bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interferon Therapy Is Predictive Factor for Improved Survival in Patients with Essential Thrombocythemia (ET).
Authors: Jabbour Elias , Harb Antoine , Giles Francis , Cortes Jorge , Pierce Sherry , Shan Jianqin , Estrov Zeev , Kantarjian Hagop , Verstovsek Srdan 
Published: April 2020

Abstract
Essential thrombocythemia (ET) is a Philadelphia chromosome-negative Myeloproliferative Disease characterized by a relatively indolent clinical course, a predisposition to thrombotic and bleeding events, and a delayed occurrence of disease transformation into myelofibrosis (MF) or acute myelogenous leukemia (AML) in selected patients (pts). Current therapy for ET has not been shown to affect in a positive way either survival or risk of disease transformation.
We retrospectively assessed 158 pts with ET seen at our institution between November 1983 and February 2006, and evaluated their long-term outcome, risk of disease complications and transformation, and prognostic factors for both survival and disease complications. Median age was 51 years (range, 17–83), 59% were females. The median time from diagnosis to MD Anderson visit was 5 years (range 0–21) and from MD Anderson visit median follow up was 1.5 years (range 0–19). Fifty-two % of pts had received therapy before MD Anderson visit. At presentation 53% of the pts were symptomatic, including fatigue in 32%, weight loss in 8%, headache in 7%, and night sweats in 5%; splenomegaly was present in 18 pts (11%); median hemoglobin was 13.3 g/dL (range 7.1–16.6), white blood cell count 9.4 × 109/L (range 1.9–21.9), and platelets 909 × 109/L (range, 153–1000 × 109/L); karyotype was diploid in 129 of 139 evaluable pts (93%).
During the follow up 34 pts (22%) have never received any cytoreductive therapy, while 66 pts (42%) received more than one therapy. Therapy included hydroxyurea in 71 (45%), anagrelide in 47 (30%), and interferon/pegylated interferon in 67 pts (42%). Thrombotic and bleeding events occurred in, respectively, 33 (21%; 22 arterial and 11 venous thrombosis) and 29 (18%) pts. Transformation to MF occurred in 7 (4%) pts after a median of 73 months (range 5–159). At tranformation the karyotype was diploid in all but one pt (+1, der (1;17)(q10;q10), +8). Presently 135 pts (85%) are alive. The 5-year and 10-year overall survivals from MD Anderson visit were, respectively, 88.5% and 77.3%. The median survival has not been reached. The multivariate analysis of patients’ characteristics at presentation to and since MD Anderson visit identified interferon therapy as favorable predictive factor for survival (unlike other therapies). In contrast, this therapy constitutes an independent risk for a thrombotic event. No predictive factor for transformation has been identified.
We conclude that ET is a good prognosis disease with a low rate of transformation into more aggressive disease, and that interferon therapy may improve the outcome. Patients were referred to MD Anderson at different time in the natural history of their disease, and the evaluation of probable impact of interferon therapy on patients’ survival in ET should be verified in newly diagnosed patients.
Delta (9)-Tetrahydrocannabinol Contributes to the Development of Kaposi’s Sarcoma.
Authors: Zhang Xuefeng , Wang Jian Feng , Kunos George , Groopman Jerome E. 
Published: April 2020

Abstract
Kaposi’s sarcoma-associated herpesvirus (KSHV), a DNA tumor virus, appears to be necessary but not sufficient for the development of Kaposi’s sarcoma (KS). This is highlighted by the observation that most KSHV infections are asymptomatic, and more than 95% of persons who become infected never develop KS or other KSHV-related cancers. In addition to KSHV, a variety of factors, including HIV-1 Tat protein, may contribute to the pathogenesis of KS. These cofactors usually induce immunosuppression, enhance susceptibility to infection, modulate the viral life cycle, and/or stimulate angiogenesis and tumorigenesis either individually or in combination.
