bluuebunny/crossref_metadata_2025_split huggingface dataset:
Low Dose Busulfan and ATG with Fludarabine as Conditioning Regimen Was Effective in Sibling and Unrelated Donor HSCT in CML Patients.
Authors: Lange Andrzej , Sedzimirska Mariola , Dlubek Dorota , Jaskula Emilia , Mlynarczewska Anna , Sok Agnieszka 
Published: April 2020

Abstract
Allogeneic hematopoietic stem cell transplantation offers complete remission in CML patients. However, transplant related mortality and long term consequences especially associated with cGvHD make patients reluctant to accept this treatment modality especially in the era of Imatinib. Therefore, in 1999 we started a transplant program for CML patients characterized with a reduced dose of Busulfan to 8 mg/kg of. b.w., Fludarabine (120 mg/m2 in sibiling and 150 mg/m2 in MUD setting) and ATG to facilitate engraftement. At the beginning ATG cumulative dose was 40 mg/kg of b.w. (5 patients), or 20 mg/kg of b.w (13 patients). In this high dose ATG group 6 patients had CMV or EBV reactivation what prompted us to decrease ATG dose to 2.5 mg/kg of b.w. given in three consecutive days and then on day 4 the dose was increased to 5 mg/kg of b.w. if patients lymphocyte count did not reach the target values (≤300/ul of WBC and &lt; 0.1% of CD3+ cells in nucleated blood cells population).
With the use of the above program 52 adults and two children (F/M: 22/32, age from 11 to 55 yrs (median: 34) were transplanted from sibling (20 patients) and alternative (33 MUD and 1 related haploidentical) donors. Thirty nine and 15 patients received PBPC and marrow, respectively. Seven patients died by + 100 days post transplant (6 infectious complications including 1 case with viral encephalitis and 1 blast crisis). One patient had marrow failure, 15 patients developed ≥ IIo aGvHD, 23 patients had cGvHD and 14 of them extensive form. Thirty four patients (63%) are alive with an observation time from 1 to 81 months post transplant (median 22 months). Survival was better in sibling than in MUD transplanted patients (77% vs 50%, p=0.03, Cox analysis). In alive patients group STR technique proved complete chimerism in 26 out of 31 examined patients. Five cases lacking full chimerism include: 1 patient with hematological relapse, and 4 with molecular relapse. All other cases were bcr/abl negative.
In conclusion: low dose ATG was sufficient to secure the take and the employed reduced intensity conditioning was associated with:
low rate of transplant related mortality, aGvHD was infrequent and mild, cGvHD was the main cause of late complications, full chimerism and bcr/abl free status were observed in a vast majority (84%) of long term survivors.
Acquired Mutations in the BCR-ABL Kinase Domain in Imatinib Resistant Patients. Multicentric Experience in Argentina and Uruguay.
Authors: Gargallo Patricia , Moiraghi Beatriz , Bullorsky Eduardo , Santarelli Rosa , Riva Maria , Magarino Alicia , Giuliani Ricardo , Bianchini Michele , Milone Jorge , Rosenfeld Ester , Pavlovsky Santiago , Lanari Emilio , Arizo Adriana , Avila Celina , Miguel Castro R. , Conti Rafael , Alu Fernanda , Barreyro Paula , Custidiano Rosario , Bitton Roberto , Larripa Irene , Bengio Raquel 
Published: April 2020

Abstract
Imatinib induces complete cytogenetic response (CCyR) in 82% of patients with CML in chronic phase. There is a subset of patients who either failed to achieve or lose hematological/CCyR. Kinase domain mutations have emerged as a potential cause for treatment failure.
Aims: In the current study we have investigated ABL kinase domain mutations, amplifications and quantification of BCR-ABL transcripts by Q-PCR in Imatinib resistant patients.
