bluuebunny/crossref_metadata_2025_split huggingface dataset:
Is Family History of Breast Cancer Associated with Therapy-Related Myelodysplastic Syndrome and Therapy-Related Leukemia? .
Authors: Li Loretta S. , Huo Dezheng , Karrison Theodore , Larson Richard A. , Olopade Olufunmilayo 
Published: October 2019

Abstract
Therapy-related myelodysplastic syndrome (t-MDS) and therapy-related acute myeloid leukemia (t-AML) occur in a subset of patients treated with chemotherapy and/or radiation for various primary malignancies. Whether or not a patient develops t-MDS/t-AML can be influenced by a combination of genetic and environmental factors. We conducted a retrospective analysis of t-MDS/t-AML patients who had cytogenetic analyses performed at the University of Chicago Hospitals between 1972 and 2001 to determine if a family history of cancer could be associated with t-MDS/t-AML development. These included 141 males and 165 females whose median age was 51 years (range was from 3–83 years) at the time of primary diagnosis and 58 years (range was from 6–86 years) at the time of t-MDS/t-AML presentation. Out of 306 patients, data on first-degree family history of cancer was documented in 160 patients, but there was no statistically significant difference in the characteristics examined below between patients with self-reported family history of cancer and patients with undocumented family histories. A first-degree family history of any cancer was reported in 89 patients (55.6%). The prevalence of family history of specific sites were: 25 (15.6%) of breast cancer, 23 (14.4%) of lung cancer, 13 (8.1%) of colorectal cancer, 11 (6.9%) of hematologic malignancy, 10 (2.3%) of prostate cancer, 6 (3.8%) of stomach cancer, 5 (3.1%) of uterine cancer, 5 (3.1%) of CNS cancer, 5 (3.1%) of pancreas cancer, 4 (2.5%) of melanoma, 3 (1.9%) of oral-pharyngeal cancer, 3 (1.9%) of ovarian cancer, 3 (1.9%) of cervical cancer, 2 (1.3%) of vulvar cancer, 1 (0.6%) each of bladder cancer, sarcoma, renal cancer, or esophageal cancer. Of note, only a family history of breast cancer was associated with clinical presentation as show in Table 1 below. Patients with a family history of breast cancer were also more likely to have a chromosome 5 and/or 7 abnormality (84%) than patients without (62%, p=0.04). There was no significant association between family history of cancer at other sites and clonal cytogenetic abnormalities. A subgroup analysis was conducted in patients with a primary diagnosis of breast or ovarian cancer. Of the 24 patients who had data on family history of cancer, 16.7% reported having a first degree relative with breast cancer. These findings suggest a possible genetic component linking family history of breast cancer and development of t-MDS/t-AML, as was previously reported by Rauscher et al. (2002) for de novo adult leukemia incidence. Further studies of family histories of cancer, in particular breast cancer among patients receiving chemotherapy and/or radiation, could potentially elucidate the genetic basis of leukemia and ultimately lead to new tools for risk assessment, early detection or prevention of secondary leukemia in cancer survivors.
The Role of DNA Methylation of HoxA5, a Regulator of Haematopoiesis, in Progression to Myeloid Blast Crisis in CML.
Authors: Strathdee Gordon R. , Holyoake Tessa L. , Sim Alyson , Brown Robert 
Published: October 2019

Abstract
Hox (homeobox) genes are known to be key regulators of development and haematopoiesis and several have also been implicated in leukaemogenesis. Overexpression of HoxA5 in human haematopoietic progenitors leads to an increase in myelopoiesis, suggesting a role for this hox gene during induction of myeloid differentiation. Inactivation of genes by CpG island DNA methylation is known to be important in the development and progression of leukaemia, and inhibitors of DNA methylation are currently of great interest as novel therapeutics for a number of haematopoietic malignancies. Here we show that in peripheral blood from healthy volunteers HoxA5 exhibits methylation of 50% of alleles across an extensive CpG island covering the promoter region/1st exon of HoxA5. In patients with chronic myeloid leukaemia, 33% (15/45 patients) exhibited increased methylation of HoxA5 (80–100% of alleles methylated) in the chronic phase of the disease. However, such hypermethylation of HoxA5 was invariably present in samples from patients in myeloid blast crisis (15/15 patients). In contrast, patients in lymphoid blast crisis did not exhibit increased levels of hypermethylation. Analysis of patients in chronic phase demonstrated a statistically significant correlation (p < 0.006) between hypermethylation of the HoxA5 gene and other prognostic factors associated with high risk of progression to blast crisis (high Hasford/Sokal score, incomplete response to Imatinib, known early progression, del 9), suggesting that methylation of HoxA5 may be a clinically useful prognostic indicator. The results are also compatible with a direct role for hypermethylation of HoxA5, and consequent loss of HoxA5 expression, in inhibition of myeloid differentiation during progression to blast crisis and implicate HoxA5 as a therapeutic target for inhibitors of DNA methylation in the treatment of leukaemia.
Modelling Molecular Consequences of Leukemia Initiation by TEL-AML1 Fusion.
Authors: Ford Anthony M. , Cardus Penny , Greaves Mel F. 
Published: October 2019

