bluuebunny/crossref_metadata_2025_split huggingface dataset:
Extremely Peculiar Nuclear Changes in Cultured Primary Myeloma Cells, Including Bulging and Duplication/Multiplication of Nuclei and Cell Expansion without Apparent Mitotic Forms.
Authors: Cohen Yossi , Zipori Dov 
Published: October 2019

Abstract
Using our new cytokine-free, mitogen-free in vitro culture system for primary multiple myeloma cells (see abstract by Cohen Y and Zipori D), we have observed peculiar nuclear changes occurring during the first days in culture. After 3–4 days small lymphocytic-like cells are frequently seen, accompanied by typical plasma cells together with plasma-like cells possessing a single bulge in one edge of the nucleus (Figure 1). This nuclear bulging has been seen only in cultures from primary myeloma cases therefore it might represent a pathognomonic disease related phenomenon. Later in culture, multiple cells show nuclear bulging of variable shapes and degrees. It seems that this heterogeneity represents a spectrum of the same nuclear process (Figure 2). In addition, binucleated cells with eccentric nuclei are commonly seen at this stage, whereas multinucleated cells can be seen occasionally. Another observation is an apparent burrier-like structure between those nuclei in binucleated cells. Most interestingly, despite extensive expansion of the cultured myeloma cells (whose clonality was confirmed by FACS analysis, PCR and FISH-Bioview), mitotic forms are very rare. Furthermore, by combined FISH/morphology analysis of some cultured binucleated myeloma cells from a patient with del 13, a single signal was seen in each of the two nuclei using a probe for chromosome 13. Altogether, these unusual myeloma cell forms can now explain the yet unexplained finding frequently seen by FACS analysis of nuclear hyperploidity in myeloma cells. Currently, we use time lapse cinematography to assess the possibility that cultured myeloma cells undergo nuclear replication, through budding, and examine the possibility that these changes lead to the emergence of two daughter cells.
Figure Figure
Thalidomide-Induced Peropheral Neuropathy in Newly Diagnosed and Pre-Treated Multiple Myeloma Patients.
Authors: Tosi Patrizia , Zamagni Elena , Cellini Claudia , Cangini Delia , Tacchetti Paola , Perrone Giulia , Tura Sante , Baccarani Michele , Cavo Michele 
Published: October 2019

Abstract
Thalidomide is remarkably active in advanced relapsed and refractory multiple myeloma (MM), so that its use has been recently proposed either in newly diagnosed patients or as maintenance treatment after conventional or high-dose therapy. This latter therapeutic approach has risen the concern of side effects occurring after long-term therapy with this drug. In order to investigate this issue we analyzed the outcome of 74 patients who have been treated with thalidomide + dexamethasone for longer than 8 months at our Institution. Thirty-four patients (18M, 16F, median age = 55 years) had newly diagnosed symptomatic MM and were treated with four monthly courses of thalidomide 200mg/day + dexamethasone 40 mg on days 1 to 4 (even cycles), or on days 1 to 4, 9 to 12 and 17 to 20 (odd cycles), followed by cyclophosphamide 7g/m2 + G-CSF, peripheral blood stem cell (PBSC) collection, and double autologous PBSC transplant. Thalidomide + dexamethasone was administered throughout the whole treatment program. Forty patients (27M, 13F, median age = 61 years) were treated with thalidomide 200mg/day +dexamehasone 40mg on days 1–4 every four weeks as salvage therapy for relapsed (n = 14) or progressive (n=26) MM. Neurotoxicity was the most troublesome and frequent toxic effect that was observed after > 8 months treatment, the incidence averaging 74% in newly diagnosed patients and 75% in pretreated ones. Symptoms included paresthesias, tremor and dizziness; serial electromyographic studies revealed a symmetrical, mainly sensory peripheral neuropathy, with minor motor involvement. The severity of neuropathy, graded according the NCI-CTC 2.0 scoring system, varied greatly in the two groups of patients, as pretreated patients showed grade 2 and 3 toxicity in 32.5% and 27.5% of the cases, respectively, while the majority of newly diagnosed patients complained about grade 1 toxicity (57%), and none of them experienced grade 3 toxicity. In both groups thalidomide neurotoxicity was not related to sex, M protein isotype, and thalidomide daily dose. In pretreated patients, a significant correlation between grade 2 + 3 neurotoxicty and longer disease duration was found, thus suggesting that subclinical MM-related neurotoxicity could favour drug-induced toxic effects. These results suggest that long-term thalidomide therapy in MM may be hampered by the remarkable neurotoxicity of the drug, and that a neurological evaluation should be mandatory prior to thalidomide treatment, in order to identify patients at risk of developing a periperal neuropathy.