Patients and Methods: A total of 84 patients (pts) with CML treated with Imatinib were studied and 82 were evaluable. Sixty-one (74%) were in chronic phase (CP), eleven (14%) were in accelerated phase (AP), and ten (12%) were in blast crisis (BC).We analyzed the DNA from blood samples. Mutations were screened by conformation sensitive gel electrophoresis (CSGE). The amplification products displaying an abnormal pattern were sequenced using automatic system. The amplification of BCR-ABL rearrangement was studied in interphase nuclei using Vysis extra-signaling probe. Real time quantitative PCR (RQ-PCR) of BCR-ABL transcripts was performed in a subset of 44 patients to assess molecular response, using Light Cycler (Roche®), Syber Green Method.
Results: Eleven mutations from 82 evaluable patients were detected (13%). Seven were in p- loop: M244R (1), L247A (1), G250E (2), Q252H (1), E255K (2), and four in the Imatinib binding: T315I (3), H318L (1). Two patients had BCR-ABL amplifications with 4–6 signals in interphase nucleous and one of them showed extramedullary involvement in skin nodules. Five patients had clonal evolution with double Ph chromosome. Most of mutations were found in patients in late chronic phase (6/11: 54%). The detection occurred at a median of 49 months (range 12–154) after diagnosis. Eighty four percent of cases studied with RQ-PCR, had null molecular response (&lt;1Log Reduction). Imatinib dose in patients with mutations had been escalated to 600–800 mg/day previously.
Conclusion: This is the first multicentric study in spanish-speaking South America. T315I was the most frequent mutation detected in our study and was associated with poor outcome. We found 13% of resistant cases with point mutations, all of them located in the p-loop or imatinib binding.This is an ongoing study and further recruitment is needed to confirm these findings. Early detection of mutations can have prognostic implication and allow therapeutic intervention such as dose escalation, combination therapy or second generation tyrosine kinase inhibitors.
Front - Line Combined Immuno-Chemotherapy (R-CHOP) Significantly Improves the Time to Treatment Failure and Overall Survival in Elderly Patients with Advanced Stage Follicular Lymphoma - Results of a Prospective Randomized Trial of the German Low Grade Lymphoma Study Group (GLSG).
Authors: Buske Christian , Kneba Michael , Lengfelder Eva , Pfreundschuh Michael , Ludwig Wolf-Dieter , Graeven Ullrich , Hallek Michael , Dreyling Martin , Unterhalt Michael , Hiddemann Wolfgang 
Published: April 2020

Abstract
Follicular lymphoma (FL) is an indolent disease of the advanced age with more than 40 % of the patients being older than 60 years at diagnosis and an age-specific incidence peaking above 75 years. We now analyzed the treatment outcome of elderly patients in the GLSG multicenter phase III study comprising a prospective randomized comparison of R-CHOP versus CHOP alone in patients with advanced stage FL. 221 patients &gt; 60 years with untreated FL were randomized for therapy with R-CHOP (R-CHOP: Rituximab 375 mg/m2 d0–1; cyclophosphamide 750 mg/m2 d1; doxorubicine 50 mg/m2 d1; vincristine 1.4 mg/m2 d1; prednisone 100 mg/m2 d1–5) (n=109) or CHOP alone (n=112). Patient characteristics were well balanced between the treatment groups, also with regard to the distribution of the FLIPI risk groups (≥ 3 adverse factors 73% and 66 % in the R-CHOP and CHOP arm, respectively). R-CHOP induced higher overall response rates and significantly prolonged the time to treatment failure (TTF)(median 5.0 years versus 2.1 years, respectively; logrank test: p&lt;0.0001) compared to CHOP in the elderly patient group. Furthermore, the estimated 4-years progression free survival was 62.2% for R-CHOP versus 27.9 % after CHOP (logrank: p&lt; 0.0001). Importantly, R-CHOP was able to prolong the overall survival in elderly patients compared to CHOP with an estimated 4-years overall survival of 90% after immunochemotherapy versus 81 % after CHOP alone (logrank test: p=0.039). In the multivariate analysis individual FLIPI risk factors such as elevated serum LDH level, a hemoglobin level below 12 g/dl, the number of nodal areas (&gt; 4) as well as application of CHOP alone were independently associated with a shorter TTF. Treatment related side effects were similar in both patient groups and comprised predominantly myelosuppression. In summary, the addition of Rituximab to CHOP significantly improves the outcome of elderly patients with previously untreated advanced stage FL without adding major side effects.
