bluuebunny/crossref_metadata_2025_split huggingface dataset:
Philadelphia-Negative Clonal Hematopoiesis Following Imatinib Therapy in Patients with Chronic Myeloid Leukemia (CML).
Authors: Lin Yulia , Bruyere Helene , Horsman Douglas E. , Barnett Michael J. , Hogge Donna E. , Nevill Thomas J. , Nantel Stephen H. , Sutherland Heather J. , Toze Cynthia L. , Shepherd John D. , Lavoie Julye C. , Song Kevin W. , Smith Clayton A. , Forrest Donna L. 
Published: April 2020

Abstract
There is an increasing number of reports of Philadelphia-negative (Ph-) clonal hematopoiesis developing in patients (pts) with CML treated with imatinib. The significance of these abnormalities remains unclear. To examine the incidence, natural history and risk factors for the development of Ph- clones, we undertook a retrospective review of 142 consecutive pts with CML treated with imatinib and followed at VGH or BCCA between June 1999 and July 2004. Four pts were excluded due to incomplete records. Out of 138 pts, there were 76 (55%) males. The median age at diagnosis was 48.6 yrs (range 19.3–82.8). At the time of initiation of imatinib, 93 (67%) pts were in stable phase, 33 (24%) in accelerated phase and 12 (9%) in blast phase. 126 pts had received prior therapy with hydroxyurea (81%), interferon (53%), hematopoietic stem cell transplantation (17%), cytarabine (11%), or other therapy (17%). The median number of prior therapies was 2 (range 0–4). The median time from diagnosis to treatment with imatinib was 12.7 mos (range 0–240.1) and the median duration of imatinib therapy was 15.2 mos (range 0.6–45.1). Best responses to imatinib were complete hematologic response (96%), major cytogenetic response (53%) and complete cytogenetic response (43%). The event-free survival (EFS) at 3 yrs from the start of imatinib was 59% (95%CI 47–70%). Of the 138 pts, 7 (5%) pts developed Ph- clonal abnormalities: −7 and +8 (2 pts), +8 (2 pts), −7 (1 pt), −X and −22 (1 pt) and t(12;16) (1 pt). One pt had −7 and 1 pt had +8 in both Ph- and Ph+ cells. For the pts who developed Ph- clonal abnormalities, the median time from diagnosis to the start of imatinib was 28.4 mos (range 0.7–143.9). Six of these 7 pts had received prior therapy. The median time from the start of imatinib therapy to the development of the Ph- clone was 11.9 mos (range 2.7–23.5). All but two of the Ph- clones were transient and none was associated with myelodysplasia. Two of the 7 pts had progressed on imatinib. There was no difference in EFS or overall survival between pts with or without Ph- clones. In univariate analysis comparing characteristics of pts with and without Ph- clones, no predictive factors could be identified. In conclusion, the development of Ph- clonal hematopoiesis in pts with CML treated with imatinib occurred in ~5% of this series and did not appear to confer a worse prognosis. The majority of the Ph- clones included −7 and/or +8 and were transient without associated myelodysplasia. Finally, the observation of −7 (to our knowledge the first such case reported) or +8 in both Ph- and Ph+ cells in the same patient could be explained by the existence of a Ph- monoclonal state prior to the BCR/ABL mutation.
Chronic Myeloid Leukemia Patients Treated with Imatinib Show Increased IFN-Gamma Synthesis in T Cells and Hypogammaglobulinemia.
Authors: Gulbas Zafer , Akay Meltem O. , Sahin Fezan , Gunduz Eren 
Published: April 2020

Abstract
Background: In patients with untreated chronid myeloid leukemia(CML), lymphopoesis has been affected and Th1 cytokine levels are decreased. Imatinib tretment for CML has been shown to induce clinical and cytogenetic remission and increases plasmocytoid dendritic cells, affects lymphopoesis. Flow cytometry has been used to detect Th1 IFN-gamma, IL-2 and Th2 IL-4 cytokines in T cells.
