bluuebunny/crossref_metadata_2025_split huggingface dataset:
Outcomes after Autologous Stem Cell Transplantation for Mantle Cell Lymphoma Based on Remission Status and Induction Chemotherapy Regimen.
Authors: Till Brian G. , Gooley Theodore A. , Crawford Nathan , Gopal Ajay K. , Maloney David G. , Petersdorf Stephen H. , Pagel John M. , Holmberg Leona , Bensinger William , Press Oliver W. 
Published: April 2020

Abstract
Mantle cell lymphoma (MCL) has one of the worst prognoses of any subtype of non-Hodgkin’s lymphoma (NHL), with a median survival of 3–4 years in most series. High-dose therapy followed by autologous stem cell transplantation (ASCT) is an increasingly common treatment approach for MCL, and some ASCT studies suggest that less heavily pre-treated patients have a longer duration of progression-free survival (PFS), suggesting that ASCT may lead to more favorable outcomes if used earlier in the course of therapy. We analyzed the outcomes of ASCT with respect to remission status at the time of transplantation and induction regimen used in 56 consecutive transplanted patients with MCL. Twenty-one patients received induction chemotherapy with HyperCVAD with or without rituximab (±R) followed by ASCT in first complete or partial remission (CR1/PR1), 15 received CHOP (±R) followed by ASCT in CR1/PR1, and 20 received ASCT following disease progression. A variety of conditioning regimens were used for ASCT in all 3 groups. Estimates of overall (OS) and progression-free survival (PFS) at 3 years among patients transplanted in CR1/PR1 were 93% and 63%, compared with 46% and 36% for patients transplanted with relapsed or refractory disease, respectively (Figure 1). The hazard of mortality among patients transplanted with relapsed or refractory disease was 6.09 times that of patients transplanted in CR1/PR1 (P=.006). Patients in the CHOP (±R) group appeared to have a higher risk of failure for PFS compared to patients in the HyperCVAD (±R) group, though the difference did not reach statistical significance (hazard ratio [HR] 3.67, P=.11) with the small sample size available. The estimated 3-year PFS was 81% for patients in the HyperCVAD group and 44% for patients in the CHOP group. Patients who received R with induction therapy had a reduced risk of mortality (HR 0.33, P=.05) and failure for PFS (HR 0.28, P=.005) compared to those who did not. In summary, these results suggest that ASCT in first remission leads to improved survival outcomes for patients with MCL compared to ASCT with relapsed or refractory disease, and a HyperCVAD (±R) induction regimen may be associated with an improved PFS among patients transplanted in CR1/PR1.
Figure 1. Kaplan-Meier estimates of overall survival from the time of ASCT, with respect to remission status at ASCT. Figure 1. Kaplan-Meier estimates of overall survival from the time of ASCT, with respect to remission status at ASCT.
BEAM as a Frontline High Dose Chemotherapy Supported by Autologous PBSCT in Elderly Patients (≥60 Years) with Diffuse Large B-Cell Lymphoma (DLBCL): Comparison with Younger Cohort of Patients.
Authors: Ivanov V. , Coso D. , Rey J. , Aurran T. , Stoppa A.-M. , de Collela J.-M. Schiano , Gastaut J.-A. , Blaise Didier , Bouabdallah R. 
Published: April 2020

