bluuebunny/crossref_metadata_2025_split huggingface dataset:
Follow-Up of Patients with Curable Lymphomas Ouside of Clinical Trials: A National Survey of Practice Patterns.
Authors: Imrie Kevin R. , Rohlehr Yvonne , Cheung Matthew C. 
Published: October 2019

Abstract
With increasingly effective therapy for patients with aggressive histology non-Hodgkin’s Lymphoma and Hodgkin’s Lymphoma, more patients are attaining complete remission and are eligible for follow-up monitoring. Such monitoring offers the potential for early detection of relapse and surveillance for late effects of treatment, but is resource-intensive and may lead to unnecessary investigation of false relapses and cumulative radiation exposure. A number of Practice Guidelines (PG) provide recommendations on follow-up of patients with lymphoma, but provide conflicting recommendations particularly relating to the use of imaging. The PG of the American College of Radiology (ACR) and the National Comprehensive Cancer Network (NCCN) recommend routine use of imaging in follow-up, while those of the Canadian Association of Radiologists (CAR) and Cancer Care Ontario (CCO) recommend limiting imaging to patients suspected of relapse and those at higher risk of recurrence. We conducted a survey of practicing hematologists across Canada to document follow-up practice of patients outside of clinical trials. A 12-question survey was mailed to 244 Hematologists identified from the database of the Royal College of Physicians and Surgeons of Canada. The Dillman method was used to administer the questionnaire with a second mailing sent at 4 weeks to non-respondents. The target response rate was 50%. 127 responded (52%) after the second mailing. 93% indicated that they routinely follow-up patients in remission following curative treatment. 41% reported following patients indefinitely, 39% followed patients for up to 5 years, and 22% tailored the duration to the risk of relapse (generally 2–5 years). The median visit interval in years 1–2 was 3 months, years 3–5 6 months, and beyond 5 years 12 months. 41% used imaging (generally CT scans) routinely in all patients, while 31% used scans only in patients in partial remission and 21% in patients felt to be high risk at presentation. The majority of respondents performed CBC and LDH blood testing routinely in all patients and performed serum TSH levels in patients following mediastinal radiation. Serum electrolytes, liver function testing and blood films were ordered routinely only by a minority of respondents. 27% of practitioners reported utilizing printed educational material for patients and/or primary care practitioners regarding follow-up. 25% indicated an intent to change their follow-up practice in the near future, generally citing a plan to limit the duration of follow-up and to decrease reliance on CT scanning.
Conclusion: This national survey indicates that the majority of Canadian hematologists routinely follow patients with lymphoma after curative treatment. The use of imaging in follow-up is variable, but is more consistent with the recommendations of the CAR and CCO than the ACR and NCCN.
Long-Term Follow-Up of Monoclonal Gammopathies in Gaucher Disease Patients on Enzyme Replacement Therapy.
Authors: Park Jae H. , Moore Allan F. , Kuter David J. 
Published: October 2019

Abstract
Gaucher Disease is a lysosomal storage disease in which glucocerebroside accumulates in macrophages because of a deficiency of the lysosomal enzyme, β-glucocerebrosidase. Polyclonal and monoclonal gammopathies (MG) have been frequently associated with long-standing Gaucher Disease, and there have been reports suggesting an increased incidence of multiple myeloma (MM) in these patients. Chronic stimulation of the immune system secondary to progressive glucocerebroside storage and increased expression of cytokines such as Interleukin 6 have all been postulated to be the mechanism underlying this association. The purpose of this study was to ascertain the incidence and natural history of MG in Type 1 Gaucher Disease patients on enzyme replacement therapy (ERT) followed for up to 15 years. Twenty-eight patients with Type I Gaucher Disease on ERT seen at a single medical center were selected for the analysis. Of the twenty-eight patients, 17 (60.7%) were male; 11 (39.3%) were female; and the median age at the initiation of therapy was 42 years (range 25–85 years). Serum protein electrophresis (SPEP), immunofixation, and immunoglobulin quantitation were performed in all of these patients before initiating ERT and at intervals during follow-up. The patients were categorized into three groups based on their initial SPEP results: Group 1: those with normal SPEP pattern; Group 2: those with polyclonal gammopathy; and Group 3: those with MG. At the time of initiation of ERT, Group 1 contained 12 patients (42.8%) while Groups 2 and 3 each had 8 patients (28.6%). During follow up for a median of 8.5 years (range 1–15 years), 2 patients from the Group 1 (16.7%) and 4 patients from Group 2 (50%) developed MG. Of the patients in Group 3, 3 patients (21.4%) reverted to a normal SPEP pattern. Overall, 14 patients (50%) in all three groups had a MG identified at the time of initiation of therapy or during follow-up: 3 (all in Group 3) reverted to a normal SPEP pattern while the other 11 patients showed no change in M-spike levels after a median of 8.5 years of follow up. All 14 patients with MG had a monoclonal IgG immunoglobulin, and 3 of them also had a monoclonal IgM immunoglobulin. There was no association between the occurance or type of MG with any particular Gaucher Disease genotype, patient age, or other clinical variable. Only one of the patients developed a malignancy: an elderly man with MG developed Hodgkin’s Disease. None of our patients developed MM. In conclusion, these data confirm the high rate of MG in patients with Gaucher Disease but a low rate of progression to any other plasmacytic or lymphocytic disorder.
The Use of Erythropoietic Agents in Patients with Non-Myeloid Hematological Malignancies.
Authors: Shehata Nadine , Walker Irwin , Meyer Ralph , Haynes Adam , Imrie Kevin 
Published: October 2019

