bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multiple Displacement Amplification Enables Large Scale Clonal Analysis after Retroviral Gene Therapy.
Authors: Bleier Stephanie , Maier Patrick , Wenz Frederik , Zeller W. Jens , Laufs Stephanie , Fruehauf Stefan 
Published: October 2019

Abstract
Analysis of the fate of retrovirally transduced cells after transplantation is often hampered by the scarcity of available DNA. We evaluated a promising method for whole genome amplification named multiple displacement amplification (MDA) with respect to the even and accurate representation of retrovirally transduced genomic DNA. We were able to show that MDA is a suitable method to subsequently specify engraftment efficiencies by quantitative real-time PCR as the retroviral integrations are amplified the same way and by the same probability as all other parts of the genome. We validated the method by analyzing a dilution series containing retrovirally transduced DNA and untransduced background DNA and retroviral integrations found in primary material from a retroviral transplantation model by quantitative real-time PCR. The representation of the portion of retroviral DNA in the amplified samples was 0.9-fold (range 0.2 – 2.1-fold) of the portion determined in the original genomic DNA. Furthermore, the succession of the combination of MDA and integration site analysis by ligation-mediated PCR showed an increase in the sensitivity of the method as a specific integration site could be detected in a background of untransduced DNA, while the transduced DNA made up only 0.001%. These results show that MDA enables large scale sensitive detection and reliable quantification of retrovirally transduced human genomic DNA and therefore facilitates follow up analysis in gene therapy studies even from smallest amounts of starting material.
Quality of Life and Myelodysplasia.
Authors: Prommer Eric E. 
Published: October 2019

The myelodysplastic syndromes (MDSs) are heterogeneous hematopoietic diseases associated with bone marrow failure, peripheral cytopenias, and a propensity for progression to acute myeloid leukemia (AML). In 2000, an International Working Group (IWG) of investigators proposed standardized response criteria which included quality of life as an important treatment goal. Quality of life becomes important when we are presented with a patient who is not a candidate for intensive curative therapy for myelodysplasia. The purpose of this literature review is to determine what quality of life instruments are optimal for this disease process and review is to examine the types of quality of life tools that have been used in published phase II and III studies of myelodysplasia. The focus is on adult hematology, and excludes studies with curative intent such as bone marrow transplantation, as well as phase I studies. Clinical trials from 1996—2006 were reviewed. 80 clinical trials were analyzed for the presence of attention to quality of life data. 7 trials used a quality of life instrument. All of the studies which used a quality of life instrument were published after 2003. Types of quality of life instruments used were the
(EORTC) QLQ-C30 FACT-An along with the Geriatric Depression Scale (GDS) Short Form-12 (SF-12).
The most common tool was the FACT-An. This was used in 5/7 studies that had quality of life tools. Of the 7 studies, 4 included the effect of therapy in all domains. The remainder focused on fatigue and/or anemia symptoms and their relation to quality of life.
Conclusion: While the IWG response criteria have prompted consideration of quality of life as response criteria, there must be better uniformity in quality of life assessment, as well as determination of the optimal tool to use. A disease specific quality of life instrument should be considered one solution to this problem.
Cyclosporin A, a P-gp Inhibitor, Augments the Anti-Central Nervous System Ph+ Leukemia Effects of INNO-406.
Authors: Yokota Asumi , Kimura Shinya , Masuda Satohiro , Ashihara Eishi , Urasaki Yoshimasa , Terui Yasuhito , Ruthardt Martin , Ueda Takanori , Hatake Kiyohiko , Inui Ken-ichi , Maekawa Taira 
Published: October 2019