Delta (9)-Tetrahydrocannabinol (THC), the major active component of marijuana, has been prescribed for medicinal use and has also been reported to induce immunosuppression. To date, contradictory observations have been made about its effects on viral infection/replication and on tumor cell growth. This prompted us to study the biological effect of Δ9-THC on KSHV, and obtain more evidence to assess the potential risks versus benefits of THC administration among KSHV-positive populations. We found an increased efficiency of KSHV infection (40% vs 15%) in human dermal microvascular endothelial cells (HMVEC) in the presence of low concentrations of Δ9-THC (10–100 nM). THC enhanced endocytosis and cell-cell adhesion by 30–60%, which may account for this increase in infection efficiency. Using real-time DNA PCR technology, the number of copies of the KSHV latent gene, LANA-1, was quantitated and correlated with the viral load in endothelial cells. We found that Δ9-THC increased the viral load 20–100 fold in KSHV-infected endothelial cells as compared to treatment with the vehicle control. We then quantitated expression of the KSHV lytic switch gene ORF50 (RTA) by real-time RT-PCR, in the presence or absence of Δ9-THC. ORF50 expression was shown to be up-regulated by Δ9-THC, leading to increased KSHV loads. We also observed that comparable concentrations of Δ9-THC up-regulated vGPCR expression, thereby fostering endothelial transformation and inducing significantly more colony-formation (1.5 fold) in soft agar. Our results indicate that Δ9-THC may enhance KSHV infection, transmission, replication, and viral-mediated endothelial transformation. Thus, THC administration may put individuals at greater risk for the development and growth of Kaposi’s sarcoma.
Imatinib Mesylate in the Treatment of Systemic Mastocytosis with Wild-Type c-Kit Codon 816.
Authors: Hsieh Fred H. , Lichtin Alan E. , Katz Hary T. , Lubell Susan , Vasas Dorothy , Gibbons Aridth , Sharma Pankaj , Haque S.J. 
Published: April 2020

Abstract
Mastocytosis is a heterogeneous group of disorders characterized by the abnormal growth and accumulation of mast cells in one or more organs. Somatic mutations in the c-kit gene are associated with &gt;80% of mastocytosis cases with the most common mutation identified as c-kit D816V. Imatinib mesylate is a potent inhibitor of c-kit tyrosine kinase activity, though the D816V mutation has been demonstrated to confer imatinib resistance both in vitro and in vivo. In this study we sought to determine the safety and efficacy of imatinib in patients with systemic mastocytosis who had no identified mutation that conferred imatinib resistance. We screened 24 patients and identified 5 patients who met study criteria, which included systemic mastocytosis by WHO consensus criteria (Valent et al, Leuk Res, 2003), impaired organ function to justify cytoreductive therapy, and wild-type c-kit exon 17 (including codon 816) DNA sequence analysis from peripheral blood, bone marrow, or lesional tissue specimens. In all cases patients were negative for the FIP1L1-PDGFRA fusion kinase. Four patients consented to the study and were treated with 400 mg of imatinib orally once daily in a dose-escalation protocol up to 800 mg daily for six months. Of the four patients entering the study, two had systemic mastocytosis with an associated hematologic non-mast cell disorder (in both cases CMML) and two had aggressive systemic mastocytosis. At the end of the six month treatment period all patients were assessed to have a partial response. Serum tryptase had fallen between 19–44% and skin lesions diminished in all patients with cutaneous involvement but did not resolve. All subjects reported subjective symptom improvement with regards to pruritis, flushing, GI symptoms, and other constitutional manifestations. However, bone marrow examination performed after the trial period when available demonstrated persistent mast cell infiltration. In two patients cutaneous mastocytosis lesions progressed within 6 months after discontinuation of imatinib. Imatinib was generally well-tolerated, though dose-dependent toxicity was noted in all patients and especially in patients &gt; 65 years of age, and included edema, nausea, muscle cramps, conjunctivitis, cough, fatigue, and anemia.
Imatinib mesylate is safe and may have some efficacy in treating patients with systemic mastocytosis who lack imatinib-resistant mutations in c-kit.
Epidermal Growth Factor Is an Independent Prognostic Factor in Patients with Chronic Lymphocytic Leukemia.