Abstract
Practice guidelines for use of an erythropoietic agent (EpA) have been previously developed for patients with all cancers, but these have not specifically addressed non-myeloid hematological malignancies. Given issues of benefit, cost, access to treatment and practice variation for these patients, the Cancer Care Ontario Program in Evidence - Based Care (CCO PEBC) conducted a systematic review and has developed a practice guideline. Entries to MEDLINE, CANCERLIT, EMBASE, the Cochrane Library databases, and abstracts of the American Societies of Clinical Oncology (ASCO) and Hematology (ASH) were searched. A hierarchy of outcomes was developed that included survival, quality of life (QoL), transfusion requirements and improvements in hemoglobin concentration/hematocrit. To validate conclusions and recommendations, the practice guideline was sent to Ontario practitioners in July 2006; responses are now being collated. Eighteen reports (14 articles, 4 abstracts) of randomized trials met eligibility criteria. None of the 3 trials reporting survival outcomes detected a benefit with use of an EpA. Of 7 trials evaluating QoL, 6 reported superior outcomes in patients receiving an EpA. None of those trials sufficiently reported methodologic parameters required by proposed guidelines for analyzing, interpreting and reporting QoL measures. Use of an EpA significantly reduced the proportion of patients transfused in 5 trials evaluating this outcome; reductions ranged from 15% to 40%. The absolute risk reduction ranged from 15% to 24%; the number needed to treat to prevent a transfusion ranged from 4 to 6. Use of an EpA was not associated with a reduction in the mean/median number of units transfused. In 10 studies, either a statistically significant increase in the hemoglobin concentration/hematocrit or in the proportion of patients with an increase in the hemoglobin concentration/hematocrit was seen. For this practice guideline, we interpreted the evidence as providing insufficient data to justify use of an EpA in order to improve survival or QoL. However, there are compelling data showing that use of an EpA reduces the risk of requiring a transfusion. Initiatives such as the Commission of Inquiry on the Blood System in Canada (“the Krever Commission”), state that alternatives to transfusion be offered to patients because of associated known and potentially unknown adverse consequences of blood products. Thus, the use of an EpA is recommended as an alternative to transfusion. However, the decision to use an EpA to reduce transfusion requirements should primarily consider individual patient values and the likelihood that a patient will require a transfusion so that patients are not exposed to unnecessary treatment and the health care system to additional costs.
Treatment of Osteopenia/Osteoporosis after Allogeneic Hematological Cell Transplantation with Zoledronic Acid.
Authors: Hill Wolfgang , Ullmann Johanna , Baur Andrea , Ledderose Georg , Tischer Johanna , Muehlbayer Dieter , Hausmann Andreas , Schmidt Michael , Haus Ulrike , Kolb Hans-Jochem 
Published: October 2019