Abstract
Central nervous system (CNS) relapse accompanying prolonged administration of imatinib mesylate, an Abl-specific tyrosine kinase inhibitor, has recently become apparent as an impediment to the therapy of Philadelphia-chromosome-positive (Ph+) leukemia. CNS relapse may be explained by limited penetration of imatinib into the cerebrospinal fluid due to presence of P-glycoprotein (P-gp) at blood-brain barrier. To overcome imatinib-resistance mechanisms such as bcr-abl gene amplification, point mutations within ABL kinase domain, and activation of Lyn, we recently developed a specific dual BCR-ABL/Lyn inhibitor, INNO-406 (formerly NS-187), which is 25–55 times more potent than imatinib in vitro and at least 10 times more potent in vivo (Blood106: 3948–3954, 2005). The aim of this study was to investigate the efficacy of INNO-406 in treating CNS Ph+ leukemia. The intracellular accumulation of [14C]INNO-406 in P-gp overexpressing LLC-GA5-COL150 cells was much less than that in parental LLC-PK1 cells. The addition of 10 mM cyclosporin A (CsA) increased the intracellular accumulation of [14C]INNO-406 in both LLC-PK1 cells and LLC-GA5-COL150 cells. The peak concentration of INNO-406 in the brain when 30 mg/kg INNO-406 was administered p.o. was 50 ng/ g (87 nM), representing only 10% of plasma drug level. These findings suggested that INNO-406 is also a substrate of P-gp, as is imatinib. However, the residual concentration of INNO-406 in the CNS was enough to inhibit the growth of Ph+ leukemic cells according to the in vitro data. To increase the concentration of INNO-406 in CNS, we next examined the combined effects of CsA. In the brain, the concentration of INNO-406 was doubled following prior administration of 50 mg/kg CsA. Since pharmacokinetic studies suggested the possible effects of INNO-406 against CNS Ph+ leukemia, we investigated in vivo anti-CNS Ph+ leukemia effects of INNO-406 alone and combination of INNO-406 and CsA using immunodeficient mice (nude or NOD/SCID) which received Ph+ leukemic cells into the cerebral ventricle. INNO-406 alone inhibited growth of leukemic cells harboring either wild type or mutated BCR-ABL such as E255K and M351T in CNS. Furthermore, CsA significantly enhanced anti-CNS Ph+ leukemia effects of INNO-406 in vivo not only against cells harboring wild type BCR-ABL but also against cells harboring BCR-ABL/M351T (Figure). In conclusion, INNO-406 was found to inhibit Ph+ leukemic cell growth in CNS in spite of efflux of the compound by P-gp, and CsA augmented the anti-CNS Ph+ leukemia effects of INNO-406. Phase I clinical study on INNO-406 was initiated in the U.S.A. in July 2006. The efficacy and safety of INNO-406 in the treatment of leukemias is expected to be verified by early-phase clinical trials.
Figure Figure
Rituximab Monotherapy for Cold Agglutinin Disease. Report on 16 Patients from a Single Institution.
Authors: Arriaga Francisco , Jarque Isidro , Paciello Mari-Liz , Cantero Susana , de la Rubia Javier , Sanz Guillermo , Sanz Miguel 
Published: October 2019

Abstract
Background: Cold agglutinin disease (CAD) is an acquired autoimmune hemolytic anemia mediated by cold-reactive autoantibodies that bind erythrocyte carbohydrate antigens, causing hemagglutination, complement-mediated hemolysis and C3d positive direct antiglobulin test. Conventional therapies for CAD are largely ineffective, but remissions after treatment with the anti-CD20 monoclonal antibody rituximab are increasingly being reported.
Patients and Methods: A total of 16 CAD patients (10 women, 6 men) with a median age of 48 years (range, 20–86 years), were treated in our center between May 2002 and January 2006. CAD was idiopathic in 7 cases and associated with other conditions in 9 (systemic lupus erythematous in 4, chronic lymphoproliferative disorder in 3, and unrelated donor cord blood transplant in 2). Hemoglobin concentration before treatment ranged from 4.9 to 10 g/dL. Median IgM anti-I titer was 512 (range, 128–100,000). Rituximab was given as single agent in doses of 375 mg/m2, at days 1, 8, 15 and 22.
Results: The overall response rate was 62.5%, with 9 patients achieving complete remission (56%). Median duration of response was 24 months (range, 5–48 months). Of the 6 non-responders, 5 died from disease progression and 1 remains alive with transfusion dependence. No serious infusion-related adverse events occurred with rituximab.
Conclusion: Rituximab is a safe and effective therapeutic option and should be considered as first-line treatment for patients with CAD.
Paroxysmal Nocturnal Hemoglobinuria (PNH): Long-Term Epidemiological Study.
Authors: de Latour Regis Peffault , Mary Jean Y. , Salanoubat Celia , Terriou Louis , Etienne Gabriel , Mohty Mohamad , Roth Sophie , de Guibert Sophie , Cahn Jean Y. , Socie Gerard 
Published: October 2019

