bluuebunny/crossref_metadata_2025_split huggingface dataset:
Compared Molecular Monitoring of BCR-ABL Transcripts in Peripheral Blood and Bone Marrow Samples in CML Patients after Allogeneic Hematopoiteic Stem Cell Transplant.
Authors: Dominietto Alida , Cirmena Gabriella , Garuti Anna , Raiola Anna Maria , Ibatici Adalberto , van Lint Maria Teresa , Frassoni Francesco , Bacigalupo Andrea 
Published: October 2019

Abstract
Background. Molecular monitoring of the BCR-ABL transcripts in patients with chronic myeloid leukemia (CML) using quantitative real-time polymerase chain reaction (QRT-PCR) provides important information about the leukemia cell mass and the response to therapy. After allogeneic hematopoietic stem cell transplants (HSCT) patients with persistently positive levels of BCR-ABL transcript have a molecular relapse and some of these patients progress to develop a cytogenetic or hematologic relapse.
Objectives. To test whether molecular detection of BCR-ABL transcripts is comparable using peripheral blood (PB) and bone marrow (BM) aspirate samples after allogeneic HSCT.
Patients and Methods. BCR-ABL transcripts were monitored the interval of time 2003 – 2005 in 118 patients who received an allogeneic HSCT in chronic or advanced disease phase. BCR-ABL transcripts were evaluated concomitantly in 200 blood samples and 200 marrow samples (total 400 determinations) using real time PCR (QRT-PCR) assay to analyze BCR-ABL gene rearrangement (p210 b2a2 and b3a2). A complete molecular response (CMR) both for PB and BM we defined has undetectable levels of p210 and Major molecular response (MMR) was defined when p210/ABL ratios where <0.02%.
Results. 135 double BM+PB determinations (67%) proved BCR-ABL negative; 61 double determinations (31%) were classified as “persistently positive” both in peripheral blood and in blood marrow; 4 determinations (2%) were discordant. Therefore 196/200 BCR-ABL determinations in peripheral blood and bone marrow (98 %) were concordant.
Conclusions. This study shows that BCR-ABL QRT PCR monitoring of CML patients after allogeneic HSCT with peripheral blood cells is concordant with bone marrow cells in 98% of cases, and thus may be used to monitor the disease. This may be relevant for patients, especially when quality of life issues are discussed together with the need for post-transplant monitoring.
A Prospective, Randomised Trial of Chlorambucil, Mitoxantrone and Dexamethasone (CMD) Versus Fludarabine, Mitoxantrone and Dexamethasone (FMD) for Advanced Follicular Lymphoma (Real Grades I-III, Stages III/IV).
Authors: Haynes Andrew , McMillan Andrew , Jack Andrew , Qian Wendi , Jakupovic Ira , Smith Paul , Prentice Archie 
Published: October 2019

Abstract
Fludarabine, alone and in combination, has activity in de novo and relapsed/refractory follicle centre cell lymphoma (FCCL), as do many other combinations of chemotherapy, including chlorambucil, mitoxantrone and steroids. In this multicentre study, between May 2000 and April 2006, 400 adults with FCCL (REAL grades I-III) were randomised to receive either CMD (chlorambucil 10mgs po, od, days 1–10, mitoxantrone 12mgs/m2 IV, day 1 and dexamethasone 20mgs po, od, days 1–5) or FMD (fludarabine 25mgs/m2, IV days 1–3, with M and D as for CMD) on physicians’ decision to treat advanced stage (III or IV) disease (B symptoms, bone marrow failure, bulk or progression and compression syndromes). Rituximab (R) was not available for this trial. Randomisation was prospectively stratified by IPI score. Patients received four courses before assessment of response, then had no further trial therapy with progression or inadequate response or had a maximum total of eight courses if responding. The primary end points were progression-free survival (PFS) and overall survival (OS) and the secondary end points were complete (C) and partial (P) remission rates (RR). This preliminary report is at median follow-up of 31 months (range 0–71). Clinical features and pathological diagnoses (reviewed centrally) were equivalent across both arms. The median age in years (range; number >60 y) for CMD was 56 (32–72; 68) and for FMD 55 (29–75; 68) and 70% in both arms had stage IV FCCL. For CMD versus FMD, the CRR and PRR after course 4 were 18% v 21% and 72% v 68% and after course 8 or at the end of treatment were 44% v 45% and 47% v 47%. The hazard ratios were in favour of CMD, for OS at 1.65 (95%CI 0.97–2.8, p=0.063) and for PFS at 1.61 (95%CI 1.2–2.17; p=0.0018). The numbers of deaths due to lymphoma were equivalent (19 v 21) but there were fewer deaths in the first year (most due to lymphoma in both arms) with CMD (7 v 15; ns). The difference between those who received between 6 and 8 courses in either arm was not significant (152[80%] v 135[71%]). With CMD there were higher rates of grade 3/4 neutropenia (8 v 1) and infections (29 v 20) but these differences were not statistically significant; other toxicities were low grade and equivalent for both arms. Days between cycles (median 28 days in both arms) and dose adherence (96% and 97%) were equivalent; both regimens were well tolerated and relatively easy to deliver. The equivalent dose intensity, toxicities and RRs of the two arms indicate that the statistically significant superior PFS for CMD was not due to undertreatment in the FMD arm. The outcomes for CMD are at least as good as those reported for other combinations of chemotherapy without R and R-CVP.