Abstract
Recent developments in supportive care increase the number of elderly patients available for high dose therapy (HDT) supported by autologous PBSCT. In several clinical trials high dose chemotherapy supported by PBSCT as a part of first-line treatment in young NHL patients with poor prognostic features suggested survival benefit. It is not clear if the same strategy is applicable into the older patients. The Institute Paoli-Calmettes database was reviewed for all DLBCL patients received BEAM followed by PBSCT in two age cohorts: 50–59 years old and &gt;=60 years old between January 1998 and December 2006 (9 years). All patients were HIV-negative and received BEAM intensification as a part of front-line treatment. All of them were grafted in situation of complete or partial response after CHOP or R-CHOP induction. There was no significant difference into the aaIPI score between the groups (aaIPI score ≥ 2: 17 pts (63%) in elderly and 17 pts (61%) in younger group. Factors evaluated included treatment-related mortality (TRM), overall survival (OS) and event-free survival (EFS). Fifty five patients were identified, among them 27 into the older cohort (median age 63 y, range 60–68) and 28 patients into the younger cohort (median age 55 y, range 51–59). The median follow-up for the whole group was 23,5 months (0,5–93 months). TRM into the older group (1/27 pts (3,7%)) was not statistically different from the younger patients (0/28 pts) and was comparable with previously published data. The estimated 5-year OS (figure 1) was 75,5% (95%CI 52–90%) for the older group (curve 1) compared to 85% (95%CI 63–95%) in the younger group (p=0,47) (curve 2). There were 8 events (1 TRM and 7 relapses) in the older group and 3 events (all relapses) in the younger group (3-year EFS (figure 2) 66% (curve 1) vs 85,5% (curve 2), p=0,16 and 5-year EFS 49,4% vs 85,5%, p=0.051). We conclude that front-line autologous PBSCT with BEAM conditioning can be safely performed in patients 60 years old and older with DLBCL after CHOP of R-CHOP induction. The toxicity profile and TRM may not be different from that of younger patients. The high rate of OS in older group is encouraging, but the relapse still remains the important obstacle for durable remission.
Figure Figure
Incorporating Target Immunotherapy into Standard Conditioning Regimen Prior to Autologous Stem Cell Transplantaion (ASCT) Improves the Transplant Outcome for Pateints with Relapsed/Refractroy B Cell Non-Hodgkin Lymphoma (B-NHL).
Authors: Farhat Mohamed I. , Karmali Reem , Gregory Stephanie A. , Venugopal Parameswaran , Kassar Mohamad , Shah Neel , Brooks Terrance , Fung Henry C. 
Published: April 2020

Abstract
Background: Refractory or relapse B-NHL has a poor prognosis with conventional chemotherapy. Autologous stem cell transplant (ASCT) preceded by high dose chemotherapy has been the preferred therapeutic choice for such patients. The majority of the treatment failures occur within one to two years post transplant with disease progression after transplant accounted for most of the failures. The incorporation of targeted immunotherapy (rituximab) into the upfront and relapse setting is becoming of the standard of care for patients with B-NHL. The objective of this study is to evaluate the impact of rituximab (R) on disease free survival (DFS) when added to a standard conditioning regimen -- BEAM (carmustine, cytarabine, etoposide, and melphalan) prior to ASCT.
Methods: A single institution retrospective analysis of 53 patients (pts), whom were heavily pre-treated, underwent ASCT between 08/98 & 07/06. All pts received rituximab in combination with high dose cytoxan for stem cell mobilization. 37 pts received R-BEAM and 16 received BEAM prior to ASCT. Actuarial rate for DFS was estimated from the day of SCT using the Kaplan-Meier method.
Results: The group was predominantly men, 73% and 78%, with a median age of 57 years for both the R-BEAM and BEAM group. With a median follow up of 15.7 months, 13/37 (32%) and 11/16 (64%) pts who received R-BEAM and BEAM respectively developed disease progression after ASCT. The 2-yr actuarial disease-free survivals (figure1) were 60% and 21% for the R-BEAM and BEAM arm respectively (p=0.006).
Conclusion: In this study, the outcome of pts who received R-BEAM compares favorably to those who receive BEAM alone with significant improvement in disease-free survival. Thus, incorporating target immunotherapy into standard conditioning regimen may have altered the natural history of the disease for pts undergoing ASCT for relapsed/refractory B-NHL.
Disease Free survival Disease Free survival
Durable Responses to Lenalidomide (Revlimid®) in Patients with AL Amyloidosis: Follow Up of a Phase II Trial.
Authors: Seldin David C. , Rosenzweig Michael , Finn Kathleen T. , Fennessey Salli , Shelton Anthony , Zeldis Jerome B. , Skinner Martha , Sanchorawala Vaishali 
Published: April 2020

