bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Stanford V Regimen Is an Effective Treatment for Good Prognosis Patients with Hodgkin’s Disease.
Authors: Abuzetun Jamil Y. , Loberiza Fausto , Bast Martin , Vose Julie M. , Bierman Philip J. , Bociek R. Gregory , Armitage James O. 
Published: October 2019

Abstract
Despite recent therapeutic advances, the treatment of Hodgkin’s disease remains controversial. Among the most commonly used regimens are ABVD, Stanford V and BEACOPP. Studies of Stanford V have shown conflicting outcomes with some excellent and some much less good results. To address this discrepancy we reviewed 113 patients with previously untreated Hodgkin’s disease, all of whom were HIV negative, who received the Stanford V regimen from physicians in the Nebraska Lymphoma Study Group between January 1997 and January 2006. The median age was 36 years (range 15–88) with only 10 patients over 60 years of age. Fifty-two (46%) of the total were males. Seventy-eight (68%) had nodular sclerosis, subtype and 69 (61%) were stage I and II. Constitutional symptoms were present in 36 (32%) patients. Tumor bulk > 5cm was evident in 68 (60%). Four or more nodes were involved in 57 (50%) and 84 (78%) received radiotherapy. Median follow up was 63 months (range 8–114). Univariate analysis of the data identified 4 adverse risk factors which included age > 60 years, stages III or IV, constitutional symptoms, and mixed cellularity subtype. Complete remission or unconfirmed complete remission was achieved in 82(72%), 21 (18%) had partial response, 2 had progression of disease (PD) and 3 were unable to be evaluated. There were 5 early deaths; 3 of which were definitely related to the treatment. For the entire group, the 5 year overall survival (OS) was 84% and the 5-year event free survival (EFS) was 74%. However, the results were dependent on the presence or absence of the adverse risk factors of age >60, stage III or IV, non-nodular sclerosis histological subtype, and B symptoms as shown below:
Risk Factors 0 (N=53) 1–2(N=50) 3–4(N=10) OS 100% 90% 40% EFS 87% 82% 20%
The Stanford V regimen represented an excellent treatment for patients with stage IA and IIA nodular sclerosis Hodgkin’s disease under the age of 60 and patients with 1–2 adverse risk factors did only slightly less well. The regimen yielded a much poorer outcome in patients with multiple adverse risk factors.
Relationship between the Hematopoietic Phenotype and the Subtype of Fanconi Anemia Mice.
Authors: Navarro Susana , Rio Paula , Meza Nestor W. , Chinchon Raquel , Segovia Jose C. , Bueren Juan A. 
Published: October 2019

Abstract
Fanconi anemia (FA) is a rare inherited disease associated with aplastic anemia and cancer predisposition. Great progress has occurred at a molecular level that allowed the identification of 13 genes involved in the disease. Additionally, several FA mouse models have been developed with the purpose of investigating the biological basis of the disease, and of facilitating the development of new therapies for FA. Because of the genetic heterogeneity of FA, here we have investigated the relevance of different FA genes to preserve the function of the hematopoietic stem cells (HSCs) of the mouse. To this aim, we have comparatively investigated the hematopoietic phenotype of different FA mice: Fanca−/−, Fancc−/−, Fancd1/Brca2Δ27/Δ27and Fancd2−/−. Normal counts of peripheral blood (PB) cells were observed in the different FA mice. Flow cytometry analyses were also incapable of demonstrating significant changes in the hematopoietic subpopulations present in PB, bone marrow (BM) or spleen of the different FA mice. In contrast to these observations, a reduction in the content of the hematopoietic progenitors was observed both in the BM and the spleen of Fancd1/Brca2Δ27/Δ27 and Fancd2−/− mice, either in young or adult. Significantly, a similar reduction in hematopoietic progenitors was only observed in old Fanca−/− and Fancc−/− mice. Moreover, hematopoietic colonies from mice defective in FA proteins downstream the FA core complex were smaller, compared to colonies from wild type, Fanca−/− or Fancc−/− mice. As expected, hematopoietic progenitors from all studied FA mouse models were highly sensitive to the DNA cross-linking agent, mitomycin C (MMC). Concerning the function of the HSCs of these FA mice, reduced competitive repopulation ability was always observed, compared to WT HSCs. However, in animals defective in FA proteins downstream the FA core, CRA values progressively dropped along the transplantation period. Additionally, a spontaneous chromosomal instability was observed in bone marrow cells from Fancd1/Brca2Δ27/Δ27. These animals also showed a marked repopulation defect in their HSCs assessed in their natural physiological environment, when wild type cells were transplanted in unconditioned Brca2Δ27/Δ27 recipients. In summary, our results show a more severe defect in the functionality of the HSC compartment in mice with mutant FA proteins downstream the FA core complex.
Updated Survival Analyses after Prolonged Follow-Up of the Phase 2, Multicenter CREST Study of Bortezomib in Relapsed or Refractory Multiple Myeloma.
Authors: Jagannath Sundar , Barlogie Bart , Berenson James R. , Siegel David , Irwin D. , Richardson Paul , Niesvizky Ruben , Alexanian Raymond , Limentani Steven , Alsina Melissa , Esseltine Dixie-Lee , Anderson Kenneth C. 
Published: October 2019