Methods: 10 patients with CML before imitinib treatment, 29 patients after at least 2 months imatinib treatment and 10 healthy controls were tested to detect Th1 IFN-gamma, IL-2 and Th2 IL-4 cytokines in T cells using FITC, PE, PerCP monoclonal antibodies by flow cytometry(FacsCalibur,B.D.). Also; IgG, IgM, IgA levels by nepholometry and lymphocytes subpopulations by flow cytometry were detected.
Results: 10 patients before imatinib treatment showed decreased Th1 IFN-gamma, IL-2 and Th2 IL-4 cytokines in T cells according to the controls (p&lt;0.05). 29 patients after at least 2 months imatinib treatment showed increasing statistically important Th1 IFN-gamma cytokine but statistically insignificant increase IL-2 cytokine and Th2 IL-4 cytokines in T cells (Table 1). Hypogammaglobulinemia were developed 17% of the patients. No correlation was found imatinib treatment period and Th1 IFN-gamma, IL-2 and Th2 IL-4 cytokines in T cells.
Conclusions: Imatinib treatment increases Th1 IFN-gamma producing T cells and also causes hypogammaglogulinemia. This suggest that enhanced Th 1 cell function is achievable with imatinib treatment in patients with CML.
Percantage of Th1 IFN-gamma, IL-2 and Th2 IL-4 cells in CML patients and controls
before imitinib after imitinib healthy control CD4+IL-2+(%) 15+/− 13 25+/−14 44+/−12 CD4+ IFN-gamma+(%) 7+/− 5 11+/−7 15+/−2 CD4+ IL-4+(%) 1+/− 1 2+/− 1 4+/− 1
Prevalence of MDS in Shanghai, China Using the WHO Classification.
Authors: Irons Richard D. , Bao Liming , Wang Xiao Qin , Ryder John , Ji Jeirong , Du Xinyu , Gross Sherilyn A. , Chen Hui , Chen Yan , Kerzic Patrick J. , Fu Hua , Lin Guowei 
Published: April 2020

Abstract
The prevalence of subgroups of myelodysplastic syndrome (MDS) was determined in an unselected series of 92 patients presenting at Shanghai hospitals over a 10 month period. Diagnosis was established in a single laboratory, analyzing morphologic, immunophenotypic, fluorescence in situ hybridization (FISH) and cytogenetic data, according to the World Health Organization (WHO) revised classification. The frequencies of the major MDS subgroups were: refractory anemia (RA) 9.7%, refractory anemia with ringed sideroblasts (RARS) 1%, refractory anemia with excess blasts (RAEB) 15.2%, refractory cytopenia with multilineage dysplasia (RCMD) 52.6%, and MDS-unclassifiable (MDS-u) 7.6%. The subgroup, myelodysplastic/myeloproliferative diseases, unclassifiable (MDS/MPD-u) (9.7%) was also included for comparison with other studies. The median age at diagnosis for all cases was 57 yr. Males slightly predominated (53%). The overall incidence of clonal cytogenetic abnormalities was 24.7%. The most frequently encountered lesions were trisomy 8, 20q-, 5q- and 7q-. The prevalence of clonal cytogenetic abnormalities in each subgroup differed significantly from none in RA to 31% in RCMD. Deletions involving 5q- and 7q- were found predominantly in RAEB and RCMD subgroups. The incidence of MDS in China has been reported to be less than that in the West. However, information on the frequency of different subgroups of MDS in Shanghai previously has not been available. These cases presented at 24 hospitals serving a population of approximately 18 million. These results suggest major differences in the presentation and frequency of different subgroups of MDS between China and the West.
Predictive Progenitor Profiling in Chronic Myelomonocytic Leukemia.