Abstract
We have previously shown that TEL-AML1 (ETV6-RUNX1) fusions in acute lymphoblastic leukemia commonly arise pre-natally. The fusion protein initiates, presumably via transcriptional deregulation, a pre-leukemia condition that infrequently (~1%) converts over a 10 year period to overt leukaemia in the presence of post-natal, secondary genetic changes including TEL deletion.
One challenge is to identify the molecular mechanisms by which TEL-AML1 elicits and sustains stable pre-leukemic clones which are then vulnerable to additional genetic alterations in the context of particular etiological exposures (e.g. infection). We have established cell lines of murine lymphoid progenitor cells that stably express a regulatory, truncated human progesterone receptor ligand-binding domain (pSwitch, Invitrogen) that undergoes a conformational change in the presence of the steroid agonist, mifepristone and conversion to an active form. The active binding domain is then able to bind to and activate transcription from an otherwise silent TEL-AML1 gene that we have also stably introduced into these cells. In the presence of sub-physiological levels of mifepristone, TEL-AML1 becomes abundantly expressed in the nucleus within a few hours. Microarray analysis comparing uninduced (time 0) cDNA with cDNA from both control and TEL-AML1 induced cells grown for 4 days in the presence of mifepristone showed changes in the expression pattern for over 250 genes. The majority of these genes were down regulated in the presence of TEL-AML1, in keeping with a repressive activity for the fusion gene. A number of apoptotic and cell cycle genes were down regulated, while anti-apoptotic genes were up regulated in the presence of the fusion protein. These genes are currently being examined by both in-silico and laboratory-based validation techniques and may provide key insights into the pathways that are deregulated by TEL-AML1 in ALL.
Lack of Value of Clinical Predictors of Heparin Induced Thrombocytopenia (HIT) in Complex Patients.
Authors: Baker Jessica , DeLoughery Thomas G. , Boshkov Lynn 
Published: October 2019

Abstract
HIT is a devastating complication of heparin use that can result in thrombosis and death. However, it can be difficult to diagnose. Although the clinical hallmark of HIT is a drop in platelet counts in patients receiving heparin, in complex patients there may be many confounding reasons for thrombocytopenia and thrombosis. One proposed diagnostic tool for HIT is to quantitate the percent drop in platelet count from the highest level. Also Warkentin has proposed the “4T’s” scoring system where 4 clinical indicators (% drop in platelet count, timing of heparin dosing, presence of thrombosis, and lack of other causes of thrombocytopenia) are used to derive a score to indicate High, Intermediate, or Low probability of HIT.(Curr Hem Rep, 2, 148–157) We sought to verify the predictive value of these clinical systems. Over a 30 month period, we reviewed the charts of 544 patients who were suspected of having HIT. 61% of these patients were in intensive care units, 47% were peri-operative, and 22% were cardiac patients. HIT was diagnosed by a combination of review of the clinical course plus results of platelet activation assay, and with at least 2 faculty hematologist agreeing on the diagnosis. Data was abstracted concerning platelet count, timing and use of heparin, presence of thrombosis, and other causes of thrombocytopenia including infection and major surgery. 18 out of 544 patients (3.3%) had heparin induced thrombocytopenia. 16 of 18 patients received therapeutic standard heparin and 2 patients received only prophylactic doses of LMWH. There was no difference in nadir platelet count nor percent drop in HIT (75±79,000/Ul, 65±26%) vs those without HIT (90±71,000/uL, 53±24%). Two major causes of thrombocytopenia in this population were infections and surgery. 175 patients (32%) had positive blood cultures with a mean platelet drop of 55±23% preceding the positive cultures. 47% had major surgery with a mean platelet drop afterwards of 60±22%. A drop in platelets of over 50% had a 82% sensitivity for HIT but only a 43% specificity. Using different cut-offs did not reveal a value with better predictability. Interestingly, only 2 (11%) of the HIT patients scored on the 4T’s as High probability with 39% being Intermediate and 50% as Low. This was due to presence of other causes of thrombocytopenia in patients and the fact that 30% of the HIT patients were on heparin longer that 10 days. 4% of the non-HIT group scored as High and 28% as Intermediate but close review of their subsequent clinic course did not reveal evidence for HIT. Simple clinical tools for diagnosing HIT are of limited utility in ill and complex patients due to other competing causes of thrombocytopenia and the potential for long duration of heparin exposure.
Clinical Features and Effects of Eradication on Helicobacter Pylori Positive 207 ITP Cases in Japan.
Authors: Fujimura Kingo , Kuwana Masataka , Kurata Yoshiyuki , Imamura Masahiro , Harada Hiroshi , Sakamaki Hisashi , Teramura Masanao , Koda Kyuhei , Nomura Shosaku , Sugihara Sayaka , Shimomura Takeshi , Fujimoto Tetsuro Takahiro , Oyashiki Kazuma , Ikeda Yasuo 
Published: October 2019

