly diagnosed multiple myeloma (MM). Patients ≤ 60 years were enrolled to receive three 3-week treatment cycles with bortezomib 1.3 mg/m2/dose on days 1, 4, 8, and 11 in combination with DEX 40 mg/day orally on the day of bortezomib injection and the day thereafter. In addition, patients received CY intravenously on day 1 at either 600, 900, 1200, or 1500 mg/m2 - the optimal dose had to be defined. Recommended concomitant medication included bisphosphonates, antacids, prophylactic antiviral treatment, prophylaxis against pneumocystis pneumonia, and oral non-absorbable antifungal medication. In addition, antiemetics, cytokines, and intravenous immunoglobulins were allowed. DLT was defined using the National Cancer Institute common terminology criteria for adverse events, version 3.0 as grade 4 hematologic toxicity, ≥ grade 3 non-hematologic toxicity (except emesis, vomiting, and alopecia), ≥ grade 3 peripheral neuropathy, and ≥ grade 2 peripheral neuropathy with pain. MTD was defined as the highest dose studied for which the incidence of DLT was ≤ 33%. Thirty patients completed 78 treatment cycles. Twenty seven patients were evaluable for CY dose definition. Start dose level for CY was 1200 mg/m2. Since no patient experienced a DLT the dose level was increased to 1500 mg/m2. On this dose level a DLT occurred in 2/3 patients (67%). Therefore the dose level was decreased again to 1200 mg/m2 with 4/12 (33%) of patients experiencing DLT. On the next lower dose level a DLT was observed in 8% (1/12). Thus, the MTD for CY in combination with bortezomib and DEX based on cycle 1 was defined as 900mg/m2. Dose-limiting toxicities included leukopenia (n=5), neutropenia (n=1), and pneumonia (n=1). No patient died. Other adverse events not reaching dose-limiting intensity included thrombocytopenia, gastrointestinal irritations, fatigue, neuropathy and one patient with herpes zoster. Median time to best response was 63 days. The overall response rate (EBMT criteria) to up to three cycles of this combination was 87%, with 3 complete responses, 20 partial responses and 3 minor responses. No patient experienced progressive disease. Bortezomib combined with DEX and CY is a highly effective treatment for newly diagnosed MM. Recommended phase II/III dose of CY in this combination is 900 mg/m2. This schedule is currently being evaluated as pretransplant induction in newly diagnosed MM in a prospective trial of the Deutsche Studiengruppe Multiples Myelom (DSMM).
Chromosomal Abnormalities in the Early Stem Cell Population of CML Patients in Complete Cytogenetic Remission.
Authors: Bumm Thomas G.P. , Newell Amy Hanlon , Oost Jay , VanDyke Jonathan , Olson Susan B. , Druker Brian J. , Deininger Michael W.N. 
Published: April 2020

Abstract
Clonal cytogenetic abnormalities, most commonly involving chromosomes 7 and 8, are detectable by conventional karyotyping in Ph-negative metaphases of some chronic myeloid leukemia (CML) patients with a major cytogenetic response (MCyR) to imatinib. It is unknown whether these abnormalities involve the primitive progenitor cell compartment, and whether their frequency in this compartment may exceed the frequency detected by karyotyping. To answer these questions we analyzed lineage-negative CD34+/CD38− and CD34+/CD38+ cells from CML patients in complete cytogenetic response (CCyR), using by fluorescent in situ hybridization (FISH) for chromosome 7 and 8 abnormalities and BCR-ABL.
Methods: Mononuclear cells (MNC) were selected from the bone marrow of patients with CCR by Ficoll-Hypaque density gradient centrifugation and enriched for lineage-negative cells using an immunomagnetic column. Lineage-negative cells were further sorted into CD34+/38− and CD34+/38+ cells by multicolor FACS. Interphase FISH analysis was performed using 7 LSI D7S522 Spectrum Orange / CEP7 Spectrum Green (chromosome 7), CEP8 Spectrum Aqua (chromosome 8) and LSI BCR/ABL +9q34 TriColor Dual Fusion Probe. Thus far, 5 CML patients with CCR (3 with a normal karyotype and 2 with trisomy 8) and 1 normal control have been analyzed.
Results: Of the three CML patients in CCR with normal karyotype, one had 9% deletion 7q (internal cut off of 0.5%) and the second 1.2% trisomy 8 (just over the internal cut off of 1%) cells in the CD-34+/38− population, while the CD-34+/38+ cell population did not show abnormalities. The third CCR patient had no abnormalities in the CD-34+/38− and CD-34+/38+ cell populations. Two CML patients in CCR with 45% trisomy 8 abnormal cells by conventional cytogenetics had 44% and 60% trisomy 8 positive cells in the CD34+/38+ population (two few CD34+/CD38− cells were available for analysis). No BCR-ABL signal was detected in any cell. In the healthy control, the CD34+/38+ cells were normal, but 4.1% of CD34+/38− showed a deletion of 7q.
Conclusion: Clonal chromosomal of chromosomes 7 and 8 in Ph-negative primitive hematopoietic progenitor cells may be more common than suggested by conventional karyotyping. A larger cohort of CML patients in CCR and healthy individuals is under study to determine if this phenomenon is indeed related to CML or occurs also in normals. Results will have implications for the interpretation of karyotypes in patients with hematologic malignancies.
A Phase II Trial of Myeloma Induction Therapy with Cyclophosphamide, Bortezomib, and Dexamethasone (Cybor-D): Improved Response over Historical Lenalidomide-Dexamethasone Controls.
Authors: Reeder Craig B. , Reece Donna E. , Fonseca Rafael , Bergsagel P. Leif , Hentz Joseph , Pirooz Nicholas A. , Boesiger Jacy E. , Pisa Jesus G. , Kukreti Vishal , Chen Christine , Trudel Suzanne , Mikhael Joseph R. , Lacy Martha , Rajkumar S. Vincent , Stewart A. Keith 
Published: April 2020

