bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lenalidomide (L) in Combination with Dexamethasone (D) Improves Survival and Time to Progression in Elderly Patients (pts) with Relapsed or Refractory (rel/ref) Multiple Myeloma (MM).
Authors: Chanan-Khan Asher Alban , Weber Donna , Dimopoulos Meletius , Chen Christine , Niesvizky Reuben , Wang Michael , Belch Andrew , Attal Michel , Spencer Andrew , Prince Miles , Olesnyckyj Marta , Zeldis Jerome , Yu Zhinuan , Knight Robert 
Published: October 2019

Abstract
Introduction: Treatment of elderly pts (age >65 years) with rel/ref MM remains a challenge due to concurrent comorbid conditions and poor tolerability to chemotherapy limiting therapeutic options. Recently, 2 phase III randomized clinical trials (MM-090 and MM-010) demonstrated superiority of the LD combination over D alone in previously treated MM pts. We examined the clinical benefit of LD combination in elderly pts enrolled in these 2 clinical trials.
Methods: This is a retrospective data analysis of pts enrolled on the MM-090 and MM-010. All elderly pts (>65 years) were identified and parameters of clinical outcome (overall response, OR; time to progression, TTP; overall survival, OS) recorded. To determine the clinical benefit of L in elderly pt population, we compared the group of elderly pts who received LD combination with those who received D + placebo as well as with the group of younger pts who received the LD combination in these studies.
Results: Collectively, 704 pts were enrolled with 285 identified as elderly. In the elderly group, 146 pts were randomized to LD combination and 139 to D + placebo. There were no significant differences in baseline characteristics of these two groups. In the elderly group who received LD, median time from diagnosis was 3.3 yrs (range 0.5–14.7) and 77.4% had received ≥ 2 prior therapies (prior D and/or thalidomide in 69% and 32% respectively). Using the Blade criteria, the overall response (ORR) was significantly better in pts on combination treatment vs. D alone (58.9% vs. 20.9%; p<0.001). On an intent-to-treat analysis, the median time to progression (TTP; primary endpoint) for pts treated with D alone was 20 vs. 60 wks on combination (p<0.001) and the median overall survival was 79 wks and has not been reached (p=<0.001) in the combination group, respectively. We then compared the elderly pts with the younger pts who received LD combination. The ORR and median TTP was (58.9% vs. 60.9%) and (60 wks vs. 47.3 wks), respectively. The OS was 128 wks in the younger pts and is not reached in the elderly.
Conclusion: L when combined with D improves ORR, prolongs TTP and OS in elderly pts with rel/ref MM and thus offers an important treatment option for this pt population. This clinical benefit of L achieved in the elderly is comparable to that in the younger pts and thus is irrespective of age of the pt treated. The availability of L as an oral formulation provides an added benefit in the management of elderly pts population.
Aberrant Immunoglobulin Class Switch Recombination and Switch Translocations in Activated B Cell-Like Diffuse Large B-Cell Lymphoma.
Authors: Lenz Georg , Nagel Inga , Siebert Reiner , Sanger Warren , Wright George W. , Zhao Hong , Rosenwald Andreas , Muller-Hermelink Hans-Konrad , Gascoyne Randy D. , Campo Elias , Jaffe Elaine S. , Smeland Erlend B. , Fisher Richard I. , Kuehl W. Michael , Chan Wing C. , Staudt Louis M. 