Abstract
In 1998, Gasbarrini et al reported that in ITP cases with Helicobacter pylori (H.pylori) infection, elevation of platelet counts was observed by eradication of this bacterium. Since then, several reports from Italy and Japan confirmed the elevation of platelet counts after eradication. However, the characteristic background in the H.pylori positive ITP and eradication effects on platelet counts is unclear. On the other hand, reports from Spain, North Europe and USA could not show the evidence that eradication is effective on elevating platelet counts in H.pylori positive ITP.
Therefore, we designed a nationwide retrospective study in Japan to evaluate the incidence of H.pylori positive ITP cases and the effects of eradication on platelet counts and to clear above problems.
Four hundred and thirty-five ITP cases were enrolled over a period of one and half years (2002. 7~2003.12) from 12 hospitals. H. pylori infection was found in 300 cases(65%), who were significantly (P<0.005) older and showed hyperplastic megakaryocyte in bone marrow (P=0.011) comparison with negative cases. Eradication to H. pylori was performed in 207 H. pylori positive ITP cases and as a whole, the platelet count response was observed in 63% of eradication succeeded group. In the successful group, CR and PR rate were 23% and 42% respectively at 12 months after eradication. The platelet count response was significant in the successfully eradicated group (P<0.005) and the increased platelet count was maintained without ITP treatment for over 12 months. In conclusion, H. pylori infection was involved in most ITP patients over 40 years old in Japan and eradication therapy proved effective for increasing platelet counts even in splenectomy non-responsive cases and the platelet count response appeared one month after eradication. This evidence suggests that eradication therapy is the first line of treatment in H. pylori positive ITP patients.
Mabthera (Rituximab) in the Treatment of 92 Patients with Refractory Immune Thrombocytopenic Purpura.
Authors: Cabrera JRafael , Penalver F. Javier , Millan Isabel , Jimenez-Yuste Victor , Almagro Manuel , Alvarez-Larran Alberto , Rodriguez Lluis ,   other 36 participants in the multicentric retrospective Spanish Study on use of Rituximab in Refractory ITP
Published: October 2019

