bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pilot Study of the Feasibility of Assessing DNA Damage and Apoptosis Induced by Chemotherapy in Children with Acute Leukemias.
Authors: Halicka Dorota , Ozkaynak Fevzi M. , Huang Xuan , Traganos Frank , Darzynkiewicz Zbigniew 
Published: October 2019

Abstract
The aim of the present study was to explore whether early assessment of the extent of DNA damage in leukemic blasts and incidence of apoptosis induced during chemotherapy is feasible. The long term goal is to develop a rapid assay to assess the effectiveness of chemotherapy early in the course of treatment of leukemia. Mononuclear cells were isolated from blood samples of 7 ALL patients with peripheral blasts, 4 of whom were, at diagnosis, high-risk ALL while the remaining 3 were in relapse. The median age of the patients was 17 yrs (2–25 yrs) and all were entered into an anthracycline-containing drug regimen. Samples were collected:
prior to drug administration; and, one hour after completion of the drug infusion.
The extent of DNA damage was assessed by analysis of histone H2AX phosphorylation (γH2AX) occurring at sites of DNA double-strand breaks (DSBs), which could be detected immunocytochemically and measured by multiparameter flow cytometry in conjunction with DNA content. The incidence of apoptosis was estimated 1 h after drug administration and also after 24 h ex vivo culturing, by identification of cells with DNA fragmentation detected by the TUNEL assay. In patients with complete clinical response (6 of 7) at the end of the induction phase, an increase of γH2AX (post treatment - pretreatment mean) was detected 1 h after the administration of drug treatment. The apoptotic index in this group after 24 h ex vivo culture was 1–16%. In the only patient not responding to treatment - one of 2 relapsed ALL patients -, there was no induction of DSBs or increase in apoptosis.
Response to induction therapy γH2AX mean fluorescence in arbitrary units Apoptotic index ex vivo (%) post 24 h Complete response 8 16 Complete response 8 5 Complete response 5 1 Complete response 29 7 No response 0 0 Complete response 4 2 Complete response 4 Not estimated
Although the number of patients is very small in this pilot study, the results suggest that a cytometric assay that reveals the extent of DNA damage based on detection of H2AX phosphorylation may provide an early prognostic marker.
Attenuated Dose of Idarubicin for the Elderly De Novo Acute Myeloid Leukemia with Normal Karyotype.
Authors: Cheong June-Won , Kim Yuri , Park Sun Young , Park In Hae , Kim Jin Seok , Min Yoo-Hong 
Published: October 2019

Abstract
The incidence of acute myeloid leukemia (AML) increases with age. Because of poor performance status, co-morbidity and treatment-related side effects, a conventional dose chemotherapy containing anthracyclins may be toxic to the majority of elderly patients. In contrast, the administration of suboptimal dose of myelosuppressive chemotherapy could lead to an unsuccessful clinical outcome including lower complete remission (CR) rate. To evaluate the effect of attenuated dose of idarubicin, compared to the standard dose, on the clinical outcome and chemotherapy-related complications, we analyze the consecutive 32 elderly de novo AML patients (range, 60 – 74 years) with normal karyotype. Eleven patients received one cycle of conventional-dose remission induction chemotherapy (idarubicin, 12 mg/m2/day on days 1–3 and cytarabine 100mg/m2/day on days 1–7) (Group 1) and 21 patients received attenuated-dose idarubicn (8 mg/m2/day on days 1–3) and cytarabine (100mg/m2/day on days 1–7) (Group 2). Six cases (54.5%) in Group 1 and 12 cases (57.1%) in Group 2 had CR. The difference of CR between the two groups was not significant (P = 0.59). The intervals from the chemotherapy-starting date to the date of CR documentation were not also different between two groups (median 31.5 days on Group 1 vs 27.0 days on Group 2) (P = 0.29). The median number of transfusion requirement during the induction therapy was not different in the red blood cells (10 units, each) and platelets (16.5 units in Group 1 vs 18.0 units in Group 2; P > 0.05). Thirty patients received the recombinant human granulocyte colony-stimulating factor (G-CSF) three days after termination of chemotherapy. The duration of G-CSF administration was not different between two groups (P = 0.86). However, the frequency of septicemia and septic shock after induction chemotherapy was statistically significantly higher in Group 1 (54.5% and 9.5%, respectively) compared to that in Group 2 (36.3% and 0.5%, respectively) (P < 0.01). We also observed a higher incidence of clinically-documented invasive fungal infection in Group 1 (45.5%) compared to Group 2 (15.0%), although the difference was not statistically significant (P = 0.095). The incidence of other regimen-related toxicities including renal dysfunction, hepatic dysfunction and heart failure was not different between two groups. Overall survival and disease-free survival also were not different between the groups. In conclusion, the attenuated dose of idarubicin can be recommended for the remission induction chemotherapy for the elderly de novo AML patients with normal karyotype since it is associated with lower incidence of sepsis and septic shock with comparable CR rate.
Extended Study for Topotecan, Idarubicin, and Intermediate-Dose Cytarabine Combination Chemotherapy in Patients with Refractory or Relapsed Acute Myelogenous Leukemia and High-Risk Myelodysplastic Syndrome.
Authors: Kim Yuri , Cheong June-Won , Kim Jin Seok , Park In Hae , Park Sun Young , Lee Seung Tae , Min Yoo-Hong 
Published: October 2019