Fludarabin/Cyclophosphamide Reduced Intensity Conditioning for Allografting Offers an Excellent Outcome for Heavily Pretreated Lymphoma Patients.
Authors: Jonkhoff A. Roel , Janssen J.J.W.M , Visser O. , van Roessel H.M. , Huijgens P.C. 
Published: October 2019

Abstract
To test the value of non-TBI based reduced intensity stem cell transplantation (RIST) in high risk patients with NHL, CLL and MM, 52 patients were transplanted using fludarabin 25 mg/m2 and cyclophosphamide 500 mg/m2, for 5 days and an undepleted HLA-identical sibling allograft.
Patients: diagnosis: indolent NHL (10), diffuse large cell lymphoma (8), mantle cell lymphoma (2), multiple myeloma (17), CLL (10), other diagnosis (5).
Patient characteristics: 34M/18F, median age 52.9 yr (range 18–66 yr). All patients were extensively pre-treated. None of CLL patients had received an autologous transplant, but of all remaining patients 71% had been autografted previously. Best response in NHL patients at transplant: CR in 2; PR in 16; PD in 2. The graft consisted of 6.8 × 106/kg CD34+ cells (median, range: 2.7 – 20) and T-cells 34.1 × 107/kg (range 14.5–66).
Results: Hematological recovery: nadirs respectively: WBC: 0.34 × 109/l (median, range <0.1 – 1.6) at day +4, platelets: 38 × 109/l (2–130) at day 8, ANC: 0.09 (0 – 0.36). Toxicity was minimal: mucositis > grade I: 4 patients; TPN: 7 patients; antibiotics i.v.: 8 patients; hemorrhagic cystitis: 2.
Engraftment was prompt in all but one patient. Chimerism measured by short tandem repeats (STR) at day +30, +100 and +180 were 85%, 95% and 95% respectively (median, range 15 – 100%). Acute GVHD grade I/II was seen in 10 (19%) and grade III/IV in 11 (21%). Chronic GVHD occurred in 12 patients (limited 5 (10%), extensive 7 (13%). Transplant related mortality was only 10%. With a median follow-up of 48 months for NHL patients the estimated survival is 78%. For CLL and MM patients follow-up is still to short for conclusions, but survival seems inferior in MM patients
Conclusion: fludarabin/cyclophosphamide allogeneic transplantation provides an excellent rescue treatment for heavily pretreated lymphoma patients.
Survival Flu/Cy allogeneic RIST transplantation Survival Flu/Cy allogeneic RIST transplantation
A Fludarabine-Based Non-Myeloablative Conditioning Regimen in Allogeneic Stem Cell Transplantation from Related and Unrelated Donors in Chronic Myeloid Leukemia.
Authors: Luo Yi , Huang He , Cai Zhen , Tan Yamin , Han Xiaoyan 
Published: October 2019

Abstract
Objective: To evaluate the efficacy and safety of a fludarabine-based non-myeloablative conditioning regimen in allogeneic stem cell transplantation (SCT)from related and unrelated donor for chronic myeloid leukemia in chronic phase(CML-CP).