Abstract
AL amyloidosis is a clonal plasma cell dyscrasia in which misfolded immunoglobulin light chains deposit in tissues and produce organ failure and death. Untreated, median survival is short. Melphalan-based regimens can produce hematologic remissions and improvement in organ function; more than 20% of patients treated with high dose melphalan and autologous stem cell transplantation (HDM/SCT) have survived more than 10 years (Blood, in press). The combination of lenalidomide and dexamethasone can also produce partial and complete hematologic responses (Blood2007;109:492–496). Here we report on remission duration and long-term results of treatment in the original 34 patients and an additional 9 patients, with median follow up of 26.5 m. The median age of the 43 patients was 64 (range, 44–84), 70% were male, 67% were lambda isotype, 46% had multi-organ involvement, and 42% had cardiac involvement. 90% had received prior melphalan-based therapy; in 60% this was HDM/SCT. 14% of patients had received thalidomide and 5%, bortezomib. 10% had no prior treatment. Patients were begun at 15 mg lenalidomide per day for 21 days per month; the median tolerated dose was 10 mg. The response rate was 60% (24% CR, 36% PR); an additional 15% of patients had minor responses. Of the 8 patients who achieved a CR, 6 occurred at 3–6 months of treatment, but 2 were late (18m, 19m). 7 of 8 are alive; one died of cardiac allograft rejection. 3 of 8 have relapsed. 5 of 8 maintain remissions for 6–30 m, of which 4 of 8 continue in CR off therapy for 6–21m. Kaplan-Meier survival for all 43 patients is shown. 7 of 8 patients achieving CR had significant proteinuria: in 2 patients (29%), proteinuria resolved (2 g to 120 mg, 8.8 g to 140 mg); in 3 (43%) it improved by 50% or more; and in 2 there has been no change. Thus, lenalidomide can produce beneficial hematologic and organ responses in AL amyloidosis patients, and remissions can be durable off therapy. Further trials should be done to determine how and when to incorporate lenalidomide into treatment protocols for AL amyloidosis.
Figure Figure
Role of Jagged/Notch Signaling in the Cell Fate Determination of Bone Marrow Human Mesenchymal Stem Cells.
Authors: Ugarte Fernando , Ryser Martin F. , Thieme Sebastian , Bornhaeuser Martin , Brenner Sebastian 
Published: April 2020

Abstract
Notch, expressed on hematopoietic progenitors plays a crucial role in hematopoiesis. Mesenchymal stem cells (MSC) express both, Notch and its ligand Jagged and are known to support self renewal of hematopoietic progenitors via cell-cell contact and cytokine secretion. The Jagged/Notch signaling pathway has been implicated in the differentiation process of MSC, however it is not completely understood and current observations are contradictory. In order to analyze the effect of Notch signaling on human MSC differentiation we constructed lentiviral vectors that contained either the GFP-marker gene, hJagged1 IRES GFP, hNotch1 intracellular domain (NICD) IRES GFP or a gene fusion between dominant negative Mastermind1 (MAML1dn - inhibitor of Notch signaling) and the Cherry reporter gene. Primary hMSC that were obtained from bone marrow of 3 different donors were transduced with respective lentivirus vectors to greater than 98%. After exposure to adipogenic and osteogenic differentiation stimuli hMSC differentiation was quantified by Alizarin red or oil red staining, alkaline phosphatase (AP) activity and expression levels of adipogenic or osteogenic markers by Real-time PCR. Jagged1 transduced hMSC demonstrated enhanced calcium phosphate deposits and enhanced AP activity and expression levels in osteogenic differentiation medium, while adipogenic differentiation was strongly inhibited as quantified by oil red staining and low mRNA expression of genes upregulated during adipogenic differentiation (pprY, Fabp4). Similarly, overexpression of NICD induced strong and rapid osteogenic differentiation while inhibiting adipogenic differentiation and reducing cell viability. Moreover, NICD overexpression upregulates the expression of endogenous Jagged1 up to 5-fold. Inhibition of Notch signaling via overexpression of MAML1dn partially blocked the effect of hJagged1 and NICD in co-transduction experiments. In another approach MSC samples obtained from 20 donors with various osteogenic differentiation potential as measured by AP activity were analyzed for Notch1 and Jagged1 expression. While there was no correlation between AP activity and Notch1 levels we observed a significant positive correlation for AP activity and Jagged1 expression. In summary, our data strongly suggest that increased Jagged/Notch signaling enhances the osteogenic differentiation of hMSC while inhibiting their adipogenic fate.
Effect of Pax3 Overexpression on the Engraftment of Mesenchymal Stem Cells in Dystrophic Mice.
Authors: Gang Eun Ji , Darabi Radbod , Bosnakovski Darko , Xu Zhaohui , Perlingeiro Rita 
Published: April 2020