Abstract
The development of more effective therapy for patients with refractory or relapsed acute myelogenous leukemia (AML) and high-risk myelodysplastic syndrome (MDS) is a major concern in hematology. We previously reported a preliminary data that combination chemotherapy with topotecan, idarubicin, and intermediate dose cytarabine had a significant anti-leukemia activity and acceptable range of toxicity for the high-risk AML/MDS patients. In this study, we demonstrate an extended data for investigating larger number of patients with long-term follow-up of five years. The forty-seven patients were enrolled: 10 with primary refractory AML, 16 with AML in first relapse, 9 with AML in second relapse, and 12 with MDS-RAEB/RAEBT. Patients received as salvage therapy a single course of idarubicin 12 mg/m(2) IV bolus on days 1–3, cytarabine 1 g/m(2) over two hours q 12 hr on days 1–5, and topotecan 1.25 mg/m(2) over 24 hr on days 1–5. Median age of patients was 47 years (range 17–69 years). Patients with AML were categorized to high-risk (n=21), intermediate-risk (n=11), and low-risk (n=3) cyrogenetic group. All patients were evaluable for response: 23 (48.9%) achieved complete remission, 18 with AML (51.4%) and 5 with MDS (41.7%), respectively. The median remission duration and survival of patients with AML were 7 and 13 months, respectively. Median remission duration and survival of MDS patients was 10 and 15 months, respectively. Severe myelosuppression was observed in all patients, resulting in the fever or documented infections in 85.1% of patients. Median time to recovery of neutrophils > or =0.5 x 10(9)/l was 23 days (11–37 days) and for platelets > 20 x 10(9)/l 37 days (11–63 days). Reversible grade 3–4 toxicities included diarrhea (3 patients) and mucositis (13 patients). The relapsed AML patients (n=16) were grouped into four categories to stratify the probability of achieving complete remission (CR): group 1, first CR duration > or = 2 years and receiving first salvage treatment (S1); group 2, first CR duration 1–2 years and receiving S1; group 3, first CR duration 0–1 years and receiving S1; and group 4, first CR duration 0–1 years and receiving S2, S3, or S4 after failing S1. The response rate of group 4 (33.3%) was significantly lower than that of other groups (P < 0.05). We conclude that combination chemotherapy with topotecan, idarubicin, and intermediate dose cytarabine is an effective salvage chemotherapy for high risk AML/MDS patients, and the first CR duration is a significant predictor for response.
Does High Dose Cytosine Arabinoside Improves Disease Free Survival for Down Syndrome Acute Myelocytic Leukemia Patients?.
Authors: Saleh Mahasen , Khairy Ashraf , Al-Mahr Mohammed , El-Solh Hassan , Al-Musa AbdulRahman , El-Hassan Ibrahim , Belgaumi Asim F. 
Published: October 2019