Methods: Fifteen consecutive patients with CML-CP between May, 2005 and July, 2006 were treated with a single non-myeloablative conditioning regimen in this study. They were 10 males and 5 females with a median age of 41 years (range, 18–49). Donors were HLA-A, B and high resolution DR fully matched siblings (n=8), matched unrelated donors (n=6), and 1-locus mismatched unrelated donors (n=1). The stem cells were collected from either peripheral blood (n=9) or bone marrow (n=6). The conditioning regimen included fludarabine 30 mg/m2/day (days -10 to -5), oral busulfan 4 mg/kg/day (n=4 patients), or intravenous busulfan 3.2 mg/kg/day (n=11 patients) (days -6 to -5) and anti-thymocyte globulin (Fresenius, Germany) (5mg/kg/day) (days -4 to-1). Mycophenolate mofetil combined with cyclosporin A and methotrexate was used for prevention of acute graft-versus-host disease(GVHD) after transplantation. Lipoprostagandin E1 was used in prophylactic regimen for hepatic veno-occlusive disease(VOD). To assess engraftment, degree of chimerism, minimal residual disease and relapse, all patients were monitored by cytogenetic analysis and donor vs host-specific DNA markers using short tandem repeats (STR) assay. The average cell number of MNC transfused was 4.83 (3.14~11.5)×108/kg; CD34+ cells were 3.47(2.38~6.24)×106/kg, CFU-GM was 2.15 (1.85~3.06) ×105/kg.
Results: Engraftment of neutrophils and platelets was achieved in 14 out of 15 (93.3%) patients within a median of 13 days (range, 8–21) and 18 days (range, 10–35), respectively. Fourteen patients achieved complete donor chimerism in the peripheral blood before day +35 and one developed graft failure. No patients developed acute GVHD and VOD, but one died from interstitial pneumonia while she was in continuous complete remission 2 months following transplantation. With a median follow-up of 5 months (range 1.5 to 15), 13 of them were still in CCR. The overall non-relapse mortality in this group was 6.67% (1/15 patients). Overall survival, and disease-free survival rates were 93.3% and 86.7%, respectively.
Conclusion: A fludarabine-based non-myeloablative conditioning regimen in allogeneic stem cell transplantation from related and unrelated donors is an effective and safe choice for patients with chronic myeloid leukemia in chronic phase.
Disappearance of Minimal Residual DEK-CAN Fusion Transcript after Allogenic Hematopoietic Stem Cell Transplantation in a Child with t(6;9) Acute Myeloid Leukemia.
Authors: Kawasaki Hirohide , Imai Yuichiro , Kuroyanagi Yuichi , Noda Yukihiro , Nakano Takahide , Kaneko Kazunari 
Published: October 2019

Abstract
Chromosomal translocation t(6;9) (p23;q34) associates with acute myeloid leukemia (AML), although that is found in less than 2% of all cytogenetic events in children with AML. Recent molecular analysis of patients with t(6;9) (p23;q34) has demonstrated a rearrangement of the genes DEK and CAN resulting in the formation of a chimeric DEK-CAN mRNA. The prognosis of patients with t(6;9) is thought tobe very poor, because of poor response to chemotherapy and/or high relapse rate. However, recent reports showed that allogeneic hematopoietic stem cell transplantation may have a potential to improve the prognosis of patients with t(6;9). We report here we were able to monitor DEK-CAN fusion transcripts in the serial points along chemotherapy courses and hematopoietic stem cell transplantation in a child with t(6;9). A 5-yaer-old Japanese boy diagnosed as having AML (M5b). Chromosomal analysis revealed t(6;9)(p23:q34), and real-time quantitative polymerase chain reaction (RQ-PCR) revealed positive chimeric DEK-CAN mRNA. After diagnosis, he received an induction chemotherapy. At the end of the induction chemotherapy, he was in a hematological and cytogenetic complete remission (CR), however DEK-CAN fusion transcript was still positive. After completion of five courses of consolidation therapy, he was in hematological and cytogenetic CR, although molecular minimal residual disease (MRD) was still positive. So he received allogeneic peripheral blood stem cell (PBSC) transplantation from 1 locus mismatched father. Busulfan and Melpharan were used for conditioning regimen. Cyclosoprin A and short course of methotrexate were emplyed for the prophylaxis of graft-versus-host disease (GVHD). Engraftment of PBSC was achieved at day 15. He had mild acute GVHD and no clonic GVHD. Bone marrow analysis at the time of engraftment revealed hematological, cytogenetic, and molecular CR. Now he is still in a persistent molecular negativity of DEK-CAN fusion transcript by RQ-PCR and keeps event-free survival for five years after PBSCT. The monitoring of DEK-CAN fusion transcript in the chemotherapies was reported from some investigators. However, there were very few reports about the monitoring DEK-CAN fusion transcripts before and after hematopoietic stem cell transplantations. In coclusion, we succeeded to exclude DEK-CAN fusioin transcript after hematopoietic stem cell transplantation in a child with t(6;9) AML. We conclude that DEK-CAN molecular monitoring by RQ-PCR in is a useful tool for the management of patients with t(6;9) AML.