Published: October 2019

Abstract
To elucidate the mechanisms underlying chromosomal translocations in diffuse large B-cell lymphoma (DLBCL), we investigated the nature and extent of immunoglobulin class switch recombination (CSR) in these tumors. We used a Southern blot assay to detect legitimate and illegitimate CSR events in 92 primary tumor samples of either the activated B-cell-like (ABC; n = 50), germinal center B cell-like (GCB; n =31), and primary mediastinal B cell lymphoma (PMBL; n = 11) subgroups of DLBCL. We could clearly distinguish ABC DLBCL from GCB and PMBL by the phenotype shown in these experiments. The frequency of legitimate CSR was significantly lower in ABC DLBCL compared to GCB DLBCL and PMBL (30% vs. 58% vs. 64%; p = 0.012 and p = 0.035 respectively). In contrast, illegitimate switch recombination events were more frequent in ABC than in GCB (56% vs. 32%; p = 0.037). Similarly, ABC DLBCL had a higher frequency of internal deletions within the switch μ region compared to GCB DLBCL and PMBL (48% vs. 13% vs. 0%; p = 0.0012 and p = 0.003, respectively). ABC DLBCLs also had frequent deletions within Sγ (66%) and Sα (26%). Sequence analysis revealed ongoing Sμ deletions within ABC DLBCL tumor clones, with 4–19 separate deletions occurring per case. In addition, Sμ deletions were accompanied by ongoing segmental duplications and apparent AID-dependent somatic mutations in Sμ, consistent with failed attempts at AID-mediated CSR. Unexpectedly, short fragments derived from multiple chromosomes were interspersed within the deleted Sμ regions. Furthermore, aberrant switch recombination was responsible for translocations in ABC DLBCLs involving the known oncogenes BCL6 and MYC. In addition, we were able to identify a novel translocation involving the switch γ3 region and the gene encoding the B-cell transcription factor SPIB in the ABC cell line OCI-Ly3. These findings suggest that ABC DLBCLs have abnormalities in the regulation of CSR that predispose to chromosomal translocations.
A Systematic Review and Meta-Analysis of Thalidomide in Patients with Previously Untreated Multiple Myeloma.
Authors: Hicks Lisa , Haynes Adam , Reece Donna E. , Walker Irwin , Herst Jordan A. , Imrie Kevin 
Published: October 2019

Abstract
Background: Multiple myeloma disproportionately affects the elderly and is currently an incurable malignancy. New therapies for myeloma, particularly oral therapies, are urgently needed.
Objectives:
To determine if thalidomide with or without other agents, improves response rate (≥ 50% reduction in monoclonal protein), survival, and/or progression in patients with previously untreated myeloma. To determine the frequency and significance of major adverse events associated with thalidomide in this setting.
Methods: A literature search of Medline (1966–June 2006), Embase (1980–June 2006), the Cochrane Library, abstracts from the annual meetings of the American Society of Hematology (1999–2005) and the American Society of Oncology (1999–2006) was completed with a pre-specified search strategy. No language restrictions were applied. Randomized controlled trials of induction thalidomide (any dose, any duration) for adults with previously untreated multiple myeloma were included. Trials of exclusively maintenance therapy were excluded. Two reviewers independently extracted data. The methodological quality of selected trials was assessed and summarized. Weighted data was expressed as relative risk, risk difference, number needed to treat (NNT), and number needed to harm (NNH). A random-effects model was used.
Results: Six eligible studies involving almost two thousand patients (N=1875) were identified and meta-analyzed. Two studies were published and four were reported in abstract form only. Five studies reported overall response rate (ORR); the four largest trials reported statistically significant improvements in ORR with the addition of thalidomide to standard therapy. The weighted relative risk of responding to a thalidomide-containing regimen versus control was 1.50 (95% CI 1.21 to 1.86). The NNT to achieve one additional response with thalidomide was 4 (95% CI 2.9 to 8.3). Two trials reported improvements in EFS/PFS. One trial reported an improvement in OS. The risk of VTE, peripheral neuropathy, and constipation was consistently elevated with thalidomide such that for every 50 patients treated with a thalidomide-containing-regimen, one could expect 12 to 13 additional patients to respond, 4 additional patients to develop VTE (NNH 12.5; 95% CI 8.3 to 20), 2 additional patients to develop peripheral neuropathy (NNH 25; 95% CI 16.7 to 50), and 4 additional patients to develop constipation (NNH14; 95% CI 10 to 25). In our analyses, prophylactic anticoagulation appeared to decrease, but not abolish, the risk of VTE with thalidomide.
Conclusions: Thalidomide improves response rate and possibly progression free and overall survival in patients with previously untreated myeloma. It also increases the incidence of VTE, neuropathy, constipation and other adverse events. Further studies are required to confirm the survival advantage seen in one study, and to determine the optimum strategy for VTE prophylaxis.
Treatment Associated Venous Thromboembolism (VTE) and Survival in Multiple Myeloma Patients.
