bluuebunny/crossref_metadata_2025_split huggingface dataset:
Heat Shock Protein Localisation in Chronic Lymphatic Leukaemia.
Authors: Dempsey Nina C , Leoni Francesca , Williams John H.H. , Hoyle Christine 
Published: April 2020

Abstract
Heat Shock Proteins (Hsps) are a highly conserved group of molecular chaperones, the over-expression of which has been well documented in many cancer types. However, the location of these proteins within the cancer cell appears to be crucial in terms of tumour progression. Intracellular Hsp70 expression in particular appears to confer resistance to apoptosis, while surface Hsp70 expression has been shown to aid immune recognition of the cancer cell by NK cells. High intracellular levels of Hsp90 and Hsp27 also contribute to cell survival, while surface Hsp90 and Hsp27 have been shown to be required for tissue invasion and metastasis. However, the importance of these stress proteins in CLL progression is still poorly understood.
Using flow cytotmetry, we show that CLL patients express significantly higher levels of iHsp90 in lymphocytes (mean MFI CLL = 2463, Control = 748) and significantly higher levels of iHsp27 in lymphocytes (mean MFI CLL = 2138, Control = 760) than that expressed by age-matched control patients. The expression of iHsp90, but not Hsp27, in these patients was shown to be related to the stage of disease, and patients in Binet stage A appear to have a significantly higher expression than those in Binet stage C (p&lt;0.001).
Hsp70 expression in CD5+/CD19+ cells, both intracellular and extracellular, showed either a very high level or a very low level of Hsp70 (see figure below). The high expressing groups were found also to be significantly different (p&lt;0.01) from both the non-malignant cells from the same patients, and normal lymphocytes from age-matched controls. This was not the case for the low expressing groups. iHsp70 expression was also seen to be related to stage of disease as patients in Binet stages A and B were found to express significantly lower levels than those patients in Binet stage C.
Hsp expression was shown not to be associated with the apoptotic condition of the cell as analysis of active caspase-3 in CLL patients proved that the majority of the leukocytes were not apoptotic. Furthermore, the mean of fluorescence was significantly less in lymphocytes from CLL patients (mean MFI = 139) than those from control patients (mean MFI = 278).
Taken together these results show that Hsp expression changes with the natural progression of the disease and therefore manipulation of Hsps may be beneficial in the treatment of CLL.
Figure Figure
Bendamustine Versus Chlorambucil as First-Line Treatment in B Cell Chronic Lymphocytic Leukemia: An Updated Analysis from An International Phase III Study.
Authors: Knauf Wolfgang Ulrich , Lissitchkov Toshko , Aldaoud Ali , Liberati Anna , Loscertales Javier , Herbrecht Roul , Juliusson Gunnar , Postner Gerhard , Gercheva Liana , Goranov Stefan , Becker Martin , Hoeffken Klaus , Huguet Francoise , Foa Robert , Merkle Karlheinz , Montillo Marco 
Published: April 2020

Abstract
Introduction: Bendamustine is a purine analog/alkylator hybrid agent with a unique mechanism of action, which has shown good clinical efficacy and acceptable tolerability in various hematological malignancies, including Hodgkin’s disease, non-Hodgkin’s lymphoma, and multiple myeloma.
Patients and Methods: The efficacy and safety of bendamustine and chlorambucil have been compared in a randomized, open-label, multicenter, Phase III trial in patients with previously untreated advanced (Binet stage B/C) B cell chronic lymphocytic leukemia: an updated analysis from this trial is presented here. Patients were randomized to receive bendamustine (100 mg/m2 on days 1 + 2) or chlorambucil (0.8 mg/kg on days 1 and 15) for up to 6 treatment cycles. The median cumulative dose per patient was 1820 mg and 517 mg for bendamustine and chlorambucil, respectively. The primary endpoints were overall remission rate (ORR), which was defined as complete response, nodular partial response or partial response, and progression-free survival (PFS). Secondary endpoints included overall survival (OS) and safety. The response to treatment was evaluated by a blinded Independent Response Assessment Committee.