Abstract
PNH is a rare acquired disorder. We aimed to analyze a large cohort of patients on the long term to better determine prognostic factors. We already reported the analysis on 220 patients in 1996 (Socié et al, Lancet). Data were updated and we collected additional data on 247 patients (total of 467 patients, 252 female), diagnosed from 1950 to 2005 from 58 centers. The date of diagnosis was based on flow cytometry analysis if there was no prior positive Ham’s test. The age at diagnosis was 34 years (±17.3). The median follow-up time was 6.8 years (±0.5). Kaplan-Meier 10-year survival estimate was 76.3% (± 2.6). Sixty seven (14.6%) patients developed pancytopenia during follow-up [10-year cumulative incidence (CIn) rate of 18.3% (14% – 22%)]. Deep-vein thrombosis occurred in 108 patients (23.5%) [10-year CIn 28% (23% – 33.1%)]. Nineteen patients developed myelodysplastic syndrome (MDS) [10-year CIn 4.6% (2.4% to 6.8%)]. Eight patients developed acute leukemia [10-year CIn 2.3% (0.4% to 3.9%)]. The following factors were related to poor survival: Older age at diagnosis; age between 40 and 55 years [relative risk RR=2.4 (95% CI 1.4–4.1); p value<10−3], age over 55 years [RR 3.6 (95% CI 2.1–6); p<10−3], no thrombocytopenia [RR 3.2 (95% CI 1.4–7); p<10−3 ], pancytopenia at diagnosis [RR 3.4 (95% CI 1.5–7.9); p<10−2], progression to aplastic anemia (AA) [RR 2.3 (95% CI 1.3–3.9); p<10−2], thrombosis as a complication [RR 8.9 (95% CI 5.7–14.4); p<10−3]; secondary MDS or acute leukemia [RR 13.7 (95% CI 6.1–30.5); p <10−3]. However, we also found a strong effect of time period. Diagnosis before 1986 among 114 patients with classical PNH (hemolytic anemia and/or thrombosis at diagnosis) was associated with worse outcome [RR 2.8 (95% CI 1.1–7.2); p: 0.025]. Similar results were found for 227 patients with marrow failure (AA-PNH syndrome) diagnosed before 1996 [RR 2.9 (95% CI 1–8.7); p: 0.04]. For the remaining 96 patients (here called Unclassified PNH), the cutoff time period was to be diagnosed before 1986 [RR 3.6 (95% CI 1–12.4); p: 0.046]. Fifteen years Kaplan-Meier survival estimates were 76% (± 6.6) for patients with unclassified PNH, 70% (± 4.6) for AA-PNH patients and 63.4% (± 1.4) for patients with classical PNH. Older age and evolution to thrombosis were found to be associated with bad prognosis in each of the 3 groups. Evolutions to AA or malignant disease (MD) were related to poor prognosis in 2 of the 3 groups (Classical PNH and AA-PNH for AA; AA-PNH and Unclassified PNH for MD). We also found a protective role of the treatment in the AA-PNH group [RR without treatment 3.1 (95% CI 1.5–6.5); p<10−2] while all 20 patients with unclassified PNH treated with immunosuppressive therapy were alive.
Acute Leukemia Over the Age of Fifty: A Study of Its Incidence and Natural History
Authors: GUNZ F. W. , HOUGH R. F. 
Published: October 2019

Abstract
(1) Analysis of the death certificates of 553 patients recorded as having died from leukemia showed that 57 per cent of deaths occurred over the age of 50, that more than 60 per cent of all leukemias were acute, and that 46 per cent of acute leukemias occurred over the age of 50.
(2) Investigation of a selected group of 97 patients over 50 dying from acute leukemia suggested that the clinical, hematologic and histologic features of the disease are distinctive and can be differentiated both from those of acute leukemia in younger patients, and from chronic leukemia.
The Direct Coombs Test in Lead Poisoning
Authors: SUTHERLAND DONALD A. , EISENTRAUT ANNA M. , MINSTER MARIE 
Published: October 2019

Abstract
1. The anemia produced by lead intoxication in humans as well as experimentally induced lead poisoning in dogs results in a positive direct Coombs test.
2. The direct antiglobulin test will become positive within twenty-four hours in cases of severe lead poisoning produced experimentally in dogs.
3. The blood from cases of severe lead poisoning in dogs will form a layer phenomenon when allowed to stand with the formation of a supernatant fraction of cells above the packed erythrocytes. These cells remain suspended in the plasma for many hours. This superior fraction on a column of blood has a high per cent of reticulocytes, and cells with coarse basophilic stippling. The direct Coombs test is positive in the superior fraction of such a column. The positivity decreases as the sampling approaches the bottom. In many instances the whole blood direct Coombs test may be negative and the cells from the superior portion of the column be strongly positive. The latter phenomenon was also found in asymptomatic workers exposed to lead in a smelting plant.
4. The possible significance of the correlation of the direct anti-globulin reaction and cell immaturity or chemical trauma to the membrane is briefly discussed.
The Anemia of Trauma
Authors: TOPLEY ELIZABETH , CLARKE RUSCOE 
Published: October 2019