Haploidentical Stem Cell Transplantation without T Cell Depletion: A Brazilian Protocol.
Authors: Simoes Belinda P. , Navarro George , Favarin Maria C. , Palma Leonardo C. , Ayrosa Maria I. , Velano Carlos E. , Pieroni Fabiano , Stracieri Ana Beatriz P.L. , Moraes Daniela , Oliveira Maria C. , Voltarelli Julio C. 
Published: October 2019

Abstract
For patients with refractory or high risk leukemias, stem cell transplantation is still the only possible curative approach. Those patients, although, without a HLA identical matched sibling, unrelated stem cells are the only stem cell source. In patients with refractory disease this unrelated cells may be unavailable in a short time period. The use of HLA-mismatched familiy donors has been used before, by depleting in vitro T cells or selecting CD34+ cells. These methods are extremely expensive and patients suffer with delayed immune reconstitution. In an attempt to overcome the HLA barrier, Cyclophosphamide, a highly toxic agent against activated T cells, but not myeloablative, has been used after transplantation to ensure engraftment and avoid GVHD. We describe here two patients who were sequentially submitted to a citoreductive protocol described by Schmid et al (Blood 2006) followed after transplantation by Cyclophosphamide (50 mg/kg day +3 and day +4) as described by O’Donnel et al (BBMT 2002). We transplanted 2 boys (16 years-case 1 and 6 years-case 2) with secondary AML after MDS and AML relapse after second SCT respectively. Case 2 received two SCT from his HLA-id brother and was 8 months after the second transplant. Both had active disease at time of transplant and received full bone marrow from there HLA haploidentical mothers (3 loci mismatch). Engraftment was achieved on day +15 in both cases. Chimerism analysis on day +30 showed that they had 96% XX and 95% XX cells respectively in bone marrow. Case 1 never developed GVHD but relapsed after SCT. Case 2 are in complete remission and complete quimera day+90 after SCT. He developed GVHD (skin, liver and gut) were treated with prednisone and Basiliximab and we are now tapering imunossupression.
Herby we demonstrated that haploidentical transplantation with the use of Cyclophosphamide after transplantation can be a useful transplant strategy in high risk patients without a matched sibling donor. Relapse and infections will always be the most frequent complications. In countries with limited health resources a protocol who avoid the expensive costs of cell depletion or selection can be a real alternative for patients without suitable donors.