Abstract
Background: We previously reported an 85% response rate with 54% CR/nCR using a combination of cyclophosphamide (Cy), prednisone, and bortezomib (BZ) in relapsed myeloma (MM). We now report a Phase II clinical trial using a combination of Cy, BZ, and dexamethasone (Dex) [Cybor-D] in newly-diagnosed MM. We then compare the activity of this combination with historical controls treated with our current induction standard of Lenalidomide-Dexamethasone (L-Dex).
Methods: 30 patients have been enrolled on Cybor-D. Treatment consists of Cy 300mg/m2 p.o. days 1, 8, 15, and 22; BZ 1.3 mg/m2 days 1, 4, 8, and 11, and Dex 40mg p.o. days 1–4, 9–12, 17–20. Prophylactic use of acyclovir, a quinolone and antifungal prophylaxis was highly recommended for all patients on study. Growth factors were allowed. As a relevant contemporaneous control for speed and depth of response, we used 33 patients treated on a recent Mayo Clinic trial of L-Dex (Rajkumar. Blood: 2005 106;4050–3). Response was defined according to IMWG criteria although in the current trial, bone marrows for confirmation of CR are not yet available on all patients.
Results: At time of current analysis, 17 patients on Cybor-D were evaluable through at least one cycle for response and toxicity. Baseline characteristics included mean age of 57, 29% female, 41/24% ISS stage II/III. There were statistically more early stage patients on L-Dex; otherwise, baseline patient characteristics were similar. The mean % decline in monoclonal (M) protein from baseline following cycles 1–4 of Cybor-D were 71%, 90%, 93%, 96%. This compares favorably with L-Dex where equivalent % decline in M proteins were 66%, 77%, 80%, and 79%. Thus, in preliminary results, Cybor-D produces a more rapid initial decline and mean % reduction in M protein than L-Dex. Overall response rate (≥ PR) after one cycle of Cybor-D was 77% with 36% obtaining ≥VGPR (L-Dex 73% and 18% respectively). The % of patients obtaining ≥VGPR after each cycle was 36%, 64%, 77%, and 100% for Cybor-D as compared to 18%, 36%, 42%, and 33% for L-Dex. The overall ≥VGPR at the end of four cycles of Cybor-D is currently100% (≥ 66%nCR using older nomeclature). Major toxicities ≥ grade 3 for Cybor-D included hematologic (37%), hyperglycemia (15%) and neuropathy (11%).
Conclusions: In summary, for newly-diagnosed MM patients, four cycles of Cybor-D produces more frequent, rapid and deep responses when contrasted with historical L-Dex controls. Further confirmation of response rates and effect on TTP will be required.
Deletion of Murine Kininogen Gene 1 (mKNG1) Causes Loss of Plasma Kininogen and Delays Thrombosis.
Authors: Merkulov Sergei , Komar Anton A. , Schmaier Alvin H. , Barnes Ellen , Zhou Yihua , Lu Xincheng , Lou Guangbin , McCrae Keith R. 
Published: April 2020

Abstract
High molecular weight kininogen (HK) plays an important role in the assembly of the plasma kallikrein-kinin system. While the human genome contains a single copy of the kininogen gene, three copies exist in the rat (one encoding K-kininogen and two encoding T-kininogen). Here, we confirm that the mouse genome contains two homologous kininogen genes, mKng1 and mKng2. These genes are located on chromosome 16 in a head to head orientation with ∼ 30 kB intervening sequence, and are expressed in a tissue-specific manner. To determine the roles of these genes in murine development and physiology, we disrupted mKng1, which is expressed primarily in the liver. mKng1−/ − mice were viable, and immunoblotting using anti-bradykinin antibodies indicated a marked reduction in plasma HK and low molecular weight kininogen (LK), as well as ΔmHK-D5, a novel kininogen isoform that lacks kininogen domain 5. Clotting studies were also consistent with marked HK deficiency. Moreover, despite normal tail vein bleeding times, mKng1−/− mice displayed a significantly prolonged time to carotid artery occlusion following Rose Bengal administration and laser induced arterial injury. These results suggest that a single gene, mKng1, is responsible for production of plasma kininogen, and that plasma high molecular weight kininogen may contribute to induced arterial thrombosis in mice.
SHIP-1 Differentially Regulates Dense Granule Secretion in Platelets through Its Association with Protein Kinase C δ.
Authors: Chari Ramya , Kim Soochong , Murugappan Swaminathan , Daniel James L. , Kunapuli Satya P. 
Published: April 2020