Authors: Jamieson Catriona , Gotlib Jason , Coutre Steve , Li Kevin , Weissman Irving 
Published: April 2020

Abstract
Chronic myelomonocytic leukemia (CMML) is a unique myeloproliferative disease characterized by marrow dysplasia and an increase in monocytes. The median survival of patients with CMML is short, in part, because CMML is frequently resistant to therapy. In order to provide more effective CMML targeted therapies, a better understanding of the basic biology of CMML progenitors is required. We used FACS analysis and recently identified cell surface markers to identify phenotypic and functional differences between normal and CMML (n=14) bone marrow hematopoietic stem cells and myeloid progenitors. CMML marrow was typified by a reduction in CD34+CD38−CD90+(Thy1)Lin− hematopoietic stem cells and an expansion of CD34+CD38−CD90−Flk2+Lin- cells relative to normal bone marrow. In addition, there was a two-fold expansion in common myeloid progenitors (CMPs) and a corresponding decrease in megakaryocyte-erythroid progenitors (MEPs) suggesting that there was a skew in differentiation toward the myeloid lineage. In contrast to normal bone marrow derived CMPs, CMML CMPs gave rise to myeloid but not erythroid colonies. Moreover, real time quantitative RT-PCR analysis of highly purified FACS-sorted CMML CMPs demonstrated increased expression of two key regulators of myelomonocytic differentiation, PU.1 and c-jun, compared with normal bone marrow. A more detailed understanding of the basic biology of CMML myeloid progenitors and the genes that work in concert to expand them may aid in identifying novel molecular targets for CMML therapy.
Perforin Expressing CD4+T Cells Respond to CMV Antigens in CMV Seropositive Patients with B Cell Chronic Lymphocytic Leukaemia (B-CLL).
Authors: Walton James , Lawson Keirissa , Manoussaka Maria S. , Nathwani Amit , Emory Vincent , Lydyard Peter M. , Porakishvili Nino 
Published: April 2020

Abstract
Introduction: Perforin (PF) expressing CD4+ T cells are expanded in B-CLL patients [1] and are able to induce PF-mediated apoptosis of autologous leukaemic cells in the presence of bispecific anti-CD3/CD19 antibodies [2]. However, the role of the expanded PF+CD4+ T population in B-CLL remains unclear. In this study we have examined possible involvement of this cell subset in immune responses to cytomegalovirus (CMV).
Methods: Blood mononuclear cells from 11 CMV seropositive (SP) and 6 seronegative (SN) B-CLL patients were cultured for 4 and 18 hours in presence of Downe cell lysates containing CMV-antigen or cell lysates alone (control) and brefeldin and co-stimulated with anti-CD28 and anti-CD49 monoclonal antibodies. Anti-CMV response was assessed by flow cytometry as percentages of CD69+ and IFNγ+ cells in PF+ and PF- CD4+T cell populations.
Results: CD4+ T cells from 9 of 11 SP patients showed a strong increase in percentages of IFNγ+ cells after 18h, but not 4h, in culture with CMV antigens, compared to the control lysates and SN patients (Table) and healthy age-matched SP subjects (1.78±0.45, p=0.012). In contrast, none of the 6 SN patients as well as 2 out of 11 SP patients responded to CMV by increased IFNγ expression. In responders IFNγ+ cells were proportionally distributed between PF+ and PF- CD4+ T cells. High levels of cell activation measured by CD69 expression, especially in PF+ population, were mainly due to the Downe cell lysate since expression was significantly lower in lysate free cell cultures (8.3±11.5%, p=0.0018 for SP B-CLL patients). Anti-CMV response was accompanied by a decrease in percentages of CD4+PF+ cells suggesting antigen-induced degranulation.
Conclusion: PF+CD4+ T cells respond to CMV antigens suggesting an expansion of mature CMV specific cytotoxic CD4+ T cells in the majority of CMV seropositive B-CLL patients.