Authors: Zhang Zhong , O’Brien Susan , Keating Michael , Jilani Iman , Kantarjian Hagop , Estrov Zeev , Ferrajoli Alessandra , Giles Francis , Albitar Maher 
Published: April 2020

Abstract
Epidermal growth factor (EGF) is a polypeptide expressed in various epithelial tissues and organs. EGF is believed to play an important role in cell development, differentiation, growth, apoptosis, and epithelial regeneration by the activation of signal transduction pathways that include PI3K/AKT, RAS/ERK, and JAK/STAT. These pathways may lead to both pro- and anti-apoptotic proteins. While hematopoietic cells do not express a significant amount of the EGF receptor (EGFR), bone marrow stromal cell and fibroblast expression of EGFR and EGF is important in the support of mesenchymal stem cell growth and colony formation. Since stromal cells play a major role in hematologic diseases, we evaluated the level of EGF in the plasma of 120 patients with chronic lymphocytic leukemia (CLL). EGF levels were significantly lower in CLL patients (median, 86.7; range, 2.2–500 pg/mL) than in 22 normal controls (median, 151.7; range, 35.1–389.1 pg/mL) (P = 0.02). EGF levels did not correlate significantly with β2-microglobulin (β2-M) level or IgVH mutation status, but correlated negatively with Rai stage (P = 0.0001). EGF level correlated positively with platelet count (R = 0.53, P &lt;0.001) and negatively with WBC count (R = −0.32, P &lt;0.001) as well as percent lymphocytes in bone marrow (R = −0.35, P &lt;0.01). Using univariate Cox proportional hazards models, we demonstrated a negative correlation with survival when EGF was used as a continuous variable (P &lt;0.001). The negative predictive value of EGF was independent of Rai stage, β2-M and thrombopoietin (TPO) level, IgVH mutation status, and prior therapy. EGF level as a continuous variable remained a strong predictor of survival (P &lt;0.01) even when Rai stage, IgVH mutation status, β2-M and TPO levels, and prior therapy were included in the model. When dichotomized according to the median EGF level (86.7 pg/mL), patients with higher levels had longer survival (P &lt;0.001). These data suggest that EGF levels are a powerful and independent prognostic factor in CLL and represent a simple and reliable approach to stratify patients for therapy. Further studies are needed to understand the biological basis of the role of the EGF in CLL to determine whether it reflects the general well-being of the host or the health of stromal elements in the bone marrow.
Figure Figure
Genomic Aberrations in Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma by Absolute Lymphocyte Count: Analysis of 1694 Patients.
Authors: Tsimberidou Apostolia-Maria , McLaughlin Peter , O’Brien Susan , Wen Sijin , Wierda William G. , Manning John T. , Abruzzo Lynne V. , Lerner Susan , Hess Mark A. , Kantarjian Hagop M. , Freireich Emil J. , Keating Michael J. 
Published: April 2020

Abstract
Introduction: Genomic aberrations provide information for the pathogenesis and clinical outcomes of patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). We assessed whether genomic aberrations in CLL/SLL differ by absolute lymphocyte count (ALC) and evaluated their prognostic significance in our series of patients with CLL/SLL.
Methods: We reviewed the medical records of patients with CLL/SLL who presented to The University of Texas M. D. Anderson Cancer Center from 1985 to 2005. Patients were assessed by conventional bone marrow cytogenetics and/or fluorescence in situ hybridization (FISH) analysis using probes for trisomy 12, ATM, LAMP1, D13S319, and P53 genes.
Results: Cytogenetics and/or FISH analysis was performed in 1694 of 2189 consecutive patients with CLL/SLL. Patients with ALC &lt; 5 × 109/L had lower rates of genomic aberrations by cytogenetic and/or FISH analysis than did those with ALC ≥ 5 × 109/L (25% vs. 37%, p=0.02). Deletion 17p +/− other abnormalities and 6q del +/− other abnormalities were each associated with shorter survival compared with other genomic aberrations or normal karyotype (p&lt;0.0001 for both results). The survival rates by genomic aberration are shown in the Figure [insert figure here]. In a multivariate analysis of 23 clinical and laboratory factors, deletion 17p or 6q +/− other genomic aberrations (p&lt;0.0001) was the strongest independent predictor of shorter survival. In patients who required therapy for CLL/SLL, independent factors predicting response were hemoglobin levels &gt; 11 g/dL (p&lt;0.0001), age &lt; 60 years (p=0.005), absence of 17p deletion (p=0.048), and absence of 6q deletion (p=0.03). In multivariate analysis, pretreatment parameters that remained independently significant for longer failure-free survival (FFS) were age &lt; 60 years (p&lt;0.0001), absence of 17p del +/− other abnormalities (p&lt;0.0001), and hemoglobin levels &gt; 11 g/dL (p=0.018).
Conclusions: Patients with CLL/SLL and ALC &lt; 5 × 109/L had lower rates of genomic aberrations by cytogenetic and/or FISH analysis (p=0.02), possibly because of less bone marrow infiltration in the lower-ALC group. Deletion 17p or 6q, with or without other genomic aberrations was the strongest independent adverse prognostic factor for survival in CLL/SLL.