The B4galnt2 Regulatory Polymorphism, Mvwf1, Causes Low VWF Levels and Segregates in Natural Mouse Populations
Authors: Johnsen Jill , Baines John , Tautz Diethard , Ginsburg David 
Published: October 2019

Abstract
We previously identified the cause of low levels of von Willebrand factor (VWF) in the RIIIS/J mouse strain to be a regulatory mutation, Mvwf1, in an N-acetylgalactosaminyltransferase, B4galnt2 (previously designated Galgt2). Mvwf1 causes a tissue-specific switch in B4galnt2 expression from intestinal epithelium to vascular endothelium, resulting in aberrant glycosylation of VWF and accelerated clearance from circulation. We have identified thirteen Mvwf1 inbred mouse strains that share this remarkable tissue-specific switch and a common 97kb haplotype block, including a 30kb region of 2–3% sequence divergence that flanks Exon 1. An RIIIS/J BAC transgene containing the entire Mvwf1 haplotype block and B4galnt2 gene confers vascular gene expression, while C57BL6/J BAC transgenes spanning the homologous region confer “wild-type” vessel(−), intestine(+) gene expression, indicating that one or more tissue-specific regulatory elements sufficient to recapitulate the Mvwf1 tissue-specific switch lie within the genomic region covered by these BACs. A wild-derived recombinant Mvwf1 allele containing the 3′ half of the Mvwf1 haplotype block confers the vessel(−), intestine(+) B4galnt2 expression pattern, placing the regulatory mutation(s) responsible for the Mvwf1 switch well upstream of the proximal promoter region. Sequence analysis of DNA from wild-caught individual mice confirmed the presence of a highly conserved wild mouse Mvwf1 founder allele that likely pre-dates the development of the inbred mouse strains. PCR of genomic DNA from wild caught mice representing M. m. musculus, M. m. domesticus, M. m. castaneus, M. m. molossinus, M. spretus, M. hortulanis, and M. macedonicus revealed that the Mvwf1 allele is common in wild M. m. domesticus populations in North America, Europe, and Africa, with an allele frequency as high as 60% in French mice. Population samples of M. m. domesticus from Cologne, Germany and the Massif Central region of France drastically differ in the frequency of this allele (0% vs. 60%). A significant reduction in microsatellite variability at B4galnt2 in the French population, as measured by the lnRH statistic, suggests a recent, local shift in the frequency of Mvwf1, likely due to a recent change in selective pressure. Analysis of independently trapped wild mice from the Massif Central region of France confirmed that Mvwf1 confers vascular endothelial B4galnt2 expression and causes significantly lower VWF levels (5.5+2.0 vs. 13.3+2.3, p<1x10−7) in this population. These data support a B4Galnt2 allele-specific survival advantage in wild mice, leading us to speculate that a similar survival advantage could account for the high prevalence of VWD in human populations.
Single Versus Multiple Transplants for Multiple Myeloma: Insights from In Vivo and In Silico Studies.
Authors: Dingli David , Pacheco Jorge M. , Gertz Morie Abraham 
Published: October 2019

Abstract
Background: The advent of high-dose therapy and autologous stem cell transplantation (HDT-ASCT) has significantly improved response rates and survival for patients with multiple myeloma (MM). However this form of therapy is potentially toxic and does not cure patients from their disease. The response to HDT-ASCT is variable and approximately 40% of patients achieve a complete response (CR). Patients with a CR have a significantly improved time to progression (TTP) compared to patients who do not achieve CR (nCR). Optimal timing of HDT-ASCT and considerations of the relapse kinetics may assist treatment planning for this disease. We analyzed myeloma tumor burden and kinetics before and after HDT-ASCT in order to define optimal timing of this therapy for the individual patient.
Patients and Methods: A cohort of 265 patients with MM who underwent HDT-ASCT at Mayo Clinic Rochester was studied. Disease burden before and after HDT-ASCT was estimated from serial M-spike measurements. The estimated tumor burden data were fitted to the Gompertz function and its parameters alpha and beta estimated using a non-linear least squares method. Cohorts of patients with CR and nCR were studied separately. Functions that coupled disease burden and kinetics with TTP were derived and used to determine the optimal timing of single and tandem transplantation.
Results: The Gompertz parameters alpha and beta for patients who achieved CR and for those who did not achieve CR with HDT were determined. Our values were lower than those of Sullivan and Salmon although the ratio of alpha/beta was of a similar order (implying the same carrying capacity). Using the idealized Gompertz parameters, simulations of single versus tandem transplants were performed. Our model predicts that tandem transplantation increases CR rate by approximately 10%. When the time between transplants was studied as a variable, our model suggests that the optimal time between transplants is 7 months.
Conclusions: Our modeling provides a theoretical understanding of tumor burden and kinetics for patients with MM who undergo HDT-ASCT. Patients who achieve CR with the first episode of HDT-ASCT should not be routinely offered tandem transplantation but carefully monitored and re-transplanted at an optimal disease burden. If CR is not achieved with a first cycle of HDT-ASCT, the probability of CR after a second trial of HDT is ~10% (similar to that reported by Attal et al 2003) although this depends on the tumor burden before the second transplant. TTP after tandem transplants (with its higher associated mortality) cannot be superior to TTP achieved with optimally timed serial transplants. Individualized HDT-ASCT for patients with MM is possible and may improve results.