Abstract
Objectives: Rituximab (RB) is an anti-CD20 murine/human chimeric antibody that has been used in the treatment of auto-immune diseases, including immune thrombocytopenic purpura (ITP). The effectiveness of RB in the treatment of patients with ITP has been evaluated.
Patients and methods: A multicentric retrospective study of the patients with ITP treated with RB has been carried out. A questionnaire about clinical characteristics and response to RB was sent to the participating centers. These questionnaires were filled out by the physicians in charge of each patient. We received questionnaires from 43 centers The response criteria were those published by Stasi R et al (Blood2001; 98:952): Complete Response (CR): platelets >100 x 109/l; Partial Response (PR): 50–100 x 109/l; Minimum Response (MR): 30–50 x 109/l. Data from 99 patients were analyzed. Ninety two out of 99 patients were evaluated. The median age at diagnosis was 54 years (4–98), 56% were women. 55.4% of the cases were idiopathic ITP, 14.1% were associated with B-CLL, 8.7% with auto-immune diseases and 3.3% with lymphoma. Before RB they have received several treatment schemes including steroids (98%), IVIG (88%) and cyclophosphamide (26%). 52.2% were splenectomized. Median of platelets before treatment with RB was 8 x 109/l (1–30), 66.3% had less than 10 x 109/l. 87% of the patients were treated with 4 doses of RB (1–6), while 34 received it in association with other treatments, mainly steroids.
Results: 42 patients obtained CR (46.2%) and 8 patients obtained PR (8.8%), a total of 50 global responses (55%). The majority of the responses took place in the first week (26% out of the total, 40% of the responders). The maximum response was also soon achieved, median of 5 weeks, with platelets of 141 x 109/l (10–651). There were no differences in the response between splenectomized or not splenectomized patients. 29 patients maintained the CR (69% of responders), with a monitoring median of 9 months (2–42). The toxicity of the treatment was minimum: 2 fever episodes with the infusion and 2 skin eruptions.
Conclusions: This is the widest series of patients with ITP treated with RB. These results suggest that RB can be considered as a rescue treatment for patients with refractory ITP to steroids and/or splenectomy, with an excellent tolerance. Further monitoring is needed in order to establish the real role of RB as a rescue treatment for refractory ITP.
Direct Intramarrow Injection of CD34+ Cells May Improve Long-Term Engraftment in Nonhuman Primates.
Authors: Jung Chul W. , Morris Julia C. , Beard Brian , Neff Tobias , Beebe Kate , Kiem Hans-Peter 
Published: October 2019

Abstract
Recent studies in the NOD/SCID model have shown improved engraftment of SCID-repopulating cells and higher levels of engraftment in the secondary transplantation when cells were administered by intramarrow (IM) versus intravenous (IV) injection suggesting that direct injection into the marrow cavity may be beneficial for stem cell engraftment in a clinical setting. To study whether IM injection was feasible and would result in improved engraftment in a clinically relevant large animal model, we compared IM vs IV injection in our competitive repopulation assay in baboons. Enriched CD34+ cells were split into 2 equal fractions and transduced with either a GFP- or YFP-expressing vector. Pretransplant transduction efficiencies and expansion of CD 34+ cells were similar in both fractions. One fraction was then infused into the marrow cavity of the right femur and the other fraction was given intravenously. Three baboons received gene-modified CD34+ enriched autologous bone marrow cells after myeloablative radiation. Peripheral blood granulocyte marking levels showed peaks at 2–3 weeks after transplantation and decreased thereafter. In all three monkeys, marking levels of IM injected cells (GFP) were lower than marking levels of IV injected cells (YFP) early after transplantation up to 7 weeks. However, in two of the three monkeys, GFP marking increased steadily after 2 months resulting in higher marking levels from IM injected cells. The trend sustained up to the last follow-up of nine months after transplantation, marking levels being 25.5% and 7.4% from IM and IV injected cells, respectively, in M00228. This pattern was recapitulated in the marking of bone marrow cells of the two animals. GFP (IM) and YFP (IV) marking levels of bone marrow cells from non-injected bone were 24.2% and 33.9%, respectively, at 1 month, 7.9% and 4.6% at 3 months, 19.1% and 12.6% at 6 months after transplantation in M00228. In addition, the GFP marking of the bone marrow cells from the injected bone was higher than that of the BM cells from non-injected bone while YFP marking level was similar. In conclusion, our data suggest that direct intramarrow injection of CD34+ cells may lead to improved engraftment of long-term repopulating cells. Clonal analysis is currently under way to determine the clonal pattern of the differentially marked repopulating cells.
New Aspects on the Safety of Multidrug-Resistance 1 Gene Transfers: No Indication for Clonal Dominance after Long-Term Follow-Up in a Primate Transplantation Model.
Authors: Bozorgmehr Farastuk , Buss Eike C. , Laufs Stephanie , Nagy K. Zsuzsanna , Sellers Stephanie , Zeller W. Jens , Dunbar Cynthia E. , Fruehauf Stefan 
Published: October 2019