JAK2 V617F Mutation Is Infrequent in “5q-Syndrome” and 5q-Associated MDS.
Authors: Zhang Ling , Gueller Saskia , Raynaud Sophie , Koeffler Phillip H. , Lee Stephen 
Published: April 2020

Abstract
Background: V617F mutation in Janus Kinase 2 (JAK2) gene has been found in chronic myeloproliferative disorders (MPD) including polycythemia vera (90%), essential thrombocythemia and chronic idiopathic myelofibrosis (30–50%), and occasionally in myelodysplastic syndromes (MDS). “5q- Syndrome” is a MDS that shares features with MPD and characterized by an atypical megakaryocytic hyperplasia in bone marrow and usually thrombocytosis in peripheral blood. The most common deleted region for this syndrome is 5q13.3q33.1. An interstitial deletion with variable proximal (5q12-14) and distal (5q31-33) breakpoints has been found in other MDS with/without additional chromosomal abnormalities beyond “5q- Syndrome”. To date, JAK2 mutation was detected in 6/97(6.2%) of patients having diagnosis of MDS with “5q- Syndrome”.
Design: In our study 21 MDS patients (10 with “5q- Syndrome” and 11 MDS with isolated or complex 5q-) whose diagnosis by both bone marrow aspiration/biopsy and conventional chromosomal analysis were confirmed.
Materials and Method: Primers were created to amplify a 460 bp fragment containing the site of JAK2 V617F mutation. Forty-five cycles of PCR were performed at an annealing temperature of 57°C. Resulting PCR product was digested with 2 U BsaXI for 16 hours and with an additional 2 U BsaXI for another 16 hours at 37°C, then analyzed on a 2% agarose gel. The mutant allele remained undigested whereas the wild-type allele was digested into 241 bp, 189 bp and 30 bp fragments. All experiments included a positive (HEL cells) and negative (K562 cells) control.
Results: PCR results showed clear wild type PCR patterns in all 21 cases.
Conclusion: No JAK2 mutations were detected in 21 patients either with “5q- Syndrome” or other 5q- associated MDS suggesting that JAK2 mutations are infrequent in these MDS patients.
Diagnostic Potential of Immunophenotyping CD34+ Cells in Myelodysplastic Syndromes.
Authors: De Waele Marc , Leus Barbara , Trullemans Fabienne , Verschraegen Inge , Urbino Montse , Jochmans Kristin , Renmans Wim 
Published: April 2020

Abstract
Myelodysplastic syndromes (MDS) constitute a heterogeneous group of clonal hematopoeitic stem cell disorders. They are characterized by abnormal bone marrow differentiation, peripheral blood cytopenia and a risk of transformation into acute myeloid leukemia (AML). The diagnosis of MDS depends on cytomorphology and cytogenetics and may be difficult especially in cases with normal numbers of blasts and without ringed sideroblasts in the bone marrow. Cytomorphology is subjective and dysplastic features may be present in other disorders than MDS. In this study we examined the potential of immunophenotyping CD34+ hematopoietic precursors for the diagnosis and classification of MDS. Bone marrow samples of 31 patients with low grade MDS (21 without and 10 with ringed sideroblasts), of 17 patients with refractory anemia with excess of blasts (RAEB), of 25 patients with AML and of 39 patients with cytopenia not due to MDS (controls) were examined. CD34+ cells were enumerated and the expression of B cell antigens (CD19), of myeloid antigens (CD13, CD33, CD117) and of immature antigens (CD133) was determined by flow cytometry. Statistical analysis was done with a Mann-Whitney test. A high number of CD34+ cells was found in MDS and AML. This was accompanied by an increase of the number of myeloid precursors and a decrease of the B cell precursors. CD117 appeared to be the best marker of myeloid precursors followed by CD13. A wide range of CD34+CD133+ and of CD34+CD33+ cells was found in all types of samples. Forty percent of the patients with low grade MDS showed an increased expression of CD117 on their CD34+ cells. In 25% of the cases without ringed sideroblasts a high expression of CD133 was present. Similar changes were more frequently found in RAEB and AML together with an increased expression of CD13 and CD33 and a low positivity for CD19. With a scoring system based on the expression of these antigens 57% of low grade MDS samples (score 1/6 or 2/6) could be distinguished from the controls (score 0/6). An elevated score was also found in respectively 84% and 100% of the RAEB and AML samples. 