Abstract
Decreased bone mineral density (BMD) has been found to be a relatively common complication following haematopoietic cell transplantation (HCT). Only some studies exist about therapy with antiresorptive substances such as bisphosphonates. These studies analyse either short time therapy or only the use for female patients (pts). The aim of this study was to test the effect and tolerance of zoledronic acid in long time survival pts after HCT. Methods: 40 pts with osteoporosis (WHO T-score<=−2.5 SD) or osteopenia (T-score −1,0 to −2.5) were included in this prospective phase II study. The dose was 4 mg intravenously all 3 months for 2 years (yrs) in combination with calcium, vitamin D and hormone-replacement therapy. 36 patients were evaluated, who got at least 3 doses (24 male, 12 female; mean age 43,8 yrs). The diagnoses were AML (15pts), ALL (5pts), CML (11pts), NHL (3pts), MDS (2pts). 16 pts received peripheral stem cells, 16 bone marrow, 4 pts both (median 15,6 months since HCT). All pts were evaluated according biochemical routine parameters, deoxypyridinoline (Dpd) and calcium excretion in urine by longitudinal measurements. The BMD of lumbar spine L1–L4 (LS) and total femur hip (FH) was mostly determined by dual-energy X-ray absorptiometry (Lunar Prodigy). 26 pts had at least two measurements since base line beginning of the treatment. Results: We found a significant increase of BMD at LS and FH (Table 1). The increase was better in younger pts <45yrs than in older pts at FH: 8,9 vs 2,9 % at 1 yr and 12,0 vs 3,4% at 2 yrs (p=0,007 and p=0.02). Dpd decreased from 6,2 nmol/mmol creatinine to 3,6 after 1 yr (p=0.009) and 3,2 after 2 yrs (p=0.04). By subgroup evaluation no significant changes of BMD were observed by testing pts with (n=20) or without (n=6) corticosteroid therapy for GvHD before or during the study (n= 7 and n=19) and by testing pts with osteoporosis (n=13) vs osteopenia (n=13), sex differences, diagnoses or time to HCT. Zoledronic acid was well tolerated. 1 of the 40 pts was excluded after the fist dosis because of dramatically myalgia. 6 pts had mild flu-like syndromes, bone pain, chest pain or headache. Zoledronic acid increases BMD and reduces Dpd excretion significantly in patients with bone loss after allogeneic hematological cell transplantation.
Table 1: baseline ° 1 yr°* 2 yrs°* % 1 yr* % 2 yr* °g/cm² mean values (+/−SD) *p=0.000 vs baseline LS 0.97+/−0.15 1.04+/−0.18 1.10+/−0.18 7.4+/−4,8 11.6+/−6.0 FH 0.82+/−0.10 0.87+/−0.11 0.91+/−0.10 5.6+/−5.3 7.5+/−7.0
Female Gonadal Function Following Reduced Intensity Conditioning (RIC) Allogeneic Bone Marrow Transplantation for Haematological Malignancies.
Authors: Kyriakou Chara , Davies Melanie , Chatterjee Ratna , Castleton Anna , Roberts Kim , Peniket Andy , Mackinnon Stephen , Kottaridis Panagiotis D. 
Published: October 2019

Abstract
It is generally accepted that recipients of myeloablative allogeneic bone marrow transplants will have markedly reduced gonadal function post transplantation and are likely to be rendered infertile. Many of these patients will also have received intensive pre-transplant chemotherapy leading to significant gonadotoxicity even before transplantation. During the last decade, conditioning regimes of reduced intensity have been developed in an effort to reduce the short and long term toxicities associated with myeloablative transplants,. We studied pre and post-transplant gonadal function of 27 female patients undergoing RIC using Fludarabine, Melphalan and CAMPATH-1H regimen. GVHD prophylaxis consisted of cyclosporine (CyA) except one patient with AML who received CyA/MTX rather than CAMPATH-1H. The median age at transplantation was 33 years (19–45). Fourteen patients had Hodgkin lymphoma, 6 Non Hodgkin lymphoma, 4 multiple myeloma 2 MDS and one AML. Of these patients, 22 were shown to have reduced gonadal function prior to transplantation, as a result of previous intensive chemotherapy (11 patients had previous autologous transplant). The remaining five patients were shown to have preserved gonadal function pre-transplantation as evidenced by LH, FSH, oestradiol and prolactin levels within the normal range. One patient with myeloma had received VAD chemotherapy prior to transplant, one patient with lymphoma CHOP-R × 6, one with AML standard induction anthracycline based chemotherapy while 2 patients with MDS were allografted with no preceding chemotherapy. Post transplantation, all five patients were shown to have preserved gonadal function at a median follow up of 22 months (8–35). This was evidenced by clinical (regular menstruation), biochemical (normal hormonal profile), and radiological (ovarian ultrasonography) parameters. One patient become pregnant naturally twice and gave birth to two healthy children. In contrast to patients receiving fully myeloablative conditioning regimes, female patients with normal gonadal function who receive reduced intensity conditioned allografts can retain gonadal function and fertility. These results have implications in fertility counselling and should be taken into consideration in decision making, especially in young women for whom preservation of fertility is of paramount importance.
Flow Cytometric Analysis of Specimens by a Central Reference Laboratory in a Multi-Center Study: Factors Affecting Data Quality.
Authors: Durett April G. , Gee Adrian P. , Collins Nancy H. , Eapen Mary , Weisdorf Daniel 
Published: October 2019