Abstract
Background: The initial report of the CREST phase 2 study (Br J Haematol2004;127:165–72) demonstrated the substantial activity of bortezomib (VELCADE®, Vc) at two different dose levels in patients with relapsed or refractory multiple myeloma (MM). Here, we provide an updated analysis of overall survival (OS) after prolonged follow-up (median >5 years).
Methods: 54 patients were enrolled to receive Vc 1.0 mg/m2 (n=28) or 1.3 mg/m2 (n=26) on days 1, 4, 8, and 11 of a 21-day cycle, for up to 8 cycles. Dexamethasone (dex) 20 mg on the day of and day after each Vc dose was added for 16 (57%) patients in the 1.0 mg/m2 group and 12 (46%) patients in the 1.3 mg/m2 group, upon suboptimal response to Vc alone. A total of 17 (31%) patients continued to receive Vc ± dex in an extension study, 12 (43%) from the 1.0 mg/m2 and 5 (19%) from the 1.3 mg/m2 groups. Patients received a median of 3 (range, 1–7) prior regimens. Median time from diagnosis to first Vc dose was 2 years. In the 1.0 and 1.3 mg/m2 groups, respectively, mean age was 64 vs 60 years, 50% vs 35% of patients were male, 54% vs 65% had IgG MM, 58% vs 48% had β2-microglobulin ≥4 mg/L, and 29% vs 48% had abnormal cytogenetics. Response rate (CR+PR, EBMT criteria) to Vc alone was 30% vs 38%, and to Vc ± dex was 37% vs 50% in the 1.0 and 1.3 mg/m2 groups. OS from first dose of Vc in each dose group was analyzed using the Kaplan-Meier method.
Results: Median OS in the 1.0 and 1.3 mg/m2 groups was 26.8 months and 60.0 months, after median follow-up of 61 and 65 months, respectively (Figure). In the 1.0 mg/m2 group, 21 (75%) patients have died; the 1- and 2-year OS rates were 82% and 54%, respectively. In the 1.3 mg/m2 group, only 14/26 (54%) patients have died; 1- and 2-year OS rates were 81% and 69%, respectively.
Conclusions: Vc ± dex was active in relapsed or refractory MM at both the 1.0 mg/m2 and 1.3 mg/m2 dose levels and was associated with notable OS, particularly in patients treated with the approved Vc dose of 1.3 mg/m2. The difference in OS between dose groups suggests that the higher dose of Vc is more active. Figure. Kaplan-Meier analyses of OS in patients who received Vc 1.0 mg/m2 (n=28) or 1.3 mg/m2 (n=26).
Figure Figure
T-Cells Redirected Against CD70 for the Immunotherapy of Hematological Malignancies.
Authors: Shaffer Donald , Savoldo Barbara , Dotti Gianpietro , Spencer David , Kenney Shannon , Rooney Cliona M. , Gottschalk Stephen 
Published: October 2019