Clinical Responses to Sildenafil in Waldenstrom’s Macroglobulinemia.
Authors: Treon Steven P. , Tournilhac Olivier , Branagan Andrew , Hunter Zachary , Xu Lian , Hatjiharissi Evdoxia , Santos Daniel Ditzel 
Published: October 2019

Abstract
Waldenstrom’s macroglobulinemia (WM) is an incurable B-cell malignancy. Interestingly, we have observed unusual response activity in five WM patients which appears related to their use of sildenafil, a phosphodiesterase inhibitor used to treat erectile dysfunction. One patient demonstrated a complete remission, while four other patients demonstrated less dramatic, but also unexpected responses associated with sildenafil used at doses of 25–50 mg once to twice a week. In view of these observations, we next evaluated sildenafil for its ability to induce apoptosis of lymphoplasmacytic cells obtained from WM patients. All patients provided written consent for this study which was approved by our institutional review board. Sorted (CD19+, light chain restricted) bone marrow lymphoplasmacytic cells obtained from 6 WM patients were cultured in media alone or with sildenafil (kindly provided by Pfizer Pharmaceuticals, Inc.) at 0.01 ug/ml for 24 hours. These studies demonstrated a mean 2.1 (range 1.24–4.8) fold increase in sildenafil specific/spontaneous apoptosis in lymphoplasmacytic cells from 5 of 5 patients, which included those from a patient who demonstrated a clinical response to sildenafil. Importantly, the concentrations at which apoptosis was observed in these studies is within pharmacologically achievable levels for sildenafil. The results of these studies, along with those recently reported by Sarfati et al (Blood 101:265) who demonstrated caspase mediated apoptosis of B-chronic lymphocytic leukemia (CLL) cells by sildenafil, provide the framework for investigation of sildenafil and related phosphodiesterase inhibitors in the treatment of WM and other B-cell malignancies.
Intermittent Low Doses of Thalidomide in the Maintenance Treatment of Multiple Myeloma.
Authors: Bibas Michele , Andriani Alessandro , Viva Felicetta , Gualandi Carla , Mignogna Teresa , Geraldini Claudio , Tarquini Daniela 
Published: October 2019

Abstract
BACKGROUND: Despite recent advances multiple myeloma remains an incurable plasma cell malignancy. Thalidomide has recently been recognized as an effective agent for previously untreated, refractory or relapsed myeloma.
DESIGN AND METHODS: Thirty patients with refractory/relapsed MM (22 females, 8 males) aged from 53 to 81yrs : 18 MM IgG(k), 3 MM IgA(k), 6 MM IgG(l), 2 MM IgA(l) an MM (l) were treated with thalidomide in combination with high doses (40 mg monthly) of dexamethasone and monthly zolendronate( 4 mg).All patients were treated with conventional escalated dose of thalidomide every 2 weeks starting from 100 mg daily to max tolerated dose. Of the 30 patients 19 (63 %) responded to therapy with a monoclonal reduction of more than 50% ( 4 acheived CR). Among the responders those with polineurophaty documented as a subjective simptom and with electrophysiologic objective parameters alteration entered in a reduced thalidomide schedule of 100 mg daily 10 days a month. The follow up of these patients actually ranges between 2 to 21 months, 1 patient progressed and 2 patients discontinued treatment because of a subjective progression of neurological simptoms but without electrophysiologic alterations.