Authors: Zangari Maurizio , Cavallo Federica , Fink Louis M. , Barlogie Bart , Bolejack Vanessa , Burns Michael J. , Anaissie Elias , Hollmig Klaus A. , Mohiuddin Abid , Pineda-Roman Mauricio , Tricot Guido J. 
Published: October 2019

Abstract
Background: Venous thromboembolism (VTE) is a well known cancer complication generally associated with poor survival. We have analyzed the prognostic impact of the development of a thrombotic episode in newly diagnosed multiple myeloma (MM).
Methods: Newly diagnosed patients with symptomatic MM were eligible for enrollment. At registration, patients were randomly assigned to Thalidomide (Thal) or not; both arms received otherwise identical chemotherapy. A total of 668 patients entered the study. The two study arms were well balanced, in terms of age, Ig Subtype, cytogenetic, B2 microglobulin vs CRP. Baseline patients and disease characteristics were well balanced between those individuals who experienced VTE and the others. VTE patients were treated with LMWH followed by coumadin for at least 6 months. A 12 month landmark for VTE was used; group comparisons were performed for EFS and OS using the log rank test.
Results: With a median follow up of 53 months a total of 155 (23%) patients experienced VTE during treatment, 98 (30%) patients in the Thal arm and 57 (16%) in the non Thal arm. The development of thrombotic episode was not a negative factor for EFS (p=.1) or OS (p=0.1) (Figure 1) for the entire group as well as for the Thal/chemotherapy treated group (EF p=0.7, OS p=0.6). Patients who received only chemotherapy and developed a thrombotic episode experienced a significantly longer EFS (p=0.02) (Figure 2), and a similar trend in OS.
Conclusions: OS and EFS survival of myeloma patients treated with chemotherapy ± thalidomide is not affected by VTE development. Patients treated with chemotherapy (but not Thalidomide) who developed thrombosis during treatment experienced significantly longer EFS. Our observation supports a survival benefit associated with anticoagulation therapy in multiple myeloma patients.
Figure 1: OS from 12 months post VAD by VTE Figure 1:. OS from 12 months post VAD by VTE Figure 2: EFS from 12 months post VAD by VTE in the Non Thalidomide arm Figure 2:. EFS from 12 months post VAD by VTE in the Non Thalidomide arm
Pharmacologic Evaluation of Orally Bioavailable Inhibitors of the 20S Proteasome.
Authors: Kirk Christopher J. , Aujay Monette A. , Ho Mark , Jiang Jing , Laidig Guy J. , Lewis Evan R. , Lu Yan , Muchamuel Tony , Woo Tina M. , Sun Congcong M. , Sylvain Catherine , Yang Jinfu , Zhou Han-jie , Bennett Mark K. 
Published: October 2019

Abstract
Clinical application of proteasome inhibitors in the treatment of hematologic malignancies such as myeloma and lymphoma is restricted in part by the necessity of frequent IV administration and would be improved by oral (PO) administration. Selective inhibitors of the protease subunits of the 20S proteasome can be generated from peptidyl aldehydes, boronates, vinyl sulfones, and epoxyketones. Many of these peptide based proteasome inhibitors are cell permeant and capable of systemic proteasome inhibition upon intravenous (IV) administration to experimental animals such as mice and rats. In the cases of the peptidyl boronate bortezomib (Velcade™) and the epoxyketone PR-171, proteasome inhibition can be achieved in patients with IV administration. However, systemic exposure following PO administration of these inhibitors may be limited by several factors including gastric pH, gastric and intestinal peptidases, efflux pumps, biliary excretion and intestinal and hepatic metabolic activities. We have tested over 80 peptide epoxyketones with potent (IC50 <100 nM) in vitro inhibitory activity against the chymotrypsin-like activity of the 20S proteasome for bioavailability following PO administration in mice. Systemic exposure was monitored by measuring chymotrypsin-like inhibition in a number of tissues and an approximation of the relative bioavailability for selected compounds was measured by comparing the pharmacodynamics of IV and PO administration using a range of doses. These compounds were also tested in vitro for solubility, intestinal cell permeability, intestinal and hepatic metabolism, and sensitivity to the multidrug resistance protein 1 (MDR1) efflux pump in order to determine which properties were associated with oral bioavailability. We have found that oral bioavailability in mice is associated with increased intrinsic solubility and metabolic stability and reduced MDR1 sensitivity. Proteasome inhibition following PO administration is rapid, resulting in maximal proteasome inhibition within 15 minutes. Rapid absorption and clearance of selected compounds was also confirmed in mice and rats by pharmacokinetic analysis. Repeated oral administration was well tolerated at doses that resulted in significant (>80%) proteasome inhibition in most tissues. The anti-tumor efficacy of these orally bioavailable proteasome inhibitors are being assessed in both human tumor xenograft and mouse syngeneic models. The results from these studies will enable further pre-clinical development of potent, orally bioavailable proteasome inhibitors for the treatment of malignant diseases.