Abstract
1. The anemia of civilian trauma (mainly limb injuries) has been studied in 57 patients.
2. In 22 patients the red cell volume, after primary blood loss has probably ceased, has been compared with the follow-up "normal" red cell volume. The red cell volume credit or deficit is taken as an index of the balance between primary blood loss and blood transfused, and was found to be the major factor contributing to the later polycythemia or anemia. The evidence suggests that an anemia of trauma due to unreplaced primary blood loss is still a common finding in civilian injuries today.
3. A further red cell volume estimate in 20 patients on the 4-14th day after injury showed on average a further fall of 11 per cent of the red cell volume. Evidence is presented for considering that there is a further disappearance of red cells after primary blood loss has ceased in all patients—even in those whose red cell volume did not fall.
4. The evidence suggests that the anemia of trauma is largely preventable by adequate blood transfusion in the majority of civilian injuries.
Hageman Factor (HF) Deficiency
Authors: RAMOT BRACHA , SINGER KARL , HELLER PAUL , ZIMMERMAN HYMAN J. 
Published: October 2019

Abstract
A patient with Hageman factor (HF) deficiency is described. This syndrome is characterized by complete absence of any hemorrhagic tendency in the presence of laboratory findings which, as a rule, are associated with severe disturbances in the hemostatic mechanism. The clotting time was markedly prolonged, the plasma prothrombin time was normal, but prothrombin consumption was decreased. The thromboplastin generation test revealed that HF is essential for blood thromboplastin formation at least in vitro.
Procedures for the differentiation of HF deficiency from AHF, PTC and PTA deficiency syndromes are outlined.
Transfusions of as little as 50 cc. of 20 day old blood normalized the abnormal clotting tests immediately for a period of about 36 hours.
The basis for the apparent lack of need for preoperative preparation with blood transfusions in HF deficiency is discussed.
Erythrokinetics in Pernicious Anemia
Authors: FINCH CLEMENT A. , COLEMAN DANIEL H. , MOTULSKY ARNO G. , DONOHUE DENNIS M. , REIFF ROBERT H. 
Published: October 2019

Abstract
Quantitative measurements of the erythropoietic activity of the marrow, of circulating red cell production and destruction have been made in patients with pernicious anemia in relapse and during response to vitamin B12 therapy.
Total erythropoietic marrow activity as reflected by turnover of heme components proceeds at a rate of approximately 3 times normal. The delivery of viable red cells to the circulating blood, however, does not increase above normal. This would indicate that the greater portion of marrow activity is ineffective in terms of blood production. This marrow dysfunction coupled with an increased rate of cell destruction of approximately 3 times normal is responsible for the anemia. Total erythropoiesis is somewhat less, and effective erythropoiesis considerably less, than that which may be expected of the normal marrow under the sustained stimulus of anemia.
The reticulocyte count is shown to be an unreliable index of blood production in untreated pernicious anemia due to loss of reticulum from cytoplasma of many red cells before their delivery into circulation.
During the response to vitamin B12 the ineffective erythropoiesis is converted to effective erythropoiesis, whereas total erythropoiesis remains unchanged. The rate of blood production during recovery is 3 to 4 times normal.
A Single-Centre Experience of Clinico-Pathological Features, Risk Factors and Treatment Outcome of Posttransplant Lymphoproliferative Disorders (PTLD) after Renal Transplantation.
Authors: Sondergaard Esben , Strandhave Charlotte , Pedersen Robert S. , Jorgensen Kaj A. , Bendix Knud , d’Amore Francesco 
Published: October 2019