85% of them even had a score between 3/6 and 6/6. In conclusion, immunophenotyping of CD34+ cells is able to differentiate 60% of low grade MDS samples from other causes of cytopenia. Increased expression of CD117, CD133 and CD34 are the main differences. Similar changes are even more frequently found in RAEB and AML. A scoring system based on the antigen expression on the CD34+ cells is a powerful tool for the diagnosis and classification of MDS.
Erythroid Precursors from Patients with ‘Low Risk’ Myelodysplasia Demonstrate Ultrastructural Features of Autophagy.
Authors: Houwerzijl Ewout J. , Pol Henk-Willem , Blom Nel R. , Stokroos Ietse , van der Want Johannes J.L. , De Wolf Joost , Vellenga Edo 
Published: April 2020

Abstract
Anemia in myelodysplasia (MDS) is partially ascribed to enhanced cell death of committed erythroid cells in the bone marrow compartment. To define in more detail the underlying type of cell death in MDS, immunohistochemical staining and ultrastructural analysis were performed on MDS and normal bone marrow samples. Immunohistochemistry of MDS bone marrow biopsies (n=20) demonstrated no positive staining of the erythroid lineage for active caspase -3 or -8. Ultrastructural analysis was performed in low-risk MDS patients (Refractory anemia (RA; n=3); RA with ringed sideroblasts (RARS; n=4) on isolated bone marrow hematons, which are compact hematopoietic complexes containing adipocytes, mesenchymal and endothelial cells, and hematopoietic cells. In vitro culture assays have demonstrated that these hematons contain a high number of progenitor and primitive cells. Ultrastructural analysis of the hematons of the MDS patients as well as the healthy controls demonstrated no signs of apoptosis in erythroid cells. In contrast, abnormalities compatible with autophagy were present in &gt;60% of the MDS cells. Especially, cytoplasmic vacuoles with double membranes were noticed in basophilic and polychromatic normoblasts. Morphometric analysis of the erythroid cells showed no differences between healthy controls and MDS patients with regard to cell volume, mitochondria content or nuclear surface, but a significant increase was shown for the ratio area of vacuoles/cytoplasm in the MDS basophilic and polychromatic normoblasts (healthy controls vs MDS: 0.003 vs 0.013 (p&lt;.0001) and 0.004 vs 0.014 (p&lt;.0001). In view of the reported enhanced apoptosis in MDS bone marrow cells we questioned whether the discrepancy with our results might be linked to the cell processing, especially the presence or absence of signals from the bone marrow microenvironment. Subsequently MDS (n=4) and normal (n=2) bone marrow mononuclear cells (MNC) and hematons were in vitro cultured for 24 hrs and analyzed ultrastructurally. Upon in vitro culture a significant increase in the percentage of apoptotic erythroid cells was noticed predominantly in MDS erythroid cells. In addition, after 24 hrs of culture apoptosis was more frequently demonstrated in erythroid cells of the MNC fraction than in the hematons (21 ± 4 vs 8 ± 3 %, p= 0.04). In summary, these data demonstrate that autophagy is present in MDS erythroid cells in vivo in significantly higher numbers than in healthy controls and suggest that autophagy may switch to apoptosis in the absence of an appropriate bone marrow microenvironment.