Figure Figure
The Assessment of Anti HSP70 Antibodies in Patients with Chronic Lymphocytic Leukaemia.
Authors: Piszcz Jaroslaw , Kloczko Janusz , Rudy Agnieszka , Blusiewicz Eliza , Lemancewicz Dorota , Mazgajska-Barczyk Katarzyna 
Published: April 2020

Abstract
Background: Chronic lymphocytic leukaemia (CLL) is a one of the disease in which processes of proliferation and apoptosis are seriously altered. It has been intensely studied in the recent years in order to understand the mechanisms of neoplastic development. Hsps or heat shock proteins are molecular chaperones involved in a number of cellular functions in stress conditions. Feng et al. (2002) have reported that heat-stressed apoptotic 12B1-D1 leukaemia cells (BCR-ABL(+)) express HSP70 on their surface. It has also been suggested that an increased surface expression of heat shock proteins on apoptotic tumour cells results in the generation of potent antitumour T-cell responses. Anti Hsp70 antibodies are known to play a role in immunological and neoplastic processes. However their significance in CLL has not been well documented.
Aims: The aim of our study was the assessment of the anti Hsp70 antibody concentration in the patients with CLL.
Material and methods: We assessed 20 peripheral blood samples from the patients with newly diagnosed CLL. (aged 46–74), including 11 males and 9 females. A group of healthy age matched subjects were used as a control group. The patients were in A-C stages of CLL according to Binet scale. Quantitative determination of anti-human Hsp70 antibodies in the serum was done using commercial test (anti Hsp70 Elisa Kits, Stressgen). The results are presented as mean ± SEM. Statistical analysis was done using Shapiro-Wilk, Mann-Whitney and Spearman’s tests.
Results: The levels of anti HSP70 antibodies were significantly lower in the group of patients with CLL in comparison to healthy controls (141,99±74,26 ng/ml vs.298,36±57,06 ng/ml; p&lt; 0,01). In our analysis there was no association between the levels of antibodies and the stage of the disease. There were no correlations between the levels of anti Hsp antibodies and other parametres such as age, gender and some prognostic factors (LDH, β2-microglobulin, and lymphocyte doubling time) in the studied group.
Conclusions: The significantly lower concentrations of anti HSP70 antibodies in CLL patients suggest that these molecules may play a role in the biology of the disease. The encouraging results from our study suggest that it might be interesting to assess their level depending on the response to the applied treatment. Further studies are required to elucidate the role of these proteins in leukaemic conditions.
Xanthohumol Induces Apoptosis in B-CLL In Vitro by Sustained Endoplasmic Reticulum Stress and Inhibition of NFκ-B.
Authors: Lust Sofie , Vanhoecke Barbara , Van Gele Mireille , Kaileh Mary , Boelens Jerina , Poelman Martine , VandenBerghe Wim , Philippé Jan , Offner Fritz 
Published: April 2020

Abstract
Introduction
Correct folding of new proteins is supervised in the endoplasic reticulum (ER) unfolded protein response (UPR). Misfolded proteins recruit the chaperone Grp78 that is thereby released from the transcription factors ATF6, IRE-1 leading to compensatory increase in Grp78, and PERK, leading to phosphorylation of eIF2α and block of further protein translation. UPR overload leads to ER stress and cell death. Targeting the endoplasmic reticulum (ER) is a new strategy explored in B-CLL. The hop-derived chalcone Xanthohumol (X) has been characterized as a ‘broad-spectrum’ cancer chemopreventive agent. Recently, we demonstrated that X induces dose- and time-dependent cell death of MCF7/6 breast cancer cells accompanied by ER stress. X induces apoptosis and cleavage of poly(ADP)-ribose-polymerase (PARP) in B-CLL in vitro. The present study investigates the branches of the UPR in relation to X induced apoptosis of B-CLL cells.
Materials and methods. Lymphocytes were isolated by Lymphoprep from 15 patients with B-CLL after informed consent. CD19 positive cells were selected by EasySep positive selection kit. Apoptosis was assessed by flow-cytometry (AnnexinV-PI). Western Blotting was used for Grp78, ATF6, XBP1, phospho-eIF2a, eIF2a, ATF4, CHOP, phospho-IKK, IKK, PARP, caspase-9, -8, -7, -4, cleaved caspase-3, mcl-1, bcl-xL, bax, bak, and bid. NF-kB activity was assessed by EMSA. Quantitative RT-PCR was performed to analyze Grp78 mRNA levels. Bcl-2 protein level was detected by flow cytometry and reactive oxygen species (ROS) by fluorescence microscopy.