Abstract
Acute myelocytic leukemia (AML) in Down Syndrome (DS) children is characterized by a young age of onset (< 2 years), a low white blood cell count and high frequency of Megakaryocytic leukemia. DS children with AML have higher disease free survival (DFS) rates as compared to non DS AML patients. Previous studies have suggested that intensification chemotherapy may not be necessary for the treatment of DS children with AML. The objective of this study was to clarify the effectiveness and toxicities of using high dose Cytosine Arabinoside (HD AraC) intensification in the treatment of DS AML. Clinical data for children (<14 years) with DS AML, diagnosed between September 2000 to May 2005, were retrieved from the hospital data base. Patients were divided into two groups; Group A patients received chemotherapy containing HD AraC, while Group B patients did not. A total of 15 patients were included, eight in Group A and seven in group B. The median age at diagnosis was 22 months (A=23 months, B=22 months). The two groups were matched regarding their clinical and laboratory parameters. There was no significant difference in DFS between groups A and B, 75% and 85% respectively (P = 0.82) at a mean observation period of 42.9 months for group A and 23.12 months for group B. The median time to relapse was 6 months for group A and 8 months for group B. The overall treatment related toxicity was higher in Group A patients but achieved only borderline significance (P = 0.06). However, when toxicity was assessed separately for induction and post induction phases of chemotherapy there were significantly more infectious events (17 v. 2; p=0.0006) in the post induction phase which includes HD AraC intensification in Group A. Even when only serious infections (bacteremia, fungal infection, sepsis) were included in the evaluation this difference persisted (7 v. 1; p=0.0339), with less toxicity for Group B patients. No such difference was noted between the two groups during induction chemotherapy. In conclusion the use of HD AraC in post-induction intensification phases for DS AML children does not improve DFS and is associated with more treatment related toxicity.
Retroviral Vector Integration Deregulates Gene Expression but Has No Consequences on the Biology and Function of Transplanted T Cells.
Authors: Recchia Alessandra , Bonini Chiara , Magnani Zulma , Urbinati Fabrizia , Sartori Daniela , Muraro Sara , Ciceri Fabio , Bordignon Claudio , Mavilio Fulvio 
Published: October 2019

Abstract
Retroviral vectors have raised safety concerns for the genotoxic risk associated with their uncontrolled insertion into the human genome. The occurrence of T-cell leukemia in patients treated by gene therapy for X-SCID has been correlated with insertional activation of a T-cell proto-oncogene. However, no such event has been reported in other pre-clinical or clinical trials, suggesting the existence of disease- and/or transgene-specific risk factors in the X-SCID case. We have analyzed the integration pattern of a retroviral vector expressing a suicide gene (HSV-TK) and a surface marker (ΔLNGFR) in T-lymphocytes from patients treated with donor lymphocyte infusion (DLI) after hematopoietic stem cell transplantation for therapy of acute and chronic leukemia. The suicide gene allows to control graft-versus-host disease, a major complication of DLI, while preserving anti-tumor and antiviral activities. Proviral integrations were analyzed by sequencing the vector-genome junctions in T-cell DNA obtained from 4 different patients up to 9 years after treatment. Over 85% of proviral integrations occurred within transcription units, with a preference for first introns and upstream promoter regions. Over 75% of intragenic integrations were in genes active in T cells at the time of transduction, and ~4% occurred at recurrent genomic locations (hot spots). Microfluidic real-time PCR in RNA extracted from individual T-cell clones harboring proviral integrations in proximity of transcription start sites showed that one fifth of these integrations affect the expression of nearby genes. However, transduced T-cell populations maintain remarkably stable gene expression profiles, phenotype, biological functions and immune repertoire in vivo, with no evidence of clonal selection up to nine years after administration. Analysis of transduced cells before and after transplantation indicates that integrations interfering with normal T-cell function are more likely to lead to clonal ablation than expansion. Despite the potentially dangerous interactions with the T-cell genome, retroviral integration has therefore little consequences on the safety and efficacy of T-cell transplantation.
Granulocytic Sarcoma in Erythroleukemia (M6).
Authors: Abbasi Elham , Mims Martha P. , Udden Mark M. 
Published: October 2019