Addition of Rituximab to First-Line MCP (Mitoxantrone, Chlorambucil, Prednisolone) Chemotherapy Prolongs Survival in Advanced Follicular Lymphoma - 4 Year Follow-Up Results of a Phase III Trial of the East German Study Group Hematology and Oncology (OSHO#39).
Authors: Herold Michael , Haas Antje , Srock Stephanie , Neser Sabine , Al Ali Kathrin H. , Neubauer Andreas , Doelken Gottfried , Naumann Ralph , Fietz Thomas , Freund Mathias , Rohrberg Robert , Hoeffken Klaus , Franke Astrid , Ittel Thomas H. , Kettner Erika 
Published: April 2020

Abstract
Introduction: Rituximab plus chemotherapy has been proved to be the gold - standard in treating advanced follicular lymphoma. Here we report the 4-year-follow-up data of our phase III trial comparing MCP - chemotherapy vs rituximab + MCP both followed by interferon maintenance in advanced symptomatic follicular lymphoma.
Methods: Previously untreated patients with advanced stage (III + IV) symptomatic CD 20-positive indolent NHL and mantle cell lymphoma (n=358) were randomized to receive either MCP-chemotherapy (mitoxantrone 8 mg/m² d1+2, chlorambucil 3x3 mg/m² d 1–5, prednisolone 25 mg/m² d 1–5 x 8 q 4 weeks) or MCP + rituximab (375 mg/m² d −1).
Here we report the results of the ITT population of patients with follicular lymphoma (FL) (grade 1+2), who represented the majority of patients and for whom the sample size primarily was calculated, so this is not a subgroup analysis. Study endpoints included overall and complete response rate (RR + CR), progression free survival (PFS), event free survival (EFS), time to next treatment (TTNT), overall survival (OS) and toxicities.
Results: with a median follow - up of nearly 4 years (47 months) we are able to provide relatively mature data. Concerning toxicities there was no striking difference, but there was a significantly increased risk to experience a CTC grade III or IV toxicity for leukocytes in the R-MCP arm, however this did not increase the risk of infections.
For the FL - ITT population the results are given in the table.
Conclusions: Concerning all end points rituximab plus MCP is significantly superior to MCP alone in the treatment of advanced follicular lymphoma. Special attention should be drawn to the fact, that after a median follow-up of 47 months we can demonstrate a clinically and statistically significant survival advantage for the immunochemotherapy.
Results R-MCP (n=105) MCP (n=96) p-value Response rate 92,4% 75% .0004 Complete Response 49,5% 25% .0009 PFS median n.r. 29 months &lt; .0001 PSF 4 years 71% 40% EFS median n.r. 26 months &lt; .0001 EFS 4 years 69% 35,5% TTNT median n.r. 29,4 months .0002 OS median n.r. n.r. .0096 OS 4 years 87% 74%
Azacytidine in the Management of Myelodysplastic Syndrome: A Single Institutional Retrospective Review of Responses and Tolerability.
Authors: Grinblatt David L. , Bavisi Seema , Lawton Jessica , Kaminer Lynne S. 
Published: April 2020

Abstract
Twenty two patients (pts) with primary or therapy-related MDS were treated with 5-azayctidine (AZA) at the Kellogg Cancer Care Centers (KCCC) from July 2004–May 2006. We retrospectively reviewed all consecutive patients with myelodysplastic syndrome treated at the KCCC who received this agent. Charts were reviewed for response, time to response, duration of response and rate of hospitalization with complications of therapy or disease during AZA therapy. Treated patients had Refractory Anemia with Excess Blasts-type 1 (RAEB-1, n=6), RAEB type-2 (RAEB-2, n=3), Chronic Myelomonocytic Leukemia (CMMoL, n=4) or Refractory anemia (RA, n=6). Median age at study entry was 80 yrs (range, 58–95). Patients were treated with azacytidine 75mg/m2 daily for seven consecutive days or five days followed by a two day break and an additional two days of treatment. Patients were treated until best response and treatment frequency was decreased to every 6–8 weeks once a response had occurred.