Abstract
Central reference flow cytometry laboratories are used in multicenter trials to eliminate inter laboratory variation in testing. Yet, factors that materially affect the quality of data such as graft processing, sample composition, packaging, and shipment have been little studied. The Baylor Center for Cell and Gene Therapy (BCGT) was the central reference laboratory for the NMDP IRB-2002-0068 multicenter study on the correlation of graft composition on clinical outcome. Samples of processed or non-processed grafts of 489 bone marrow (BM) and 696 peripheral blood progenitor cell (PBPC) grafts from July 2003-March 2004 were shipped to BCGT using 2 types of shipping containers with frozen gel packs to keep samples cool during transit. On arrival samples were assessed for temperature of gel packs, sample integrity (clumps, clots requiring filtration), viability by flow cytometry using 7AAD, and immunophenotype (CD34+, CD3+, and CD3+ T-cell subsets, CD25, CD69, HLA-DR). The FDA “standard” of 70% viability was used to define acceptable sample viability. Integrity and viability of BM and PBPC samples were not influenced by the method of cell processing: non-processed, plasma depletion, mononuclear cell concentration or T-cell depletion. BM samples were not affected by either temperature or time to evaluation. Viability of PBPC samples was adversely affected by both gel pack temperature and time from collection to evaluation. A 55% mean viability was observed with gel packs arriving thawed-warm vs 89% with frozen gel packs. Additionally, the samples that arrived >48hr after collection also had mean viability less than the 70% standard value. Viability of samples was inversely correlated with gel pack temperature on arrival and time from collection to evaluation. Therefore, the quality of FACS data and by implication, the graft utility was largely influenced by cell type, temperature in transit, and the time from collection to evaluation. Thus, while the use of a central reference laboratory can produce reliable data on cells following a variety of processing methods, certain factors must be optimized in order to collect data that accurately reflects the samples under study. Shipping standards to maintain graft viability and reliability of laboratory assessments of graft composition must be established and validated against the success of transplantation outcomes.
DNA Repair Genes Are Upregulated in Multiple Myeloma (MM) Patients Relapsing after Tandem Transplantation.
Authors: Tricot Guido , Zhan Fenghuang , Huang Yongsheng , Barlogie Bart , Shaughnessy John 
Published: October 2019

Abstract
Background: Repair of DNA interstrand crosslinks (ICLs) is considered the major mechanism by which resistance to high and low dose melphalan emerges (Spanswick et al. Blood2002; 100: 224). Enhanced ICL repair occurs via the Fanconi anemia (FA)/ BRCA pathway in myeloma cell lines (Chen et al. Blood2005; 106: 698). The aim of this study was to evaluate if DNA repair genes were indeed upregulated at relapse when compared to baseline in patients enrolled on our Total Therapy 2 protocol.
Methods: We compared 51 paired baseline and relapse bone marrow samples for gene expression profiling of CD138 selected plasma cells using the Affimetrix U133 Plus 2.0 microarray. The microarrays were preprocessed using GCOS 1.1 software and normalized using conventional GCOS 1.1 scaling. Baseline and relapse gene expression was compared using the paired Student t test.
Results: More than 30 genes related to DNA repair on the microarray were analyzed. We observed significantly higher expression at relapse of FANCA (p=.003), BRCA 1 (p<.001), CHEK1 (p=.006) and FANCG (p=0.03) (Figure 1). In contrast, FANCD2 was down-regulated at relapse (p=.006), while no significant changes in expression of FANCF or DNA mismatch repair genes were seen.
Conclusion: Our data supports the concept that DNA repair genes in the FA/BRCA pathway contribute to acquired resistance to melphalan in patients after high dose melphalan transplants and that inhibition of DNA repair by bortezomib, gemcitabine or the CHEK1 kinase inhibitor UCN-01, may reverse such resistance if added to high dose melphalan.
DNA Repair Genes in Paired Relapse Samples (N=51) DNA Repair Genes in Paired Relapse Samples (N=51)
CKS1B, Mapping to an Amplicon on Chromosome 1q21 and over Expressed in Aggressive Disease, Regulates Multiple Myeloma Growth and Survival through p27Kip1-Dependent and Independent Mechanisms.
Authors: Zhan Fenghuang , Colla Simona , Chen James B. , Stewart James P. , Wu Xiaosong , Huang Yongsheng , Hanamura Ichiro , Burington Bart , Yaccoby Shmuel , Epstein Joshua , Barlogie Bart , Shaughnessy John D. 
Published: October 2019