Results: A total of 319 patients were randomized (162 bendamustine, 157 chlorambucil), of whom all were included in the efficacy analysis and 312 were evaluable for safety. The mean (± SD) number of treatment cycles was 4.8 ± 1.7 in the bendamustine group and 4.6 ± 1.7 in the chlorambucil group; the median duration of follow-up was 29.2 months (29.8 bendamustine, 27.8 chlorambucil). The ORR was significantly higher with bendamustine than with chlorambucil (67% versus 30%, P&lt;0.0001). The median PFS was 21.5 months with bendamustine and 8.3 months with chlorambucil (P&lt;0.0001). No difference in OS was seen between groups. Most doses were given on schedule. The mean overall relative dose intensity was 86% and 96% in the bendamustine and chlorambucil treatment groups, respectively. At least 1 grade 3/4 neutropenia occurred in 43% of bendamustine-treated patients and 21% of those receiving chlorambucil. Grade 3/4 infections were documented in 7% of bendamustine-treated patients and 4% of chlorambucil-treated patients.
Conclusion: This study has shown that bendamustine offers significantly greater efficacy than chlorambucil, with manageable toxicity, and should be considered as first-line chemotherapy for patients with advanced B-CLL.
Treatment with Lenalidomide Has a Positive Immunomodulatory Effect in Patients with Chronic Lymphocytic Leukemia.
Authors: Gao Hui , Ferrajoli Alessandra , Cohen Evan N , Lee Bang-Ning , Tin Sanda , O’Brien Susan , Wierda William G. , Estrov Zeev , Faderl Stefan , Keating Michael J , Reuben James M. 
Published: April 2020

Abstract
Lenalidomide (Revlimid) is known to downregulate TNF-a, IL-6, IL-8, and VEGF, impair bone marrow microenviroment-neoplastic cell interaction, activate NK cells, and stimulate T-cell activity. Based on these properties, we sought to further evaluate the immumodulatory activity of treatment with lenalidomide in patients with previously untreated chronic lymphocytic leukemia age 65 and older. Nineteen patients enrolled in a phase II clinical trial were treated with lenalidomide, given orally at the dose of 5mg daily for 28 days followed by individual titration up of 5mg increments every 28 days to reach a maximum dose of 25mg daily. Patients were evaluated for response after 3 months and if an objective response or disease stability was obtained, the treatment was continued until obvious disease progression. Peripheral blood (15ml) was collected at baseline, after three months and every six months thereafter while on treatment in patients that agreed to optional correlative studies. Data at baseline and after three months of treatment are presented. Plasma cytokine levels were determined by Luminex Multiplex assay system. Percentages of CD3, CD4, and CD8 T cells and natural regulatory T cells (TR, CD4+CD25hiFoxP3+) cells, and the ability of anti-CD3 activated T cells to synthesize of IL-2, IFN-g, TNF-a, and IL-10 were measured by multi-color flow cytometry. Eleven patients had a partial response (responder, R) and 8 patients failed to respond (non-responder, NR) after 3 months of therapy. All patients had significantly higher percentages of CD3+ and CD4+ T-cells (P = 0.012) after three months of treatment respect to baseline, but only R patients had a significantly higher percentage of TR cells (P = 0.041). Both R (P = 0.016) and NR (P = 0.025) patients had higher percentages of IFN-g-producing CD8+ T cells after three months of therapy. Moreover in NR patients, the percentage of TR cells negatively correlated with the percentages of CD4+ T cells that produced IL-2 and TNF-a, and of CD8+ T cells that produced IFN-g and TNF-a. Following 3 months of therapy, plasma levels of IL-10 were significantly increased in both R (P =0.012) and NR (P = 0.05); IL-1b plasma level was elevated in NR (P = 0.012) but not in R; IL-17 plasma level was decreased in R (P = 0.006); neither R nor NR had changes in plasma levels of IL-1RA, IL-2, IL-6, TNF-a, TNF-R1, VEGF, and VEGF-R (R1, R2, R3). In conclusion treatment with lenalidomide increased the percentages of T-helper cells in both R and NR patients and of TR cells in R patients. Treatment with lenalidomide also increased the function of CD8+ T cells as exhibited by the synthesis of IFN-g in both R and NR patients. These preliminary data suggest that lenalidomide has a favorable immunomodulatory effect on patients with B-CLL. Sample collection is ongoing for further analyses.
Loss of the Y Chromosome in Philadelphia-Positive Cells Predicts a Poor Response of CML Patients to Imatinib Mesylate Therapy.