RESULTS: None of the patients treated with intermittent low doses of Thalidomide developped an increase of neurophaty. Intermittent low doses of THAL may be applicable in the maintenance treatment of myeloma patients.
Patients status
Response Responders Maintenance In Study Progressed Stopped PR 15 (50%) 6 3 1 (4 mo) 2 (3 and 6 mo) CR 4 (13 %) 2 2 0 0
Fluvastatin-Zometa (FluZom) as A Possible Therapeutic Approach to Plasma Cell Disorders.
Authors: Spencer Andrew , Baulch-Brown Cindy , Reed Kate , Lynch Kevin 
Published: October 2019

Abstract
Despite significant improvement in the outlook for newly diagnosed patients with multiple myeloma (MM) the disease remains incurable. Novel therapeutic approaches are therefore required. We have previously demonstrated in vitro that both the third generation nitrogen-containing bisphosphonate zometa and the HMG-CoA reductase inhibitor fluvastatin have anti-proliferative and apoptosis-inducing effects against human myeloma cell lines (HMCL). Furthermore, isobologram analyses with the 2 compounds have demonstrated synergistic activity against HMCL. Based on this we have undertaken a pilot study of fluvastatin and zometa (FluZom) in a group of patients with progressive plasma cell disorders (PCD). A 16-week treatment phase was planned with patients commencing fluvastatin 40mgdaily on day 1 escalating to 80mg daily from day 15 to day 112. Zometa 4mg IV over 15 minutes was given on days 29, 57, 85 and 112. Any patient demonstrating any response, based on conventional criteria, or stable disease (SD) by day 112 remained on treatment until further progression (PD). PD prior to day 112 mandated treatment withdrawal. Eleven patients were enrolled on trial - progressive MM (n = 9), smouldering myeloma (SMM) progressing to MM (n = 1) and progressive POEMS disease with multisystem involvement (n = 1). All except the SMM patient were heavily pretreated - median 3 (range, 0 – 6) prior treatment regimens, 7 with prior ASCT and 4 with prior radiotherapy. Median age was 61 years (range, 44 – 74). Six patients completed 16 weeks of therapy, 5 progressed prior. Of the former, 4 (36%) demonstrated SD and continued on therapy to a total of 20, 23 (patient no. 2), 28 (patient no.1) and 45 weeks. No patient demonstrated a disease response based on standard criteria. Patients no.’s 1 and 2 were pancytopenic prior to therapy and demonstrated normalisation of haemoglobin (no. 1), platelets (no. 1) or total leucocytes (no.’s 1 and 2). Two patients, neither of whom achieved SD but who completed 16 weeks of therapy, had a plasma cell labelling index (PCLI) undertaken pre and post therapy, both showed a reduction in the PCLI following therapy - 5.4% to 3.6% and 2.6% to 1.3%, respectively. Therapy was well tolerated with 3 patients developing transient elevation of liver transaminases. We conclude that FluZom while not producing disease response as judged by conventional criteria did nonetheless exhibit beneficial biological activity in a minority of this cohort of progressive PCD patients. Further evaluation in patients with early and/or untreated disease is warranted.
Complex Alterations in Serum Cytokines and Increased Il-4 Levels Characterize Patients Developing Chronic Thrombocytopenia after Allogeneic Hematopoietic Cell Transplantation.