Abstract
Granulocytic Sarcomas are extramedullary tumors composed of immature myeloid cells, these tumors can be seen in myeloid malignancies such as chronic myelogenous leukemia, myelodysplastic syndrome and acute myelogenous leukemia. They can be seen at the time of diagnosis of the myeloid malignancy, prior to diagnosis, or after treatment as a first sign of relapse. We report here the case of a young woman who presented with a 6 month history of a slowly enlarging nasal mass. Biopsies of the lesion had been inconclusive until a CBC revealed abnormal blasts in the peripheral blood. Subsequently bone marrow biopsy revealed more than 59% erythroid precursors with a preponderance of immature erythroblasts and 33% myeloblast consistent with AML (M6). Reanalysis of the nasal biopsy demonstrated positive staining for CD68, Myeloperoxidase, Lysozyme, and CD117, but negative for CD34, suggestive of granulocytic sarcoma. The patient received induction chemotherapy with idarubicin and cytarabine and achieved bone marrow remission along with complete resolution of the nasal mass. To our knowledge this is the first report of a granulocytic sarcoma in association with AML M6.
Phase I/II Study of Clofarabine Combined with Standard Dose Cytarabine as Remission Induction Therapy of De Novo AML in Elderly Patients ≥60 Years.
Authors: Foran James M. , The Angeline S. , Devetten Marcel , Meleth Sreelatha , Worrell Jeff , Dixon Pam , Sekeres Mikkael A. 
Published: October 2019

Abstract
Despite significant advances in the treatment of acute myeloid leukemia (AML) in younger adults, there has been little progress in the treatment of older patients (age≥60 years), who comprise the majority of those with the disease. Clofarabine is a purine nucleoside analog with single agent activity in patients with relapsed AML. In addition, clofarabine potentiates Ara-C cytotoxicity in vitro through increased intracellular Ara-CTP accumulation, making this an attractive combination.
A phase I/II study has therefore been initiated combining clofarabine with standard dose cytarabine (100mg/m2/day x 7) in pts age ≥60 years with de novo AML. The starting dose of clofarabine was 30mg/m2/day x 5 beginning on day 2 (Dose level I). Patients were accrued in cohorts of 3–6 to establish dose limiting toxicity (DLT); cohort expansion at the maximum tolerated dose (MTD) is planned in phase II using a Simon 2-stage design. Detailed plasma and intracellular pharmacokinetics were performed during induction therapy with Ara-C alone (day 1), and following the addition of clofarabine (day 2) to determine the effect of clofarabine on intracellular Ara-CTP accumulation. Pts with residual AML on d14–21 restaging bone marrow (BM) biopsy were eligible to receive Re-Induction with 5 days of clofarabine & Ara-C. Those achieving complete remission were also eligible to receive 1–2 cycles of consolidation with Ara-C (d1–5) & clofarabine (total 3 cycles of planned therapy).
Dose limiting toxicity was encountered at dose level I (see Table 1). 2/4 pts achieved CR, in 1 case with residual cytogenetic abnormality, and there were 2 treatment-related deaths from infxn (culture neg sepsis, n=1; Candida tropicalis, n=1). In the latter case (pt 4), BM aplasia was achieved, but the pt died on d25 prior to hematologic recovery. In view of the DLT, the protocol has therefore been amended to allow 25% dose de-escalation of clofarabine to Dose Level -I (22.5mg/m2/day x 5), and to limit eligibilty to pts age 60–75 yrs inclusive. Routine use of aggressive pre-hydration and antibiotic and antifungal prophylaxis is now mandated.
Clofarabine & cytarabine is a highly active induction regimen in older adults age ≥60 yrs with de novo AML, but has significant myelosuppressive and infectious toxicity. The study is proceeding in phase I at Dose Level -I to establish the MTD.
Phase I, Dose Level I PT AGE, GENDER FAB CYTOGENETICS F/U BM TOXICITY (Gr.III/IV) OUTCOME MLD - multilineage dysplasia; F&N - fever & neutropenia; CR - complete remission 1 66M M2 Diploid D21: residual AML renal, infxn Death 2 61M M2 Complex D14: aplastic F&N CR 3 69M M2 with MLD Intermediate Risk D21: recovering F&N CR 4 77F M2 Diploid D14: aplastic renal, infxn, capillary leak Death
Peripheral Blood Lymphocytic Profile in Patients with Diffuse Large B Cell Lymphoma and Follicular Lymphoma.
Authors: Cavallin Fernando , Vicario Giovanni , Manente Paolo , Di Gaetano Rosa , Tagariello Giuseppe 
Published: October 2019