Authors: Lippert Eric , Laibe Sophy , Mozziconacci Marie-Joelle , Gervais Carine , Girault Stéphane , Gachard Nathalie , Tigaud Isabelle , Dastugue Nicole , Huguet Francoise , Fort Marie-Pierre , Eclache Virginie , Mahon Francois-Xavier 
Published: April 2020

Abstract
Loss of the Y chromosome (-Y) in bone marrow cells frequently occurs in elderly patients. It is thus unclear whether loss of the Y chromosome, when found in Philadelphiapositive cells, should be overlooked, or whether it represents a clonal evolution (a criterion of cytogenetic acceleration of the disease) or an additional cytogenetic abnormality (ACA), considered of little importance in patients treated with imatinib mesylate (IM). We have collected diagnostic characteristics, clinical, cytogenetic and molecular evolution data from 29 patients diagnosed with CML from 1991 to April 2007 in 6 participating centres, who presented a loss of the Y chromosome at diagnosis (n=20) or during evolution (n=9) and who were treated with imatinib in first (n=19) or second (n=10) line. They were compared to patients with a Philadelphia chromosome as sole anomaly, diagnosed at similar dates in the same centres, thus benefitting from the same management. Age and Sokal score at diagnosis were similar. In both -Y and control groups, two thirds of patients had received prior treatment (mostly interferon, hydroxyurea and aracytine). Median follow-ups were respectively 54 months (range: 7–146) and 58 months (range: 13–149), censored if therapy was changed for a second generation tyrosine-kinase inhibitor or bone marrow transplantation. The time to achieve complete cytogenetic remission (CCR) (22 months vs 7, p=0.02) and major molecular response (MMR) (not reached vs 30 months, p=0.0015) were significantly higher in -Y patients. Acceleration (8/29 vs 1/29, p=0.003), acutisation (4/29 vs 1/29, p=0.1) and death (3/29 vs 1/29) were more frequent in the -Y group, but owing to the rare occurrence of these events, statistical significance was clear for acceleration only. Interestingly, prognosis (time to CCR, MMR and occurrence of acceleration) was worse if loss of the Y chromosome was present in a subclone (suggesting a clonal evolution) rather than all mitoses (ACA) and also when it was observed at diagnosis rather than during the evolution of the disease. Consequently, survival was significantly reduced (55 months vs not reached, p=0.009) in those patients for whom -Y was present in a subclone at diagnosis. In conclusion, loss of the Y chromosome in Philadelphia-positive cells is an important finding since it affects the prognosis of CML patients, especially, but not exclusively, when present at diagnosis in a subclone. In this case, loss of the Y chromosome even predicts a decreased survival after imatinib treatment.
Long-Term Immune Deficiency (ID) after Allogeneic Stem Cell Transplantation (allo-SCT) Following a Myeloablative (MA) Conditioning Regimen.
Authors: Corre Elise , Carmagnat Maryvonnick , Busson Marc , de Latour Regis Peffault , Robin Marie , Ribaud Patricia , Toubert Antoine , Rabian Claire , Socie Gerard 
Published: April 2020

Abstract
Background; although numerous studies have described ID in the short-term post transplant, few include data on long-term ID following allo-SCT.
Aim; describe longitudinally the evolution of T-, B-, and NK-cells in a cohort of 140 consecutive pts following allo-SCT and to correlate this evolution with the advent of late clinical infections.
Patients & Methods; 140 pts with a median follow-up of 38 months (mo) were studied [median age 27 (39 less than 16) & 77% with malignancies]. Bone marrow (81%) from sibling (66%) was used before MA conditioning regimen (TBI 42%). 51% had grade II–IV acute- and 30% extensive-GvHD. All pts were monitored before and at 3, 6, 12, & 24 mo post transplant for both CD4 & CD8 subsets [CD45RA (naïve), 45RA+62L- (terminally differentiated), 45RO+ (memory), 28+ (competent), and Dr+ (activated)],NK cells (CD3-, 16+56+), and B cells CD19+/5+, 19+/27- (naives) and 19+27+ (memory).