Abstract
Collagen-induced glycoprotein (GP) VI-mediated and thrombin-induced protease activated receptors (PAR)-mediated activation are important signaling pathways regulating dense granule secretion in platelets. Protein kinase C (PKC) isoforms play a crucial role in platelet secretion and we have previously shown that PKCδ plays a ying-yang role in dense granule release by different agonists (Murugappan et al, J. Biol. Chem. 2004). PKCδ isoform positively regulates PAR-mediated platelet dense granule release, whereas it negatively regulates GPVI-mediated dense granule release. In this study, we investigated the mechanism of such differential regulation by PKCδ downstream of PAR and GPVI pathways. We hypothesize that the differential association of PKCδ with phosphatases downstream of GPVI and PAR receptors differentially regulate dense granule secretion. More specifically, we explored the functional relevance of the interaction of PKCδ with Src homology 2-domain containing Inositol Phosphatases (SHIP), 5′-inositol phosphatases in platelets. In our studies, SHIP-1 was tyrosine phosphorylated by both PARs and GPVI receptors and its phosphorylation followed different activation kinetics. Whereas PAR-mediated SHIP-1 phosphorylation (Y1020) was delayed and occurred as late as 120 seconds, the GPVI-mediated SHIP-1 phosphorylation was rapid, starting as early as 15 seconds and peaked at 60 seconds. Co-immunoprecipitation experiments revealed that SHIP-1, and not SHIP-2, associated with PKCδ upon stimulation of platelets with GPVI agonist, convulxin. However, such association did not occur with the PAR agonists. GPVI-mediated SHIP-1 phosphorylation failed to occur in platelets from mice lacking Lyn kinase suggesting a role for Lyn in regulating SHIP-1 phosphorylation. In murine platelets lacking either Lyn or SHIP-1, dense granule secretion was potentiated by convulxin and not by thrombin. We attribute the phosphorylation and association of SHIP-1 with PKCδ to be critical for the regulation of agonist-induced dense granule secretion in platelets. Based on the above results, we conclude that the preferential association of SHIP-1 with PKCδ upon stimulation of GPVI receptor results in the negative regulation of collagen-induced dense granule release in platelets.
Loss of Sema4D Signaling in Platelets Impairs the Formation and Stability of Arterial Thrombi In Vivo and Reduces Myocardial Infarct Size.
Authors: Zhu Li , Stalker Timothy J. , Wang Tao , Jiang Hong , Kumanogoh Atushi , Kikutani Hitoshi , Gruber Peter , Brass Lawrence F. 
Published: April 2020

Abstract
Contact-dependent signaling between platelets helps to promote thrombus growth and stability. One mechanism for contact-dependent signaling involves the binding of cell surface ligands to corresponding receptors on the surface of adjacent cells. In our efforts to identify novel participants in this process, we have recently reported that platelets express on their surface the semaphorin family member, sema4D, and its two known receptors, CD72 and plexin-B1 (Zhu, et al, PNAS, 2007). We have also shown that although their initial tail bleeding time is normal, platelets from sema4D(−/−) mice have a defect in collagen-induced signaling and platelet aggregation in vitro. In the present studies, we used matched sema4D(−/−) and wild type (WT) mice to examine the consequences of impaired sema4D signaling in models of platelet function in vivo. In the first model, irradiated Rose Bengal dye was used to produce an arteriolar injury in an exteriorized cremaster muscle. Platelets were identified with a fluorescent CD41 antibody and detected in real time using digital microscopy. The results showed that thrombus formation occurred in all of the mice that were tested, but while stable occlusion was observed in approximately half of the control mice, none of the sema4D(−/−) mice developed stable occlusions during the period of observation (p&lt;0.02). Similarly, when a laser was used to produce a focal injury in cremaster muscle arterioles, both the initial rate of platelet accumulation and the peak extent of accumulation were approximately 50% lower in the sema4D(−/−) mice than in the matched controls. To test the contribution of sema4D to platelet responses in a larger artery, the right common carotid was injured by transient exposure to FeCl3 and changes in flow were measured using a Doppler probe. The results showed that the time to occlusion was 35% greater in the sema4D(−/−) mice than in controls (p&lt;0.02). Furthermore, stable occlusion occurred in only 9 of 16 (56%) sema4D(−/−) mice Vs. 7 of 9 (78%) WT mice. Finally, myocardial infarct size was measured in an ischemia/reperfusion injury model 48 hrs after transient ligation of the left anterior descending coronary artery. Although infarction occurred in all cases, infarct volume was 56% smaller in the sema4D(−/−) mice than the matched controls (p&lt;0.01). In summary, these results show that there is a substantial impairment of platelet function in vivo in mice that lack sema4D. This impairment was observed in both arterioles and arteries using several different methods to evoke platelet activation. When combined with our earlier observations, the results show that signaling by sema4D and its receptors provides a novel mechanism to promote thrombus growth and stability.