Abstract
While deregulated expression of a D-type cyclin is thought to represent an initiating event in myelomagenesis, the molecular mechanisms of disease progression are not understood. We recently reported that disease progression and high-risk disease are strongly correlated with increased copy number and expression of genes mapping to chromosome 1q. Here we report that elevated expression of CKS1B, a regulatory subunit of the SCF-Skp2 ubiquitin ligase that regulates p27Kip1 protein stability, mapping to an amplicon at 1q21 and over expressed in high-risk myeloma, is required for myeloma cell survival both in vitro and in-vivo. CKS1B expression, absent in plasma cells from healthy individuals and the benign plasma cell dyscrasia monoclonal gammopathy of undetermined significance, is inversely correlated with p27Kip1 protein levels in primary MM. Silencing of CKS1B in MM cell lines JJN3 and OCI-MY5 using shRNAs delivered by constitutive and inducible lentivirus vectors induced stabilization of p27Kip1, cell cycle arrest and apoptosis. Over expression of a non-degradable form of p27Kip1 in JJN3 and OCI-MY5 cells inhibited cell cycle progression, but did not induce apoptosis. We propose that CKS1B may play in important role in myeloma progression through p27Kip1-related and unrelated mechanisms.
Modulation of the Mitochondrial (Type 2) Apoptotic Pathway Can Enhance Apo2L/TRAIL - Mediated Killing of Human Multiple Myeloma (MM) Cells.
Authors: Khong Tiffany , Yeh Sung Lin , Souris Karly , Spencer Andrew 
Published: October 2019

Abstract
We and others have previously demonstrated that Apo2/TRAIL effectively induces apoptosis of human myeloma cell lines (HMCL) but exhibits only modest activity against primary MM cells derived from patients with advanced MM. A commonly acquired drug-resistance mechanism found in these patients is the over-expression of the anti-apoptotic protein Bcl-xl. Based on these observations and the potential of Apo2/TRAIL as a specific anti-MM therapeutic agent we have investigated further the mechanism(s) of apoptosis induction in MM and whether inhibition of bcl-xl expression enhances the efficacy of Apo2L/TRAIL induced killing of MM cells. Four HMCL selected on the basis of high (U266 and RPMI 8226) or low (LP-1 and NCI H929) Bcl-xl expression, as determined by both Western blotting and ELISA, were chosen for study. We have previously demonstrated no correlation between the absolute levels of caspase 8 and cFLIP or the caspase 8:cFLIP ratio of these 4 HMCL and their sensitivity to Apo2/TRAIL. HMCL were treated with 1μg/ml of recombinant human trimeric TRAIL (LZ-TRAIL) (Amgen) and the level of apoptosis was measured by AnnexinV expression at 2 hours - U266 24%, RPMI 8226 53%, LP-1 57% and NCI H929 26%. The experiment was then repeated and both whole cell lysates and cytosolic fractions were prepared for immunoblot analysis of caspase 8 cleavage and cytochrome C/SMAC protein levels, respectively, at various time-points from 0 to 120 minutes following treatment. Two patterns of apoptosis induction were observed. All 4 HMCL had demonstrable increases in cytosolic cytochrome c and SMAC by 15 minutes post LZ-TRAIL. Similarly both RPMI and LP-1 demonstrated contemporaneous cleavage of caspase 8. In contrast, no evidence of caspase 8 cleavage was seen in U266 or NCI H929 until 30 – 60 minutes post LZ-TRAIL. The impact of pre-treatment with a caspase 9 inhibitor, (Z-LEHD-FMK) prior to LZ-TRAIL correlated with the immunoblot findings: RPMI 8226 and LP-1 (7% and 20%, respectively) showing less relative reduction in apoptosis inhibition than U266 and NCI H929 (64% and 49%, respectively). Finally, treatment with TRAIL alone, the bcl-xl inhibitor 2MAME (10, 15 or 20μg/ml) alone or both (2MAME 4 hours prior to TRAIL) demonstrated synergistic killing of both ’high’ bcl-xl expressing HMCL (RPMI 8226 synergism quotients = 1.1, 1.3 and 1.3 and U266 synergism quotients = 1.6, 1.4 and 1.4 for 2MAME 10, 15 and 20μg/ml, respectively) but not the ’low’ bcl-xl expressing HMCL (NCI H929 and LP-1). From these data we conclude that human MM cells exhibit variable apoptotic responses to Apo2L/TRAIL that involve both the Type 1 and Type 2 apoptotic pathways and that the targeting of known inhibitors of the Type 2 pathway can enhance Apo2L/TRAIL-induced apoptosis.