Authors: Elshal M. , Takahashi Y. , Chakrabarti S. , Srinivasan R. , Suffredini D. , Igarashi T. , Solomon S. , Lundqvist A. , Barrett A. J. , McCoy J. P. , Childs Richard 
Published: October 2019

Abstract
Isolated chronic thrombocytopenia (CT) following allogeneic HCT is associated with an increased risk of transplant-related mortality and a reduction in long-term survival. Although the pathogenesis of CT is not entirely clear, it has been speculated that immune activation and cytokine dysregulation characteristic of chronic GVHD (CGVHD) play a similar role in the pathogenesis of this disorder. To better understand the impact of endogenous cytokine expression on platelets, we analyzed pro and anti-inflammatory cytokines in the serum of patients with CT following allogeneic HCT, comparing levels to healthy donors and to patients with normal platelet counts after allo-transplantation. Serum was obtained from 3 patient groups; Group 1- healthy donor controls (n=12): Group 2- post-transplant from allogeneic HCT patients with normal platelet counts (n=31): Group 3- post transplant from patients with CT (n=11). Using micro sphere-based Luminex flow cytometry, serum was analyzed for levels of the pro-inflammatory cytokines IL-6, IL-8, and TNF-α as well as Th(1) cytokines IL1-b, IL-2, IL-12, IFN-g and Th(2) cytokines IL-4, IL-5, and IL-10.
Results: Both post transplant cohorts (Group 2 and 3) had higher mean levels of GM-CSF (110 and 120 pg/ml), IFN-g (17 and 16 pg/ml), and IL-12 (318 and 202 pg/ml) compared to their respective non-transplant (Group-1) controls (GM-CSF 23 pg/ml: p<.001; IFN-g 4 pg/ml: p<0.01; IL-12 60 pg/ml: p<0.05). Compared to group 2 patients, Group 3 patients with CT had significantly lower mean levels of TNF-α (46 vs 26pg/ml: p<0.03), IL-12 (318 vs 202 pg/ml: P<0.05) and IL-8 (83 vs 59: p<0.05). In contrast mean serum levels of IL-4 (43 vs 26 pg/ml: p<0.001) and IL-5 (51 vs 9 pg/ml: p<0.05) were significantly higher in group 3 CT patients compared to Group 2 patients without thrombocytopenia. When subdivided into groups based on the presence or absence of chronic GVHD, mean IL-4 levels were significantly higher in CT patients with or without CGVHD (33 and 44 pg/ml respectively) compared to post transplant patients without CGVHD with normal platelet counts (18pg/ml: p<0.05). In contrast, patients with CT with or without CGVHD had significantly lower mean levels of IL-8 (89 and 49 pg/ml respectively) compared to patients with or without CGVHD (200 and 126 pg/ml respectively: p<0.05) who did not have thrombocytopenia. We conclude that complex alterations in both pro and anti-inflammatory cytokines are involved in the pathophysiology of CT following allogeneic HCT; based on these data, studies investigating the therapeutic potential of IL-4 inhibition in patients developing CT might be considered.
Latent-Membrane 2a Specific CTL’s but Not Latent-Mebrane 1 Specific CTL’s Lysis Efficiently Hodgkin Lymphoma Cells.
Authors: Topp Max S. , Diekamm Jan , Beck Olaf , Rauser Georg , Hauschulz Kai , Neff Christina , Kuntz Gabriele , Einsele Hermann 
Published: October 2019

Abstract
Relapse is the leading cause of treatment failure after allogeneic SCT of Hodgkin Disease (HD). As Ebstein-Barr infection (EBV) is associated with 60% of all HD cases, adoptive immunotherapy with donor derived EBV-specific T-cells lines has resulted in disease control of allogeneic SCT. Potential targets for the adoptively transferred T-cells are the type II latency protein LMP-1 and LMP-2a, which are both homogenously expressed by HD cells. In healthy individuals, both LMP-1 and LMP-2a elicits subdominant CD8+ T-cell responses with frequencies of less than 1:10000. LMP-1 and LMP-2a specific T-cells from 1x108 PBMC derived from HLA A*0201+healthy donors were stimulated with the HLA A*0201 LMP1-epitopes YLLEMLWRL and YLGQNWWTL and the HLA A*0201 LMP-2a epitope CLGGLLTM. Activated T-cells were selected by the cytokine secretion assay and expanded for 10 days. In 85% of donors 1.7 x106 (range 0.7 –4.5 x106; n=13) LMP-1 or LMP-2a specific CD8+ T-cell could be generated with an average purity of 83% as determined by tetramer staining. LMP1- and LMP2a-specific CD8+ T-cells were then expanded 3000 x in 14 d by the rapid expansion protocol and evaluated functionally for cytokine