Zoledronic Acid Early Increases Serum Osteoprotegerin in Early Stage Multiple Myeloma.
Authors: Gozzetti Alessandro , Martini Giuseppe , Salvadori Stefania , Gennari Luigi , Avanzati Annalisa , Franci Beatrice , Campagna Maria Stella , Nuti Ranuccio , Lauria Francesco 
Published: October 2019

Abstract
Myeloma cells are able to induce an imbalance in the OPG/RANKL system in bone environment, and due to osteoclastic activation this is responsible for myeloma bone disease. Recent in vitro and in vivo evidence suggests that bisphosphonates exerts activity on myeloma cells, which could be of therapeutic interest particularly in patients in initial phases of multiple myeloma.
We evaluated 26 patients with smoldering myeloma (stage IA) to assess basal levels of circulating cytokines as OPG, RANKL and macrophage inflammatory protein-1 alpha MIP-1α and serum markers of bone turnover at baseline and at 2, 4, 6 months and compared to 58 healthy subjects as control group. Moreover we treated 16 of those patients with a potent bisphosphonate, zoledronic acid (ZA), to find out if its antiosteoclastic activity can be related to changes in circulating levels of RANKL, OPG and (MIP-1α). Results showed serum levels of OPG significantly lower and an increase of RANKL:OPG ratio in MM patients respect to controls. A significant correlation was found between RANKL/OPG ratio and serum CTX (r=0.45;p<0.05). Patients with MM treated with zoledronic acid did not show significant changes in serum and urinary calcium as well as serum creatinine compared to untreated patients. An early and significant reduction of serum CTX was found in treated patients, while bone ALP decreased later and not significantly. Interestingly ZA increased serum OPG and reduced RANKL:OPG ratio (4,8±2,6 vs 2,9±0,8 ; p<0.05).The positive effect of zoledronic acid on bone tissue was confirmed by the increased in lumbar spine BMD at 6 months (+3.8%± 2.6 vs baseline; p<0.05). Larger studies are urgently needed to better clarify the significance of these findings.
Megakaryocytes Cultured from Patients with IMF Produced Significantly Higher mRNA but Not Protein Levels of Fibrosing Grown Factors.
Authors: Wang Jen-Chin , Chang Tsong H , Goldberg Amit , Novetsky Allan D. , Lichter Steven , Lipton Jeffrey 
Published: October 2019

Abstract
Currently, the prevailing concept concerning the etiology of bone marrow fibrosis in patients with idiopathic myelofibrosis (IMF) is that it results from excessive production of fibrosing growth factors including transforming growth factor beta (TGF-B1), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF) from megakaryocytes and monocytes. Since megakaryocytes are difficult to isolate from bone marrow in IMF patients, this concept remains speculative. We obtained megakaryocytes (CD41+ cells) from 10-day in vitro culture of blood CD34+ cells in serum-free medium with thrombopoietin and stem cell factors as described and cultured monocytes from isolating blood CD14+ cells. Then quantitative analyses of fibrosing growth factors at the mRNA and protein levels were obtained. mRNA levels were obtained from real-time RT-PCR technique, and protein levels were obtained from ELISA analysis of the supernatant of CD41+ cells cultured 4 h in serum-free medium. The results showed 1) mRNA levels of TGF-B1, PDGF, and FGF produced by the megakaryocytes were significantly elevated in agnogenic myeloid metaplasia (AMM) compared with those in normal controls (p<0.05). While these growth factors were elevated several-fold in AMM compared with other myeloproliferative disorders (MPD) including essential thrombocythemia and polycythemia vera, they were not statistically significant. 2) mRNA levels of TGF-B1 were higher than levels of PDGF or FGF. 3) The mRNA levels of these growth factors produced from CD14+ cells were not significantly elevated in AMM compared with other MPDs or controls; the AMM mRNA levels were significantly elevated only in some patients. 4) The correlation of mRNA levels of these growth factors with the degree of myelofibrosis in AMM was significant with megakaryocytes (r=0.73) but not with monocytes (r=0.23). 5) ELISA analysis of the growth factors from the cultured megakaryocytes showed that, in most of the patients with AMM and other MPDs and in volunteer controls, the growth factors were undetectable, and only a few patients with AMM had significantly elevated protein levels of these growth factors. We conclude thatin IMF, megakaryocytes but not monocytes are the predominant cells producing fibrosing growth factors, andthe failure of finding increased protein levels of these growth factors in the in vitro system suggest that other factors are necessary to initiate translation of these growth factors in the megakaryoctes, and neutrophil emperipolesis with releasing factors may be important in this process.