Abstract
Mesenchymal stem cells (MSCs) residing within the bone marrow (BM) not only support hematopoiesis, but also differentiate into multiple lineages, including fat, bone, and cartilage. Because MSCs are multipotent and have a great expansion capacity in vitro, these cells are attractive candidates for clinical applications to repair or regenerate damaged tissues of mesenchymal origin. However, treatment of muscle degenerative diseases with MSCs has been hampered by the poor differentiation of MSCs into the muscle lineage. To date most in vitro methods require the presence of strong non-physiological agents, such as azacytidine. Accordingly, limited engraftment has been observed following the transplantation of BM into dystrophic mice (less than 4%). In the present study we explored the potential of Pax3, the master regulator of the embryonic myogenic program, to promote myogenic differentiation from human BM-derived MSCs. Upon genetic modification with lentiviral vectors encoding Pax3-GFP or GFP only (vector control), MSCs were evaluated for their potential to differentiate towards muscle in vitro. Real time PCR analyses revealed up-regulation of several myogenic regulatory factors in Pax3-transduced MSC cultures in various differentiation conditions, whereas control GFP-MSCs showed undetectable levels. When transplanted into cardiotoxin-injured tibialis anterior (TA) muscles of Rag2−/− γc−/− immunodeficient as well as dystrophic mice, superior engraftment was observed with Pax3-transduced MSCs (31% vs. 12% and 12% vs. 6.5%, respectively). To assess whether such levels of engraftment are therapeutically relevant, functional analyses of transplanted muscles are required. We are currently undertaking these experiments.
Mesenchymal Stromal Cells Derived from Human Non-Small Cell Lung Cancer, Normal Lung Tissue, and Bone Marrow: Differences in Frequency, Cytogenetics, Proliferation Behavior, and Chemosensitivity - Implications for Cancer Therapy.
Authors: Gottschling Sandra , Meister Michael , Jauch Anna , Krause Ulf C. , Seckinger Anja , Hoffmann Hans , Dienemann Hendrik , Anthony Ho D. , Thomas Michael 
Published: April 2020

Abstract
Stromal microenvironment plays a vital role for the induction and maintenance of solid tumors. Knowledge on the nature and impact of the tumor-microenvironment in lung cancer is still inadequate. In this study, we investigated and compared stromal cells (SC) derived from non-small cell lung cancer (NSCLC), normal lung tissue (NLT), and bone marrow (BM) for the presence and properties of mesenchymal stromal cells (MSC). NSCLC-SC and NLT-SC displayed mesenchymal morphology, immunophenotype, and differentiation capabilities implying their MSC character. However, their frequency, proliferation behavior, and chemosensitivity varied significantly from BM-MSC and among each other. Colony forming units-fibroblast (CFU-f) were 300-fold less frequent in bone marrow but exhibited an up to 44-fold higher colony efficiency (CE) than in lung. Compared to NLT, NSCLC specimens were four times enriched in CFU-f possessing an unfailing CE over several passages. According to colony size, the proliferation potential of NSCLC-CFU-f was double that of NLT-CFU-f and did not vary with cell density thus indicating an autonomous growth and lack of feedback regulation. Moreover, NSCLC-SC exhibited a markedly reduced sensitivity to cisplatin with delayed apoptosis and faster recovery from cytotoxic damage. In line with functional alterations multicolor-fluorescence in situ hybridization revealed genetic aberrations and chromosomal instability of NSCLC-SC but not of NLT-SC. These data provide evidence for the presence of tumor-specific MSC in NSCLC and suggest the survival of a particular tumor-stroma after chemotherapeutic treatment.
Role of Imatinib Mesylate in Osteoblastogenesis.
Authors: Tibullo Daniele , Giallongo Cesarina , La Cava Piera , Berretta Salvatore , Stagno Fabio , Chiarenza Annalisa , Palumbo Giuseppe A. , Di Raimondo Francesco 
Published: April 2020