production and specific lysis. Both LMP-1 and LMP-2a specific CD8+ T-cells retained specific cytokine production if stimulated with peptide pulsed targets, efficiently lysed peptid pulsed targets. Surprisingly, if LMP-1 was presented endogenously by EBV positive targets or by targets cells transduced with LMP-1, no cytokine production or specific lysis was detected despite protein expression of LMP-1 in all targets. In contrast, IFN-γ production could be readily detected in LMP-2a-specific CD8+ T-cells after stimulation with target cells processing endogenously the LMP-2a antigen as well as specific lysis of EBV positive target cells. Furthermore, LMP2a specific CD8+ demostrated also specific lyse of Hodgkin-cells expressing the LMP2a (30:1 E/T ratio; 29,3%) where as LMP-1-specific CD8+ T-cells could not lyse HD-cells. In summary, LMP-1 and LMP-2a specific T-cells, although present at undectable levels in healthy donors, can be readily selected and expanded to up to 6x109 antigen-specific T-cells in less than 4 weeks starting from 1x108 PBMC. Based on this data, adoptive immunotherapy of relapsed EBV positive HD after allogeneic SCT should be preferentially performed with LMP-2a specific CD8+ T-cells rather than with LMP-1 specific CD8+ T-cells.
An Interim Report Experience on Acute Leukemia and High Dose Therapy in Jehovah’s Witnesses Treated in a Single Institution.
Authors: Mazza Patrizio P. , Palazzo Giulia G. , Amurri Barbara B. , Pisapia Giovanni G. , Pricolo Giancarla G. , Prudenzano Antonella A. , Stani Loredana L. 
Published: October 2019

Abstract
The major difficulty in the treatment of Jehovah’s Witnesses with haematological malignancies is the deny to the transfusion of blood products as support to chemo-radiotherapy; since the use of any form of bone marrow transplantation it is instead not precluded, this may be an alternative. From 1997 to July 2004 we treated 9 Jehovah’s Witnesses with de novo acute leukaemia without transfusions of blood products; in the same period 10 Jehovah’s Witnesses with various malignancies received high-dose therapy as conditioning to autologous PBSCT or allogeneic BMT. Acute leukaemia consisted of FAB-M3 4 patients (pts), FAB-M4 1 pt, FAB-L1 1 pt, FAB-L2 2 pts, FAB-L3 1 pt. Hb at diagnosis was 10.3g/dL mean (5.5–14.0 range), PLT at diagnosis were 40x10^3/μL mean (5–197 range). The mean age of pts was 26.2 years (2–49 range). The treatment consisted of protocols in use in our Institution at the time of diagnosis. The nadir of Hb was 5.3g/dL mean (1.3–8.3 range) and it was reached 10 days mean from start of therapy (1–16 days range); the nadir of PLT was 16x10^3/μL mean (0–70 range) and was reached 6 days mean from start of therapy (1–13 days range). The results to therapy show that 8/9 pts reached a CR and 1 died for anaemia during induction when the Hb was 1.3g/dL; at the follow-up 2 pts relapsed 3 and 8 months, respectively and died for disease progression, 6 pts are alive and in CR 12–60 months following the end of therapy. The patients undergoing high-dose therapy included NHL 1 pt, ALL 2 pts, CLL 1 pt, Breast Cancer 1 pt, CML chronic phase 1 pt, CML blastic phase 1 pt, MDS 1 pt, MM 1 pt and AML 1 pt; 6 of them received autologous PBSCT and 4 allogeneic BMT. Three pts were in CR following first-line therapy, 5 in relapse and 2 with progressive untreated disease. High-dose therapy consisted of classic Thiotepa and Melphalan, CTX and TBI, BEAM and Melphalan alone depending the disease. Hb before high-dose therapy was 12.2g/dL mean (6.2–14.0 range) and PLT were 186x10^3/μL mean (10–328 range). The nadir of Hb was 7.2g/dL mean (2.0–11.0 range) and that of PLT 6.0x10^3/μL (1–14 range). The recovery of reticulocytes (>20x10^3/μL) was reached at 12 days from HDT mean (7–22 range) and PLT (>20x10^3/μL) at 13 days mean (8–27 range). None of patients occurred major bleeding or complications due to anaemia. One pt died for acute GVHD 2 months following TMO, 3 pts died for disease progression and 6 pts are alive in CR 2–48 months following HDT. In conclusion this study demonstrates that therapy for acute leukaemia and high-dose therapy as conditioning to bone marrow transplant are feasible in patients refusing transfusions of blood products and the results are almost similar to comparable patients accepting blood transfusions.