Abstract
Diffuse Large B Cell Lymphoma (DLBCL) and Follicular Lymphoma (FL) are the most common adult low-grade non Hodgkin’s lymphomas. The influence of these diseases in peripheral blood lymphocytes is not well defined. Indeed the lymphocytic arrangement can be altered on account of the leukaemic form (although it slightly ever occurs); on the other hand the cause of occasional anomalies can be the involvement of the immune system against neoplasm. In order to contribute to the knowledge of these conditions we have analysed, at diagnosis, the lymphocytic immunophenotype in peripheral blood of 61 subjects: 27 were affected by DLBCL, average age 68, and 34 by FL, average age 61 years. Therefore we quantified the number of lymphocytes and evaluated essential markers, using flow cytometry, to define T, B, NK subsets by: CD3, CD4, CD8, CD19, SIgk, Sigl, CD56, and expression of CD11a molecule on T CD8. The absolute peripheral blood lymphocytes count presented a reduction in 51% and in 32% of the cases with an increase in 4% and in 3% of the subjects respectively considering DLBCL and FL. On the contrary T cells (CD3) had similar decrease, 33% and 32%, and different augmentation 15% and 3%. T cells ratio CD4/CD8 was under normal in 23% and in 12% of the patients but over normal in 12% and 29% always in DLBCL and FL. B cells (CD19) were reduced in 35% and in 12% of the subjects but increased in 8% and in 14%, whereas clonal restriction was present in 8% and in 20% of the components of the two groups. Natural Killer lymphocytes (CD56) were under normal in 12% and in 6% of bthe cases but over in 40% and 20%. Finally CD11a was over-expressed in 87% and in 68% of the patients of the respective pathologies. After selecting patients aged over 60 years, following four parameters that showed a significant variability was obtained: 1) lymphopenia in 50% of the cases in both groups; 2) similar results 11% and 15% about clonal restriction; 3) increase of the NK population 42% and 30% in DLBCL and FL; 4) very high over-expression of CD11a on T CD8 of 90% and 80%. Therefore DLBCL and FL are lymphoproliferative diseases where there is an important subtraction of lymphocytes, particularly in elderly people, from peripheral blood (perhaps because of accumulation in lymphnodes). These lesions present clonal restriction of B cells only in few cases (confirming the low known leukaemic form) while Natural Killer population are well represented especially in DLBCL. The over-expression of CD11a is the most altered parameter and seems almost a typical marker of these diseases above all in over 60 years subjects. Consequently if rarely happens that a leukaemic form of DLBCL and FL are found by flow cytometry however immunological defined alterations are very frequent in most of the cases of old patients.
WNT6 mRNA Is Overexpressed in Variuos Non-Hodgkin’s Lymphoma Cases with No Apparent Relation to Cyclin D1 Level.
Authors: Swoboda Pawel M. , Gos Monika , Rymkiewicz Grzegorz , Blachnio Katarzyna , Walewski Jan , Janik Przemyslaw 
Published: October 2019

Abstract
A casual role for Wnts in the development of some human cancers seems to be established. Binding of Wnt to its receptor results in β-catenin stabilization and in consequence, translocation to the nucleus, where it activates the specific target gene’s expression including CCND1 (cyclin D1). Abnormal levels of β-catenin may therefore contribute to neoplastic transformation by causing accumulation of cyclin D1. Overexpression of cyclin D1, as a result of the t(11;14)(q13;q32) translocation, which places cyclin D1 gene under the enhancer of immunoglobulin heavy chain is considered the hallmark of mantle cell lymphoma (MCL) but high levels of cyclin D1 have also been observed with various levels in some cases of non-MCL lymphoproliferative disorders not involving t(11;14), such as hairy cell leukemia (HCL), splenic lymphoma with villous lymphocytes (SLVL), prolymphocytic leukemia (PLL) and some atypical CLL cases. Little is known about potential Wnt signaling in mature lymphocytes or lymphoid malignancies. Recent finding, that the Wnt pathway regulates the proliferation and survival of normal B lymphocytes, together with WNT16 overexpression in leukemic cell lines and high expression of five other Wnts including WNT6 in CLL suggests that Wnt family members can contribute to tumorgenesis in the immune system. In the current study we evaluated the relationship between Wnts and cyclin D1 mRNA expression level in NHL patients. WNT6 and CCND1 mRNA expression level normalized to 18 sRNA was evaluated by RT-PCR on 200 biopsy samples taken from 150 lymphoma patients. In parallel, samples underwent pathological and flow cytometry examination. WNT6 mRNA was detected in all specimens tested. The 18 sRNA/WNT6 ratio ranged from 1 to 650. Most of the CLL specimens were among those with high WNT6 mRNA expression, but no apparent correlation between the level of WNT6 mRNA expression and cyclin D1 status was found so far.