IFN-γ and CD69 expression by CD4+PF+ and PF- T cells after 18h exposure to CMV+ and CMV- lysates in CMV seropositive and seronegative B-CLL patients
CD4+ PF+ CD4+ PF-CD4+ SN SP SN SP SN SP IFN- γ, % CMV+lys 0.7±0.58 9.1±7.9 2.0±3.0 p=0.013 14.4±13.6 0.61±0.56 p=0.008 9.0±8.1 CMV−lys 0.26±0.34 0.9±1.7 p=0.007 1.1±1.7 3.9±6.9 p=0.029 0.24±0.27 1.46±2.55 p=0.013 CD69+cells, % CMV+lys 16.3±14.2 21.4±13.0 41.9±35.1 51.2±30.3 14.9±13.4 20.4±13.2 CMV−lys 14.4±12.8 9.7±7.8 28.6±34.8 39.8±33.0 13.8±12.1 12.9±15.0
A Phase I/II Study of the Oral mTOR Inhibitor RAD001 in Patients with Advanced Hematologic Malignancies.
Authors: Yee Karen W.L. , Wierda William , O’Brien Susan , Thomas Deborah , Kurzrock Razelle , Fayad Luis E. , Hagemeister Fredrick B. , Cortes Jorge , Prestifilippo Judith , Szatrowski Ted P. , Kantarjian Hagop M. , Giles Francis J. 
Published: April 2020

Abstract
RAD001 (everolimus, Novartis) is an orally bioavailable derivative of rapamycin with demonstrated anti-proliferative activity against a broad panel of tumor cell lines and antitumor activity in experimental animal models of human cancer. RAD001 inhibits the mammalian target of rapamycin (mTOR) signaling pathway, which is involved in regulating many aspects of cell growth and cell cycle progression. Several lines of evidence implicate the importance of the PI3K/Akt/mTOR pathway in hematological malignancies. As there has been extensive experience with this agent in the solid organ transplantation setting, two dose levels (5 and 10 mg/day) were evaluated in the Phase I portion of this study to determine the maximum tolerated dose (MTD) to be used in the Phase II portion. RAD001 was administered orally once a day at the starting dose level of 5 mg. Fifteen patients have been enrolled, of which 14 (3 B-CLL, 4 MDS, 1 MF, 1 NK/T cell lymphoma/leukemia, 1 MCL, 3 AML, 1 T-PLL) were evaluable for safety and toxicity. Median age was 65 years (range, 56 to 76 years). Twelve patients (86%) had received prior therapy (median, 2 regimens; range, 0 to 6 regimens). Median time on study was 29 days (range, 12 to 105 days). No dose-limiting toxicities were observed in the 6 patients enrolled in the Phase I portion of the study (cohorts of 3 patients per dose level). The most common adverse events were grade ≥ 2 and consisted of hyperglycemia, hyperlipidemia, hypocalcemia, hypomagnesemia, hypophosphatemia and hypokalemia, transaminitis, diarrhea, dermatitis, and mucositis. Grade 3 toxicities consisted of asymptomatic hypophosphatemia (2), and hyperglycemia (3). No patient experienced grade 4 toxicities or death from RAD001. Of the 14 evaluable patients, 2 patients with B-CLL had a 33% and 65% reduction in the size of lymph nodes, respectively, and 1 patient with MDS had decreased transfusion requirements. At the time of analysis, only 1 patient had discontinued therapy due to disease progression. These preliminary findings indicate that RAD001 is well tolerated at a daily dose of 10 mg/day and may have clinical activity in patients with hematologic malignancies. Enrollment is ongoing.
Successful Treatment of Cutaneous Chronic Lymphocytic Leukemia with a Topical Toll Receptor 7/8 Antagonist (Imiquimod).
Authors: Hicks Lisa , Mena J. , Spaner D. E. 