The Effects of Super-Intensified Conditioning Regimen of Allogeneic Hematopoietic Stem Cell Transplantation for Refractory Leukemia.
Authors: Liu Qifa , Sun Jing , Xu Dan , Zhang Yu , Fan Zhiping , Wei Yongqiang , Meng Fan Yi , Zhou Shuyun 
Published: October 2019

Abstract
Objective To explore the regimen related toxicity (RRT) and the effects of super-intensified conditioning regimen combined with inducing graft versus leukemia (GVL) in allogeneic hematopoietic stem cell transplantation (allo-HSCT) for refractory leukemia which can’t obtain complete remission (CR) pre- transplantation.
Methods 18 patients who did not obtain CR before transplantation received super-intensity conditioning regimen protocol(experimental group), and 62 patients with acute leukemia who obtained CR or chronic myeloid leukemian (CML) who were in the chronic phase before transplantation received total body irradiation (TBI) plus cyclophosphamide (CTX) or modified BuCY (hydroxyurea, busulfan, Ara-C, CTX) protocol (control group). Cyclosporin A was reduced rapidly and gradually or donor lymphocytic infusion (DLI) was used to induced GVL if acute graft versus host disease (GVHD) did not happened in patients with refractory leukemia at 30 days post-transplantation. The incidence and mortality of RRT during transplantation, and the rate of CR, GVHD and leukemia relapse after transplantation was investigated. Kaplan-Meier survival analysis model was used to estimate the disease-free survival (DSF) rate at 3 years post-transplantation.
Results Except one patient in experimental group and two patients in control group died of transplant-related complications, all the other patients obtained hematopoietic reconstitution.’ the total RRT incidence were both 100% in two groups. The RRT of stomach intestine were most common in all the organs and the RRT incidence of experimental group and control group was 83.3% and 85.5%, respectively, in stomach intestine. The RRT incidence was 44.4% and 62.9% in oral cavity and 16.7% and 33.9% in bladder, respectively, in the experimental group and control group. There was no significance and P value was 0.823, 0.172 and 0.244, respectively, in the RRT incidence of stomach intestine, oral cavity and bladder between the two groups. The RRT mortality was 0 and 5%, respectively, and was not different (P=0.341) in the experimental and control group. Except one patient died of infection, all the other patients obtained CR in patients who were treated with supper-intensified conditioning regimen. The incidences of acute or chronic GVHD were 58.8% and 40.0% or 92.6% and 55.8%, respectively, in the experimental and control group. The incidence of leukemia relapse was 11.8% and 18.3%, respectively, in the two groups. The DSF at 3 years after transplantation was 61.2±12.3% and 65.0±7.4% (P=0.6311), respectively, in the two groups.
Conclusion The consecutive super-intensified conditioning regimen combined with inducing GVL post transplantation protocol can increase the rate of CR and DFS, and dose not increase RRT incidence and mortality in allo-HSCT for the refractory leukemia which can’t obtain CR pre- transplantation.