Abstract
Background: PTLD is a lymphoid proliferation that develops as a consequence of immunosuppression and represents monoclonal B-cell, or rarely T-cell proliferations, occurring in a setting of decreased T-cell immune surveillance. PTLD is a major complication after solid organ transplantation. The disease is often unpredictable and devastating of nature resulting in a high rate of morbidity and patient mortality.
Methods: Between 1990 and 2005 872 renal transplantations in 793 patients were performed at Skejby University Hospital in Aarhus and 11 cases of PTLD were identified retrospectively. PTLD Patients were investigated according to transplantation procedure, patient characteristics, type of lymphoma, treatment and outcome.
Results: 11 of 793 renal transplant recipients (1,4%) developed PTLD. Patients (7 male, 4 female) ranged from 19 to 73 years of age at the time of diagnosis (mean age: 42 years). 8 had a cadaveric renal transplant while 3 received a transplant from related donor. Lymphomas were classified as diffuse large B-cell lymphoma in 10 cases and as Burkitt lymphoma in 1 case. No cases were of T-cell origin or Hodgkins lymphomas. Six cases were EBV positive (54%). Out of 11 cases, 5 were diagnosed within 1 year after transplantation, among which 4 were EBV positive, whereas 6 had a latency period of more than 1 year, among which only 2 were EBV positive. The mean latency time between grafting and diagnosis of PTLD among the early lesions was 7 months and among late lesions 6 years and 2 months (ranging from 1 month to 10 years and 8 months). Sites involved in PTLD were renal graft in 2 cases (both early lesions), lungs in 1 case, bowel system in 4 cases, CNS in 1 case, isolated lymph nodes in 1 case, widespread disease in 1 case and uncertain location in 1 case. All patients were treated by tapering of the immunosuppressive regimen. Two were treated with additional surgery and 3 with chemotherapy - all 5 of them are alive and in complete remission. Among those 5 patients 3 have preserved graft function (60%) and 2 returned to dialysis. One patient was treated with anti-CD20 monoclonal antibody, 3 had both conventional chemotherapy and anti-CD20 immunotherapy and 2 did not receive additional treatment. All 6 were dead at the end of the study period. With a median follow-up period of 5 years and 2 months (ranging from 6 months to 11½ years) 5 patients of 11 PTLD cases (45%) were alive with no sign of lymphoma relapse.
Conclusions: PTLD is a severe complication, usually running an aggressive course and the outcome remains poor. The incidence in our population-based regional study material is 1,4%. Overall survival after a median follow-up of 62 months was 45%, with 60% of survivors maintaining graft function.
Long Term Follow-Up and Retreatment of Patients with Low-Grade Lymphoproliferative Disorders (LPD) after 1 Year of Phamacokinetic (PK) Based Maintenance Therapy with Rituximab.
Authors: Duff Jennifer R. , Lynch James W. 
Published: October 2019

Abstract
Background: We previously published data from a PK based maintenance trial in patients with CD 20 positive LPD. The PK based schedule derived from that trial was 1 dose every 3 months and is currently being evaluated in a large randomized trial (ECOG 4402). There has been appropriate concern that offering maintenance therapy may select for tumor cells resistant to rituximab thereby compromising the chance of response if patients are retreated once relapsing after such therapy. We now present long term follow-up on patients with low grade LPD treated on that trial. We furthermore report the results of retreating 5 patients who initially responded but relapsed after one year of maintenance rituximab.
Methods: Patients with CD20 positive LPD (except SLL/CLL) were treated with four weekly infusions of rituximab 375mg/m2. All patients without PD were then monitored for 1 year and received a single infusion of 375mg/m2 when the level fell below <25mcg/ml. Among 22 patients with low grade LPD 10 (45%) achieved a complete response and 5 (23%) a partial response for an overall response rate with 68%. With a minimal follow-up of 69 months, all but 2 patients have sufficient data available to evaluate their subsequent treatment and response.
Results: Of the 22 patients, there were 18 with follicular lymphoma, 2 with lymphoplasmacytoid lymphoma and 1 each with MALT and NOS. The median progression free survival (PFS) for the entire group was 23 months, but for responders the PFS was 50 months. 6/22 (27%) remain in continuous complete remission with no further therapy with a median follow-up of 72.5 mo. (range 69–76). Nine patients who initially responded have subsequently relapsed and were treated at the discretion of the treating physician as follows: 2 received no treatment one of whom experienced a spontaneous CR lasting 59 months, one patient with an isolated CNS relapse received intrathecal and local radiotherapy and is currently in CR with no further therapy at 71mo, 1 patient died in PR of a presumed MI and 5 received retreatment with rituximab accompanied by 2 years of maintenance therapy given as 1 dose every 3 months. Of the 5 patients who were retreated with rituximab the outcomes are listed in table I.
Conclusions: Individualized PK dosing for rituximab for 1 year yielded 27% prolonged DFS in patients with LG LPD. Although the numbers of patients treated are very small, 80% of those who responded to rituximab and subsequently relapsed retained sensitivity to rituximab and have had durable benefits, comparable to their first course. Future trials which evaluate the efficacy of limited duration maintenance strategies should continue follow-up of patients after progression to determine whether subsequent treatment with rituximab offers clinical benefit.
Table I Patient # 1st PFS 2nd Response 2nd PFS 1 18mo CR 44mo+ 2 23mo NR NA 3 27mo CR 33mo 4 29mo CR 33mo+ 5 50mo PR 29mo+