Abstract
BACKGROUND: CD70 is a tumor necrosis family member that is expressed on a broad spectrum of hematological malignancies including multiple myeloma, non-Hodgkin’s lymphomas and Hodgkin’s disease. In contrast to other already established immunotherapy targets such as CD19, CD20, or CD52, which are widely expressed in the hematopoietic system, CD70 expression is restricted to a subset of activated B and T cells, reducing potential ‘collateral damage’ when targeted by immunotherapy. Preclinical studies in animal models using monoclonal antibodies have validated CD70 as an immunotherapeutic target for malignancies and the aim of this study was to generate CD70-specific T cells for adoptive immunotherapy approaches.
METHODS and RESULTS: To create CD70-specific T cells we constructed a CD70-specific chimeric antigen receptor (CD70-CAR) consisting of domains derived from the CD70 receptor (CD27) and the T-cell receptor CD3-ζ chain. CD70-specific T cells were generated by transducing CD3/CD28-activated T cells with a SFG retroviral vector encoding the CD70-CAR. Cell surface expression of CD70-CARs was confirmed by FACS analysis on CD4- as well as CD8-positive T cells. CD70-specific T cells from healthy donors proliferated and produced IFN-γ as well as IL-2 in contrast to mock transduced T cells after coculture with CD70-positive myeloma cells (U266 and ARH-77) and lymphoblastoid cell lines. In cytotoxicity assays, CD70-specific T cells killed CD70-positive myeloma cell lines and lymphoblastoid cell lines where as activated lymphocytes that express CD70 at low levels and CD70-negatvie targets were not killed.
CONCLUSION: We have successfully constructed a CD70-CAR and demonstrate that CD70-specific T cells selectively recognize and kill malignant cells that express CD70 at high levels. Murine xenograft studies are in progress to confirm these findings in vivo. Adoptive immunotherapy with CD70-specific T cells may represent a promising immunotherapeutic approach for CD70-positive hematological malignancies.
CD4+ CD25high Regulatory T Cells in Newly Diagnosed Patients with Acute Myeloid Leukemia.
Authors: Szczepanski Miroslaw J. , Strauss Laura , Czystowska Malgorzata , Szajnik Marta , Welsh Ann , Foon Kenneth A. , Whiteside Theresa L. , Boyiadzis Michael 
Published: October 2019

Abstract
Regulatory CD4+CD25+ T cells (T reg) are critical regulators of immune tolerance. Increasing evidence supports the existence of elevated numbers of regulatory T cells in cancer patients. Although the increase of T cells seems to be a characteristic feature in most tumors the functional role of Treg, especially in patients with hematologic malignancies, has been less well defined. Mutlicolor flow cytomerty was used to investigated the frequency and phenotype of CD4+ CD25high T cells in the peripheral blood of thirty seven newly diagnosed acute myeloid leukemia (AML) patients (prior to any treatment) and thirty one healthy donors. The suppressive function of Treg was evaluated using CFSE-labeled fresh autologous CD4+CD25− T cells activated with an anti-CD3 antibody as responders. The percentage of circulating CD4+ CD25high Treg was higher (p < 0.0001) in the AML patients (2.9 ± 0.3%, range 0.1–7%) compared to healthy donors (0.4 ± 0.02%, range 0.1–1%). Percentages of T reg expressing Foxp3, CTLA-4, CD45 RO, Fas ligand (CD95) and GITR were significantly elevated in the circulation of AML patients compared to healthy donors: Foxp3 60vs32% p<0.001, CTLA-4 47vs21% p<0.01, CD45 RO 81vs53% p<0.002, Fas ligand 23vs4% p<0.001, GITR 65vs25% p<0.001. Suppression mediated by T reg co-incubated with proliferating autologous responders was also significantly higher (p<0.001) in AML than that mediated by control T reg (75 ± 6% vs 12% ± 4%). These results indicate that T reg accumulate in the periphery of patients with AML and mediate vigorous suppression. Modulation of the Treg suppressive activity, especially during the post-induction period, in AML patients may have therapeutic implications.
The Clinical Observation on Arsenic Trioxide with ATRA in Treating Acute Promyelocytic Leukemia for Six Years.
Authors: Zhong Zhou , Liu Zhen-cai , Li Jian-wei 
Published: October 2019

Abstract
Objective: To observe the efficacy of arsenic trioxide(AS2O3) with ATRT for the treatment of patients with acute promyelocytic leukemia(APL).
Methods: Seventy-four patients with APL, from 2000 to 2006, were randomly divided into two groups. Thirty-eight patients as treating group received AS2O3+ATRA, another thirty-six patients as control group were treated only AS2O3+ARTA+chemotherapy(DA or HA).
Results: The first induced complete remission (CR) was 100%, the three-year relapse rate was 2.6%, the six-year continuous complete remission(CCR) rate was 94.6% for treating group. The rate of CR, the three-year relapse and CCR were 81.3%, 30.7% and 61.5% respectively for control group. The side effects such as myelosuppression, severe infection or septicemia, hepatic, renal and myocardial damage, and the digestive tract side effect were mild compared with that in control group(p<0.01). In treating group, the hyperleukocytosis was not observed, Incidence of the three-year treatment-related mortality (TRM) was 0%, the control group was 16.7%.
Conclusion: The combination of AS2O3 and ATRA can obtain a higher CCR, low relapse rate and mild treatment side effects.
Clinical Trials Underestimate Age of Chronic Myeloid Leukemia (CML) Patients: Epidemiological Study in a Representative Area in Germany.
Authors: Rohrbacher M. , Berger U. , Hochhaus A. , Metzgeroth G. , Adam K. , Lahaye T. , Saussele S. , Hasford J. , Heimpel H. , Hehlmann Rüdiger 
Published: October 2019