Results; we observed; for both CD4 CD8 a 1- year ID of the naive, memory and competent and above limits value for competent subsets; NK normalization at 6 mo; expansion of CD19+/5+ after 3 mo and persisting (till 24 mo) ID of memory B cells. Chronic GvHD did not influence significantly those parameters for CD8 subsets while strongly affecting the naïve and competent CD4 subsets, but the most profound defect was on B cell subsets especially on memory B. Contrasting this profound ID the cumulative incidence of late severe infections (LSE) was rather low (14% at 4 years). The only clinical factor that was marginally statistically linked to these was the use of PBSC instead of marrow. We then finally constructed Cox models to search for putative clinical or immunological risk factors for these LSE. Only low B cell counts at 6 (p=.05) & 24 mo (p=.016) were associated with the hazard of developing SLE, in particular if patients did not developed chronic GvHD (see Figure)
Figure Figure
Conclusion; despite a long lasting ID post transplant following MA conditioning the rate of LSI remains low with modern antimicrobial prophylaxis; only B cell defect correlated with LSI despite immunoglobulin supplementation in pts with low Ig level.
Genomic Instability Is Frequent in Oral and Rare in Nasal Mucosal Cells of Allogeneic HCT Recipients.
Authors: Khan Faisal , Sy Sarah , Louie Polly , Lee Robyn , Stewart Douglas A. , Russell James A. , Storek Jan 
Published: April 2020

Abstract
Genomic Instability (GI), appraised by microsatellite length alteration, is a precancerous or cancerous condition. We hypothesized that genomic instability is frequent in oral but not nasal mucosal cells of HCT recipients as oral but not nasal carcinoma is frequent in long-term HCT survivors.We examined epithelial cells from buccal and nasal mucosa of 35 subjects for the presence of GI at 15 microsatellite loci spanning 14 human autosomes. The study population included long-term allo-HCT survivors (4–22 yrs, n=18) and short-term allo-HCT survivors (2–3 months, n=5), and long-term auto-HCT survivors (4–12 yrs, n=5). Controls also included 5 patients treated with intensive chemotherapy and 2 healthy volunteers. DNA extracted from peripheral blood leukocytes and cells of nasal and buccal mucosa was PCR amplified for a panel of 15 Short tandem repeat (STR) markers (ABI-Identifiler TM). The amplicons were subjected to capillary electrophoresis and fragment size analysis was performed to identify novel allele peaks (one that was absent in donor and recipient blood pre-transplant but present in recipient mucosa post-transplant) indicative of microsatellite instability (MSI). MSI was observed in buccal mucosal cells of 56% long-term survivors of allo-HCT; the number of STR loci showing novel allele peaks ranged from 1–6 (median=3). None of the short-term survivors of allo-HCT, long-term survivors of auto-HCT, or control individuals showed MSI in the buccal mucosal cells. Only one allogeneic HCT survivor showed MSI (at one STR locus) in nasal mucosal cells. No genomic alterations were observed in blood leukocytes of any of the above patients or controls. In conclusion, genomic instability is frequently observed in long-term allo-HCT suvivors in oral mucosal cells but rarely in nasal mucosal cells. The facts that oral but not nasal mucosa is frequently involved in chronic GVHD and that MSI was not detected in recipients of auto-HCT suggest that graft-vs-host reaction induces genomic instability.
Reduced Intensity Conditioning Allogeneic Stem Cell Transplantation (RIC allo-SCT) for Patients with High-Risk Multiple Myeloma (MM): A Survey from the Societe Francaise De Greffe De Moelle Et De Therapie Cellulaire.