Responses were as follows: Complete response (CR) with normalization of cytopenias, marrow dysplasia and blasts (as defined in IWG criteria by Cheson et al) occurred in 2 pts (9%). Complete hematologic response (CHR) meeting all of the peripheral blood criteria but without a confirmation bone marrow performed was noted in 4 pts (18%) while hematologic improvement (HE) major (&gt;2 gm rise in Hgb) occurred in 1 pt (5%) and HE minor (1–2 gm rise in Hgb or 50% decrease in RBC requirements) occurred in 2 pts (9%). Thus, a response using the IWG criteria was seen in 9/22 pts yielding an overall response rate of 41%. The median time to response was 3 cycles (range, 1–4). The median duration of response was 8 months (range, 3–18+). Responses are ongoing in 4/9 of the responders. One of the complete response patients had a complex karyotype (5q-, 7q-, del (18p)) that was not present on follow-up marrow after response was noted. Though treatment related cytopenias did occur frequently in the first two cycles of therapy, there were no treatment related hospitalizations for neutropenic patients in this consecutive cohort of patients and no deaths due to therapy. Azacytidine is a well tolerated agent with responses occurring with a significant rate and duration in MDS.
Study of CD28 Costimulatory Super Family and CD4+Treg in Myelodysplastic Syndromes.
Authors: He Guangsheng , Zeng Hui , Wu De Pei 
Published: April 2020

Abstract
Objective: To explore the possible immune annormality of CD28 costimulatory super family and CD4+T regulatory (CD4+Treg) in myelodysplastic syndrome (MDS).
Methods: Gated by CD3 and SSC, the changes of CD28, CTLA-4, PD-1, and CD25, on CD3+CD4+ cells were evaluated in 38 new diagnosed cases with MDS(RA 17, RAS 1, RAEB 14, RAEB-t 6) and 11 normal controls respectively by directive immune labels.
Results: [circ1]In the group of MDS, the CD3+CD4+CD28+ was 79.82%±8.99% ( RA 78.65%±10.4%, RAEB/RAEB-t 80.10%±7.28% respectively), was lower than 89.56%±3.06% of normal controls (P&lt;0.01); CD3+CD4+CTLA-4+, CD3+CD4+PD-1+, and CD3+CD4+CD25+ were 2.14%±1.25% (RA 1.51%±0.80%, RAEB/RAEB-t 2.65%±1.33%), 1.44%±0.88% (RA 0.93%±0.63%, RAEB/RAEB-t 2.02%±0.76%), and 3.18%±2.11%(RA 2.80%±1.38%, RAEB/ RAEB-t 3.41%±2.46%) in MDS, which were all higher than those (0.11%±0.12%, 0.09%±0.14% and 1.65%±1.14% respectively) of normal controls (P&lt;0.01). [circ2] Along with the progress of MDS, the expression of CTLA-4, PD-1 and CD25 on CD3+CD4+ cells increased significantly in RAEB/RAEB-t than RA. [circ3] The antagonism costimulatory of CTLA-4/CD28 decreased from normal controls (0.11±0.11) to RA (2.14±0.97), then to RAEB/RAEB-t (3.58±1.55) significantly.
Conclusion: [circ1] In MDS, the immune priming factor-CD28 decreased while the suppressive factor-CTLA-4 increased. [circ2] The negative immune CD4+ regulatory increased in MDS, and was predominance in immune balance. [circ3] Along with progression of MDS, negative regulatory factors was enforced, which promoted clone of MDS expansion.