Abstract
Imatinib mesylate (IM), a tyrosine kinase inhibitor, currently used in chronic myeloid leukaemia (CML) may also affect the growth of other cellular systems besides CML cells. It has been reported that IM may affect bone tissue remodeling mainly by an inhibitory activity on osteoclastogenesis. We therefore evaluated possible effects of IM on osteoblatic differentiation of Mesenchymal Stem Cells derived from bone marrow (BMSCs). BMSCs are multi-potent non-haematopoietic progenitor cells that differentiate into osteoblasts, adipocytes, chondrocytes, skeletal myocytes and nervous cells. Culture of normal human BMSCs were treated with osteogenic medium (OM) with or without IM 1 μM. By RT-PCR, we assessed mRNA expression of osteogenic markers such as RUNX2, osteocalcin (OCN) and osteopontin (OPN) at 7, 14, and 21 days of culture. BMSCs treated with OM and IM 1 μM showed increased levels of osteogenic markers mRNA as compared to BMSCs cultured with OM only (RUNX2 ctrl=0,37±0,02 vs OM+IM=0,79±0,06; OCN ctrl=0,36±0,04 vs OM+IM= 0,97±0,03; OPN ctrl=0,94±0,01 vs OM+IM= 1,55±0,13). We also evaluated the OCN levels, and the OPG (osteoprotegerin)/RANKL (receptor activator of nuclear factor-kappa B ligand) ratio (OPG/RANKL ratio) in the surnatant of the culture at day 21 by ELISA assays. OPG/RANKL ratio (OM alone = 55,4±0,4 vs OM+IM = 65,3±0,7; P&lt;0,005) and OCN levels (OM alone = 1,4±0,08 ng/mL vs OM+IM= 4,02±0,21 ng/mL; P&lt;0,005) were increased in BMSCs samples cultured with IM in comparison to control (OM alone). In addition, we examined the OPG/RANKL ratio in serum of 17 CML patients treated for at least two years with IM and we found that it was increased in comparison to normal controls (ctrl=1,0±0,2 vs patients= 3,1±2,63; P= 0,036). In summary, our data show that IM increases osteogenic markers’ mRNA expression in BMSCs and increase the OPG/RANKL ratio both in surnatant of BMSCs cultured with IM and in serum of patients treated with IM, thus indicating that IM potentially favours osteoblastogenesis.
The Mutation Spectrum of CML Patients Resistant to Imatinib: More Heterogeneous Than Just BCR-ABL Kinase Domain Point Mutations?.
Authors: Lundan Tuija , Gruber Franz , Silye Aleksandra , Hjorth-Hansen Henrik , Mikkola Ingvild , Remes Kari , Simonsson Bengt , Gedde-Dahl Tobias , Porkka Kimmo 
Published: April 2020

Abstract
Cells harboring BCR-ABL kinase domain (KD) mutations are the major source for resistance to tyrosine kinase inhibitors (TKI) in chronic myeloid leukemia (CML). A second and third generation of TKIs are in development for inhibition of mutated forms of BCR-ABL. At present, clinical treatment strategies are based on molecular response and mutational profiling. Profiling is usually performed using unbiased methods (sequencing and D-HPLC of PCR products), but mutation specific methods are upcoming (ARMS-PCR, ASO-PCR, ligation-PCR). Here, we describe molecular findings resulting from a collaborative Nordic approach for molecular characterization of imatinib resistant Norwegian (N) and Finnish (F) CML patients. Complementary DNA derived from a total of 87 subjects (60 N and 27 F) with suboptimal or failed response to imatinib (less than 3 log reduction in tumor load after 12 months of treatment or loss of any response) were subjected to BCR-ABL KD sequencing of amino acid residues 240 to 420 (N) and 209 to 498 (F). In addition, single samples were analyzed by multiplex PCR for detection of transcript variants as well as cloning and sequencing of single clones. BCR-ABL KD mutations were found in 35 patients (20 N, 15 F, 40% of the total material). The most frequent findings were ABL KD point mutations with M351T and G250E representing the single most frequent mutations, 25 and 16%, respectively. The most frequently mutated cluster was in the catalytic loop (40% of all mutations), followed by P-loop (38%) and other regions (22%). Mutations in the gatekeeper cluster were extremely rare in our material (one case of a F317L). Additional sequence variations were observed in 6 patients: the L248V associated deletion of exon 5 (n=1), smaller insertion or deletion variants (2–4 basepairs) resulting in truncated proteins (n=2) and ABL exon 7 splicing (n=3). Finally, three cases with imatinib resistance expressed rare BCR-ABL transcript types without any evidence for KD mutations (two cases of e6a2 and one with e19a2 transcript). Imatinib resistance due to T315I BCR-ABL is extremely rare in Nordic CML patients. In addition to known hotspot mutations we identified novel sequence irregularities in association to imatinib resistance. We hypothesize that resistance-associated BCR-ABL isoforms are more heterogeneous than previously thought. Consequently, diagnostic procedures aiming in comprehensive molecular verification of TKI resistance should be designed as unbiased, since methods solely targeting known mutated BCR-ABL variants will miss many patients. However, an early detection of low-level mutated clones will require sensitive, mutation-specific analyses.