Abstract
Epidemiological information on chronic myeloproliferative disorders (CMPD), notably Philadelphia (Ph) and/or bcr/abl positive chronic myeloid leukemia (CML), is rare. National cancer registries and clinical trials differ with regard to median age of CML patients by 10 to 20 years (Table). Therefore, an evaluation was conducted in a defined area in Germany between 1998 and 2000 to determine incidences and compare clinical characteristics of Ph and/or bcr/abl positive CML patients participating and not participating in trials. 68 (37.4%) hospitals and 241 specialty practices (16.4%) reported 893 newly diagnosed CMPD patients. CML patients represented 24.9% of all cases with CMPD. The crude incidence of CML cases (n=218) was 0.79, that of the 172 Ph and/or bcr/abl positive CML cases 0.62 and that of CMML (n=61) 0.22. The incidence of CML and CMML cases combined was 1.01. 110 (64.0%) of the 172 Ph and/or bcr/abl positive CML patients participated in clinical studies, mainly CML Studies III and IIIA of the German CML Study Group. Median age was significantly different between patients participating and not participating in clinical trials: (54.1 vs. 64.8 years, p=0.0001). The chance for a Ph and/or bcr/abl positive CML patient < 65 years to be enrolled in a clinical study was 3.8 times higher than for a CML patient ≥ 65 years (OR=3.8, CI: 1.9–7.3). Male patients had a slightly higher probability to be enrolled in a study than females (OR=1.5 (CI: 0.8–2.8)). Our data indicate that 36% of the Ph and/or bcr/abl positive CML patients registered in a defined area of Germany are not treated in clinical trials, that elderly patients have a lower probability to be included in trials than younger patients and that patients participating in trials are 10.7 years younger than those who do not.
Age of CML Patients in Population based Registries and in Clinical Trials A) Registries Age mean (years ± S.D.) / Thames Cancer Registry, U.K. 65 (20–98) SEER Cancer Statistics Review, 1975–2004 68 (range not available) SEER cancer statistics review, 1973–1998 64 (range not available) B) Trials The Italian Cooperative Study Group on Chronic Myeloid Leukemia. N Engl J Med 1994 48 ± 14 Hehlmann et al., Blood 1994 48 (17–85) Guilhot et al., N Engl J Med 1997 50 (7–70) Hasford et al., JNCI 1998 49 (10–85) The Benelux CML Study Group. Blood 1998 56 (20–83) Baccarani et al., Blood 2002 45 ± 13 Hehlmann et al., Leukemia 2003 48 (10–83) O’Brien et al., N Engl J Med 2003 50 (18–70) Hehlmann et al., Blood 2007 49 (11–90)
Genes and Proteins Associated with the Tumor Microenvironment Are Differentially Expressed in Cured Versus Primary Chemotherapy-Refractory Diffuse Large B-Cell Lymphoma.
Authors: Linderoth Johan , Edén Patrik , Ehinger Mats , Valcich Jeanette , Jerkeman Mats , Bendahl Pär-Ola , Berglund Mattias , Enblad Gunilla , Erlanson Martin , Roos Göran , Cavallin-Ståhl Eva 
Published: October 2019