Results and conclusion
X induced an upregulation of Grp78 mRNA levels which was not translated in an increase in protein. X treatment stimulated a rapid and sustained phosphorylation of eIF2a, suggesting the involvement of PERK. In contrast, the ER-stress transducers ATF6 and IRE1 were not activated. X-induced ER stress was associated with strong induction of the pro-apoptotic protein CHOP and inhibition of the NF-kB pathway. Furthermore, the pro-apoptotic effect of X was accompanied by an accumulation of ROS, a downregulation of the anti-apoptotic proteins mcl-1, bcl-xL, bcl-2 and processing of caspase-3, -7 and -9.In conclusion, the chalcone X is capable of inducing cell death with down-regulation of bcl-2, mcl-1, bcl-xL, and activation of the caspase cascade. This is accompanied by ER-stress as evidenced by the upregulation of Grp78 mRNA levels, induction of a rapid and sustained phosphorylation of eIF2a, upregulation of CHOP, and inhibition of the NF-kB signaling.
Intense Reversal of Bone Marrow Angiogenesis after Consolidation Therapy with Alemtuzumab in Advanced Chronic Lymphocytic Leukemia.
Authors: Molica Stefano , Montillo Marco , Ribatti Domenico , Mirabelli Rosanna , Tedeschi Alessandra , Ricci Francesca , Veronese Silvio , Vacca Angelo , Morra Enrica 
Published: April 2020

Abstract
We evaluated microvessel area of bone marrow (BM) samples from 20 patients with advanced CLL (i.e., symptomatic Binet stage A, B or C) who received at least 8 weeks, after the end of treatment with fludarabine, subcutaneous alemtuzumab, three times weekly for 6 weeks, at escalating dose up to 10 mg. The patient sample included 14 males and 6 females with a median age of 51 years (range 44–60). After a median number of 6 cycles of fludarabine (range, 4–13), 11 (55%) patients could be classified in complete remission (CR) and 9 (45%) in partial remission (PR) (7 nodular-PR and 2 PR). Interestingly, the rate of CR increased to 90% (18 CR; P=0.03; Fisher’s exact test) after treatment with alemtuzumab. In keeping with hematological responses, significant changes in BM microvessel area were observed The decrease of BM angiogenesis, observed virtually in all patients, was a continuous process characterizing the sequential use of fludarabine and alemtuzumab (P = 0.002; Kruskal-Wallis test). This conspicuous feature was easily demonstrable in either ZAP-70-positive (P = 0.02) or ZAP-70-negative (P = 0.001) patients.
Residual disease was assessed using a consensus polymerase chain reaction (PCR) methodology to detect the clonality of IgH sequences. Thirteen out of 20 (65%) patients changed from a monoclonal to a polyclonal pattern of IgH after alemtuzumab consolidation. We wondered whether molecular response could translate into a change in the BM microvessel area. A separate evaluation carried out in patients with a persistent monoclonal pattern and in those who changed to a polyclonal pattern of IgH after alemtuzumab therapy showed a significant reduction of BM microvessel area only in the latter (P = 0.0002).
A new information provided by the present study concerns the impact of the cumulative dose of alemtuzumab on either molecular response or reduction in BM angiogenesis. Analysis carried out after setting as cut-off the median cumulative dose of alemtuzumab (i.e., 184 mg; range, 134–187) revealed a dose-response relationship. Only two (15.3%) out of 13 patients who received a cumulative dose of alemtuzumab higher than 184 mg had persistent monoclonal IgH in comparison to 5 (71.4%) out 7 patients who had received a cumulative dose of alemtuzumab lower than median (P = 0.007). Similarly, a significant decrease in the extent of microvessel area was observed among patients whose cumulative dose was equal or higher than 184 mg (P = 0.0001) while the same did not apply for a cumulative dose of alemtuzumab lower than 184 mg (P = 0.09).
Overall, these data demonstrate a decrease in BM vascularity after treatment with alemtuzumab, which reflects both molecular response and cumulative dose of this drug, and suggest a potential use of alemtuzumab as anti-angiogenic agent in the treatment of advanced CLL.