Published: April 2020

Abstract
Background: B cells express toll-like-receptor-7 (TLR7), a powerful modulator of inate immunity. We hypothesized that the immunogenicity of indolent B cell lymphomas and leukemias could be increased through activation of the TLR7 pathway. This might lead to increased immune clearance of malignant cells. Imiquimod 5% (an imidazoquinolone) has recently been identified as a TLR 7/8 agonist. It is available as a topical formulation and has demonstrated activity against condylomata as well as skin carcinomas. A small number of case reports also suggest activity against cutaneous T cell lymphoma.
Case: A 71 year old Caucasian man presented with Rai Stage 0 CLL. For approximately 8 years prior to presentation, he suffered recurrent, erythematous, nodular lesions on his hands, arms and torso. The lesions were removed with liquid nitrogen but recurred. At the time of diagnosis with CLL, several lesions were present. Biopsy demonstrated a diffuse infiltrate of small round lymphocytes without epidermotropism. CD20 staining was positive. Molecular analysis confirmed a monoclonal B cell population consistent with B cell lymphoma. The patient was otherwise asymptomatic and did not warrant conventional therapy for CLL. Based on the safety and efficacy of imidazoquinoline in other skin cancers, he was offered and consented to a trial of this therapy. The drug was applied to the affected area 3x per week as recommended for treatment of genital warts. After 8 weeks, an area of hypopigmentation had formed, however the size of the lesion had not decreased. The frequency of application was increased to 1x per day. Over a 6 week period the lesion gradually disappeared. Six months after stopping the drug, the lesion has not recurred. No side effects were noted. Untreated lymphomatous lesions and peripheral blood lymphocyte counts did not change over the course of treatment.
In vitro Data: We hypothesized that Imiquimod might increase the immunogenicity of CLL cells by increasing their surface expression of costimulatory molecules. To investigate this hypothesis, the above patient’s CLL cells were isolated (with his consent) directly through negative selection and then incubated for 48h with an active soluble imidazoquinalone or with a control. Expression of co-stimulatory molecules was determined by flow cytometry pre and post-incubation. CD80, 83, 86 and 54 surface expression were found to be increased significantly by TLR-7 agonists in vitro.
Conclusion: We report the first case of Imiquimod activity against a cutaneous B cell lymphoma. We propose that the drug increases co-stimulatory molecule expression by malignant B cells, thereby facilitating cytotoxic T cell activation and killing of CLL cells. We believe that further study of TLR7 agonists is warranted in B cell malignancies.
What Is Important Factor of Bone Disease in Multiple Myeloma?.
Authors: Munemasa Shoso , Sakai Akira , Okikawa Yoshiko , Kuroda Yoshiaki , Katayama Yuta , Asaoku Hideki , Kimura Akiro 
Published: April 2020

Abstract
New International Prognostic Index (IPI) staging system of multiple myeloma (MM) is a combination of the level of serum β2-microglobulin and serum albumin. Particularly, good survival (median survival &gt;5 years) is associated with absence of chromosome 13q deletion. Recently, correlations between molecular subtypes and prognosis have been identified as a good prognosis with t(11;14) and a poor prognosis with t(4;14) and t(14;16) besides chromosome 13 abnormalities. We have reported that some MM cases with cyclin D1 overexpression detected by competitive RT-PCR were not caused by t(11;14)(q13;q32) or extra copies of 11q13 (In J Oncol, in press). A recent report revealed that subtypes of MM cases with the translocation of cyclin D showed a close correlation with bone disease and high level of DKK1. We also have been studing about the correlation between bone disease and bone morphogenetic protein (BMP) 2, or connective tissue growth factor (CTGF) that is supposed to inhibit the VEGF binding to its receptor or modulate cell signaling by BMP. First, we analyzed IPI staging in 91 MM cases, and then analyzed the relation between IPI staging and existence of cyclin D1 overexpression, or t(11;14)(q13;q32) and extra