Early-Polycythemia Vera (e-PV) with Thrombocytosis: Clinical Characteristics, Morphological Features and JAK2V617F Mutational Status Contributing to the Differential Diagnosis with Essential Thrombocythemia.
Authors: Iurlo Alessandra , Gianelli Umberto , Moro Alessia , Bianchi Paola , Fermo Elisa , Vener Claudia , Savi Federica , Franca Radaelli , Bosari Silvano , Zanella Alberto 
Published: October 2019

Abstract
According to the recently published WHO classification, two well-defined stages of PV, known as polycythemic phase and post-polycythemic myelofibrosis, are clearly recognizable. A few years ago, it has been reported that erythrocytosis may develop in the course of ET, and that PV may present in the early stage of the disease with an elevated platelet count, mimicking ET. Recently, it has been suggested that PV could be preceded by an “early” phase of the disease (Thiele et al, 2005), in which the increase in the red cell mass or hemoglobin level are lower than requested for the diagnosis either by the updated diagnostic criteria of the Polycythemia Vera Study Group (PVSG) or by the WHO classification. Very recently, the European Clinical and Pathological (ECP) criteria for the diagnosis of the “early” PV have been published (Michiels et al, 2006).
The aim of this study is to examine the clinical features, the bone marrow biopsies (BMBs) and the JAK2V617F mutational status of 17 e-PV patients. All presented, at diagnosis, the clinical and morphological features of ET, and manifested a well-developed polycythemic phase of PV during the course of the follow-up (median 8.6 yrs; range 2–17 yrs). We compared the study group with 19 cases of PV and 14 cases of ET (according to WHO) as controls. Clinically, e-PV patients revealed at diagnosis increased levels of Hb (e-PV: 15.5g/dl; ET: 13.8g/dl; PV: 16.9g/dl), Hct (e-PV: 45.9%; ET: 41%; PV: 51.8%) and Ptl count (e-PV: 854×109/l; ET: 877×109/l; PV: 691×109/l), splenomegaly (e-PV: 43%; ET: 0%; PV: 61%) and hepatomegaly (e-PV: 53%; ET: 14%; PV: 61%). Morphological examination of the BMBs in e-PV patients demonstrated moderate to marked increase of the BM cellularity (e-PV: 65%; ET: 0%; PV: 73%) and pleiomorphic (i.e. clusters of small to giant) megakaryocytes (e-PV: 83%; ET: 20%; PV: 100%). Moreover, increased (e-PV: 100%; ET: 14%; PV: 100%) and left shifted erythropoiesis (e-PV: 82%; ET: 0%; PV: 79%), and increased (e-PV: 65%; ET: 14%; PV: 100%) and left-shifted granulopoiesis (e-PV: 65%; ET: 0%; PV: 58%) were also found. Mutational status analysis revealed that 15/15 e-PV cases (100%) carried the JAK2V617F mutation (6 homozygous and 9 heterozygous), in comparison to 7/13 (54%) ET (1 homozygous, 6 heterozygous) and to 17/19 (89%) PV (5 homozygous, 12 heterozygous). In conclusion, the results of our study confirm the existence of a “early” phase of PV that may mimic ET. A diagnostic algorithm, useful to differentiate e-PV from ET, may be obtained considering altogether the clinical, morphological and molecular characteristics of each patient.