Authors: Mohty Mohamad , Quoc-Hung Le , Nicolini Franck E , Garban Frederic , Socie Gerard , Attal Michel , Milpied Noel- Jean , Lioure Bruno , Bordigoni Pierre , Yakoub-Agha Ibrahim , Bourhis Jean-Henri , Rio Bernard , Deconinck Eric , Renaud Marc , Harousseau Jean-Luc , Blaise Didier , Michallet Mauricette 
Published: April 2020

Abstract
The results of RIC allo-SCT for MM are still under considerable debate. While EBMT data did not support the universal use of RIC for MM allografts, the Italian and spanish randomized multicenter trials suggested that in newly diagnosed myeloma, outcome in recipients of a hematopoietic stem-cell autograft followed by RIC allo-SCT from an HLA-identical sibling is superior to that in recipients of tandem stem-cell autografts. The aim of this multicenter retrospective national study was to identify prognostic factors for outcome of high-risk patients with MM after allo-SCT prepared by RIC. Data from 219 patients (median age 52 years, range 27–66), who received grafts from a sibling (n=197) or unrelated donor (n=22) were analyzed. At time of transplant, only 37 patients (17%) received RIC allo-SCT in CR or VGPR, while 134 patients (61%) were transplanted in PR. 48 patients were transplanted either in stable disease (n=15) or were in refractory/ progressive disease (n=33). All patients have received at least one autologous transplant prior to RIC allo-SCT. The graft source was PBSCs in the majority of patients (n=183). 21% of the patients received the Seattle Fludarabine and low dose TBI RIC regimen, while 53% of patients received Fludarabine, Busulfan and ATG. 32 patients (15%) died of transplant-related complications. The incidences of grade 2–4 acute GVHD and extensive chronic GVHD were 37% and 20% respectively. At 3 years, overall and progression free survivals (OS, PFS) were 41% (95%CI, 34–49) and 19% (95%CI, 14–27) respectively. Disease status (CR, PR, SD vs. progressive) was significantly associated with overall survival (P=0.0002). In multivariate analysis, disease status at time of RIC allo-SCT, was the strongest parameter associated with an improved OS and PFS (P=0.005 and P=0.004 respectively). Despite its obvious caveats, the relatively low TRM observed in this series, suggest that there is still space to investigate RIC allo-SCT for MM. However, RIC allo- SCT appears to result in a durable response only if it is applied early in the disease history, especially when patients are still chemosensitive. Since the latter results are also expected to be further improved with the systematic and early use of maintenance therapies (Bortezomib and/or Lenalidomide) after RIC allo-SCT, randomized or quasirandomized prospective studies are still warranted.
Prognosis Value of [18f] FDG-PET Prior Versus after Autologous Stem Cells Transplantation in High Grade Non-Hodgkin’s Lymphoma.
Authors: Roland Virginie , Milin Caroline Bodet , Moreau Anne , Gastinne Thomas , Mahe Beatrice , Dubruille Viviane , Maisonneuve Hervé , Morineau Nadine , Moreau Philippe , Jardel Henri , Planche Lucie , Moreau Philippe , Harousseau Jean- Luc , bodere Françoise Kraeber , Le Gouill Steven 
Published: April 2020

Abstract
Positron emission tomography using fluorine 18-fluorodeoxyglucose (FDG-PET) is required in the assessment of therapeutic response in diffuse large B-cell lymphoma. Limited studies addressed the interest of FDG-PET prior autologous stem cells transplantation (auto-SCT) in High-grade non Hodgkin’s lymphoma (HG-NHL). Between April 2002 and December 2005, 42 HG-NHL (DLBCL in 35 cases and aggressive transformation in 7 cases) patients underwent auto-SCT in our institution and were systematicaly explored prior and after auto-SCT using computed tomography (CT) and FDG-PET. The therapeutic strategy included R-CHOP or R-DHAP as induction chemotherapy followed by auto-SCT. In note, auto-SCT was always included in the initial strategy and scheduled after completion of induction chemotherapy for patients at least in partial response (PR) according CT assessment. Pre-auto-SCT FDG-PET results did not influence the scheduled strategy. Auto-SCT was performed as part of the first-line therapy in 35 cases (83 %) or at the time of relapse in 10 cases. Prior auto-SCT, 14 patients were in PR and 24 in CR/Cru. Conditioning regimen consisted of BEAM in all cases (except one patient). The median follow-up (calculated from the time of auto-SCT) for living patients was 34,5 months [19–74 months]. The 2-years EFS and OS estimates were 79,6 % [63,2%; 89,3%] and 90,5 % [76,6%; 96,3%], respectively. According to pre and post auto- SCT FDG-PET results, patients were classified into 3 groups: NEG/NEG (n=25) POS/ POS (n=8) and POS/NEG (n=9). The 2-years EFS and OS estimates for NEG/NEG, POS/ POS and POS/NEG patients were 88 % versus 19 % versus 100 % (p= 0,0001) and 92 % versus 75 % versus 100 % (p = 0,19), respectively. According to FDG-PET response after auto-SCT, the 2-years EFS estimates for NEG versus POS patients were 90, 9 % versus 19 % (p&lt;0,0001). In contrast, pre auto-SCT FDG-PET status has no prognosis value on both EFS (2-years EFS: 88% versus 65%) and OS (2-years EFS: 92% versus 88%). We conclude that only post and not pre-auto-SCT FDG-PET results has a prognostic value in HG-NHL. This result suggests that an pre-transplant intermediate positive FDGPET should not delay a scheduled ASCT which could clean off the negative value of an intermediate positive FDG-PET.