copies of 11q13. Competitive RT-PCR was performed in 77 cases, and cyclin D1 overexpression was detected in 40/77 (52%). Deletion of chromosome 13q was detected in 32/87 (37%), and t(11;14)(q13;q32) or extra copies of 11q13 was detected in 11/50 (22%) and 7/50 (14%), respectively. There were no significant differences of those factors among IPI staging. And we analyzed the scale of bone lesion by bone x-ray in 81 cases. We could not detect the relation between bone disease and cyclin D1 overexpression or translocation of 11q13. Furthermore, we analyzed the expression of BMP2 and CTGF by quantitative real time-PCR in purified myeloma cells or in bone marrow mononuclear cells (BMMNC) reduced myeloma cells less than 5%. We have gotten results that MM cases have a tendency to show higher CTGF expression in BMMNC compared with that of normal BM, but there was no significant difference of BMP2 expression in BMMNC between them. And there was no correlation between cyclin D1 overexpression and BMP2 or CTGF expression. So far a cause of bone lesions in MM is supposed to be the activity of osteoclast, however, our preliminary examination by TRAP staining revealed that osteoclast differentiation from BMMNC in MM cases by adding M-CSF (25 ng/ml) and RANKL (50 ng/ml) decreased compared with that in normal BM, and osteoblast diffentiation also decreased in MM by cytochemical staining for alkaline phosphatase (AP). We guess that both osteoclast and osteobalst differentiation are suppressed in MM and CTGF is a candidate for the suppressor of osteoblast differentiation. We will be able to show the result of AP activity of osteoblast and the effect of recombinant CTGF on osteoblast in meeting.
An Edible, High Molecular Weight Glycoprotein Fraction from Ganoderma Lucidum Inhibits the Akt Pathway in Resistant Myeloma Cell Lines Decreasing Mcl-1 Expression, Up-Regulating FKHR and Inducing Apoptosis.
Authors: Sultana Nazneen , Verda Larissa , Burt Richard K. , Traynor Ann E. 
Published: April 2020

Abstract
We observed apparent synergy between dexamethsone and a nutritional supplement taken by a patient with poor prognosis plasma cell leukima. The rapidity of the clinical remission induction and the duration of remission, which was sustained without consolidation, suggested possible inhibition of the Akt pathway. A review of the supplements ingested indicated two mycelial derivatives, one of which was Ganoderma Lucidum, (Ling-Zhi, Reishi) a traditional Chinese medicine used to prevent kidney and liver disease and to promote anti-tumor immunity. We obtained a known quantity of certified shell broken spore of G Lucidum from China. Dissolved in 70 degree C water and then diluted as a 2.5% v/v solution in RPMI1640, it induced apoptosis of 80% of OPM6 cells by 72 hours, which was only marginally improved by the addition of1uM dexamethasone. It induced 70% cell death in MM.R cells by 72 hours. This was associated with a 90% reduction in measurable Mcl-1 by Western blot after two hours of incubation. In additon phosphorylation of FKHR was reduced 70% at 2 hours and was undetectable after 72 hours. Phosphorylation of Akt at threonine 308 was reduced 75%. To further purify this activity we separated out molecular weight fractions by Centricon centrifugation. We were able to 10 fold concentrate the active material in the &gt;100,000 MW fraction by centrifugation. Used in the same relative dilution of 2.5% v/v, this concentrate killed between 90% and 96% of glucocorticoid resistant cells at 72 houyrs. Of interest the concentrate induced a lesser degree of apoptosis in corticosteroid sensitive cells, but enhanced the activity of dexamethasone. Spectrophotometry followed by oxidation with sodium meta-periodate and measurement absorption at 550 nm suggested a glycoprotein enrichment in this concentration. Further isolation of the active component of this fraction is underway in order to determine if it is the Lin-Zhi 8 protein sequenced in 1991 or a distinct glycoprotein from the Ganoderma Lucidum. It appears to be an orally tolerable inhibitor of the Akt pathway. It also shows activty in rheumatoid arthritis synovium RAS cells and may have usefulness in T cell supression and graft tolerance.Pre-clinical testing in a SCID mouse model has been begun.