Abstract
Background: The aim of this study was to identify possible differences in gene expression profiles (GEP) between two clinically very different patient populations, cured versus primary chemotherapy-refractory diffuse large B-cell lymphoma (DLBCL).
Material and methods: Tumor samples from 37 patients with de novo DLBCL, stage II-IV, either in continuous primary complete remission (n=24) or with progressive disease during primary treatment (n=13) were selected from a larger study cohort and examined with respect to GEP using spotted 55K oligonucleotide arrays. Formalin fixed paraffin-embedded tissue for immunohistochemical analysis was available in 33 of 37 cases, and was used for confirmation on protein level.
Results: The top 86 genes with the greatest statistical ability of discriminating the two patient groups were chosen for further analysis. Seventy-nine were over-expressed in the cured cohort, many of them coding for proteins expressed in the tumor microenvironment: CD68, several proteolytic enzymes and proteins involved in remodelling of extra cellular matrix and inflammation. Furthermore, MHC class I molecules, CD3δ, NK transcript 4, and ICAM-1 were overexpressed indicating an enhanced immunological reaction. Immunohistochemistry showed that the frequency of cells expressing CD68, defining the macrophage population, was higher in the cured cohort and that expression of lysozyme, cathepsin D, UPAR, and ICAM-1, was mainly seen within the reactive cells. Tumor infiltrating CD8+ T-cells were more frequent within the cured cohort, corresponding to the increased MHC class I expression seen within this group.
Conclusions: In DLBCL, genes coding for antigens present in the tumor microenvironment are differentially expressed in patients with cured vs. chemotherapy-refractory disease. Our findings suggest that a reactive microenvironment, including tumor infiltrating T-cells and macrophages, may have impact on outcome of chemotherapy in DLBCL.
Molecular Analysis of WASP Gene - First Report from India.
Authors: Jacob Rintu Rebecca , Rajasekar Reena , Edison Eunice S. , George Biju , Mathews Vikram , Srivastava Alok , Chandy Mammen 
Published: October 2019

Abstract
Wiskott Aldrich Syndrome (WAS) is an X-linked recessive disorder associated with severe thrombocytopenia, eczema, bloody diarrhea, profound immunodeficiency and an increased risk of malignancies. More than 200 mutations have been described in the gene encoding the WAS protein (WASP). We report here the molecular basis of WAS in six patients from India. Diagnosis of WAS/X- linked thrombocytopenia (XLT) was based on low platelet count (9000– 1, 25,000/mm3), presence of small platelets (mean: 6.2fl) and detection of WASP by flowcytometry. Patients evaluated in the study could be classified as classical WAS (n=3) and XLT (n=3) depending on the clinical severity of their disease (Zhu et.al 1995). All 12 exons and flanking splice-sites of WAS gene were amplified by polymerase chain reaction (PCR) using primers and PCR conditions adopted with modifications from Kwan et al (PNAS1995;92:4706). Mutation analysis was accomplished by conformation sensitive gel electrophoresis (CSGE) and direct sequencing. Abnormal banding pattern was observed only in 4 patients after CSGE analysis. c.995 C>T could not be detected by CSGE but was detected by direct sequencing. The types of molecular defects identified in five patients were as follows: nonsense - 2, deletion - 1 and duplication - 1. Three of these alterations (see table) have been reported previously and are associated with classical WAS. In patients detected to have nonsense mutations, flowcytometric analysis of WASP exhibited high values (table) not consistent with reported western blotting data in these mutations. c.307+10-11dupC was observed in two patients (brothers) with thrombocytopenia, small platelets and mild bleeding. This duplication is not a reported polymorphism. Though this duplication changes the acceptor splice site prediction score from 0.83 to 0.91, its functional significance has not been determined and requires further evaluation. The sixth patient in our study had thrombocytopenia (15,000–45,000/mm3), small platelets (4.8–7.2 fl), mild bleeding, similar family history and normal expression of WASP (86.2%). No mutation has been identified in the coding region of WAS gene in this patient either by CSGE or direct sequencing. Our data shows that the molecular basis for WAS is heterogenous in India. This is the first study evaluating mutations in WAS gene from India. Further mutation screening of patients with WAS will allow the genetic definition, phenotype-genotype corelation, carrier detection and prenatal diagnosis of this condition.
Molecular defects observed in WAS patients Patient ID Flow cytometry (%) Mutation *-Reported mutation, ♦-Functional Significance not known PD-22 WASP D1-98.5, WASPB9 - 94.8 c.665C>T, p.Arg211X* PD-16 WASP B9- 6.7 c. 1035-1036 delG, p.Gly314ValfsX120* PD-21 WASP D1-97.2, WASP B9-91.2 c.995 C>T, p. Arg321X* PD-34, PD-35 (siblings) WASP D1-3.6, WASP B9-2; D1-1.8, B9-1 c.307+10-11 dupC♦ PD-28 WASP D1 - 86.2 Mutation not detected