Abstract
It is of concern whether the introduction of a transgene into hematopoietic stem cells by retroviral vectors will lead to an alteration of the growth and engraftment characteristics. Earlier studies in mice indicated that retroviral multidrug-resistance 1 gene transfer may be associated with a myeloproliferative disorder. In human or primate cells this could not be reproduced in bulk cell populations. Analysis on the clonal level were lacking.
One method to study the in vivo behaviour of repopulating progenitor and stem cells is marking the cells with replication-incompetent retroviral vectors that integrate into identifiable host DNA sequences, thus allowing the tracking of cell progeny based on unique proviral insertion sites.
In this study CD34-enriched peripheral blood stem cells from 2 rhesus macaque monkeys were split into two aliquots and transduced either with a multidrug-resistance 1 gene-retroviral vector based on the Harvey murine sarcoma virus (HaMDR1-vector) or a NeoR-retroviral vector based on the Moloney murine leukaemia virus (G1Na-vector). After autologous retransplantation, DNA from blood and bone marrow was collected at different time points in a period of 4 years and the animals are still alive.
By using a highly sensitive and specific ligation-mediated polymerase chain reaction (LM-PCR) followed by sequencing of vector integration sites, we found in animal M120 32 different contributing hematopoietic clones 8 weeks and 50 weeks after transplantation and in animal M038 17 clones 58 weeks after transplantation. Based on the difference between the sequences of the HaMDR1-LTR and the G1Na-LTR, the clones can be allocated definitely to one of the two vectors. Remarkably, 36 clones descend from the G1Na-vector, whereas only 13 clones descend from the HaMDR1-vector.
We conclude that hematopoiesis in these monkeys is polyclonal for prolonged periods after transplantation and that MDR1 gene transfer does not confer a proliferative advantage over vector-control-transduced hematopoietic stem cells.
PDC-E2, a Common Auto Antigen in Primary Biliary Cirrhosis (PBC) Is Also a Target of an Antibody Response in Patients Who Achieve Complete Remission after Donor Lymphocyte Infusion.
Authors: Bellucci Roberto , Gallagher Meagan , Nguyen Hong-Nam , Alyea Edwin P. , Zorn Emmanuel , Anderson Kenneth C. , Munshi Nikhil C. , Ritz Jerome 
Published: October 2019

Abstract
The ability of donor lymphocyte infusions (DLI) to induce complete responses (CR) in patients with relapsed multiple myeloma (MM) following allogeneic bone marrow transplantation provides clear evidence of graft-versus-myeloma (GVM) immunity. To identify GVM associated target antigens, we previously screened an MM cDNA expression library with post DLI serum from 5 MM patients who achieved CR after DLI. One of the antigens identified in the screening was dihydrolipoamide acetyltranferase the E2 component of the pyruvate dehydrogenase complex (PDC-E2). Using a phage plate assay, antibody reactivity against PDC-E2 was found in 2 of 9 MM and 1 of 5 chronic myeloid leukemia (CML) patients who achieved a CR after DLI. No antibodies were found before DLI, in 20 normal donors, 10 patients who underwent T-cell depleted allogeneic BMT, 6 MM DLI non-responders and 20 patients with chronic GVHD. Primary biliary cirrhosis (PBC) is an autoimmune liver disease in which more than 80% of patients have autoantibodies against PDC-E2. In patients with PBC the major immunogenic epitope of PDC-E2 has been mapped to the region associated with the inner lipoyl domain. To better characterize the antibody response in MM patients who had a CR after DLI a GST-PDC-E2 fusion protein was purified and used to quantify the antibody response by ELISA. Using this sensitive assay we found 1 additional MM DLI responder who had antibody reactivity against PDC-E2. Analysis performed at serial time points after DLI showed that reactivity persisted for 1.5 and 3 years after DLI in two MM patients and 3 years after DLI in the CML DLI responder. To map the antibody response after DLI and compare this to antibody reactivity in patients with PBC, we synthesized a series of 85 overlapping peptides covering the entire length of PDC-E2 and analyzed the specificity of the antibody response by ELISA. Using this assay, post-DLI serum was found to be reactive against 4 peptides located in the E2 catalytic domain of PDC-E2 but no reactivity was detected against peptides located in the inner lipoyl domain of the protein, the region commonly recognized by auto-antibodies in PBC. Analysis of serial samples showed that the antibody response persisted against these peptides up to 2–3 years after DLI but no reactivity was found pre-DLI and in normal serum. In conclusion we show that PDC-E2, a common auto-antigen in the autoimmune disease PBC, is also the target of an antibody response in patients with MM and CML who achieve a CR after DLI. The antibody response found after DLI is directed against a different region of the protein. Further studies characterizing T cell epitopes in these patients are underway and they will help to better characterize the immune response against PDC-E2 in patients after DLI.