bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Plasma Concentrations of the Anorexigenic PYY and Orexigenic Ghrelin Decrease and Increase Respectively during Chemotherapy in Children with Acute Lymphoblastic Leukaemia, as the Leukemic Burden Is Gradually Eliminated and the Body Weight Improves.
Authors: Moschovi Maria , Vounatsou Maria , Papassotiriou Ioannis , Chrousos George P. , Tzortzatou-Stathopoulou Fotini 
Published: October 2019

Abstract
Anorexia and cachexia are common manifestations in children with acute lymphoblastic leukaemia (ALL) at diagnosis. Possible mediators of the anorexia-cachexia syndrome are hormones, cytokines, and adipokines from peripheral tissues, and neurotransmitters, neuropeptides, cytokines, and other hormones in the hypothalamus. Peptide YY (PYY) and ghrelin are gastrointestinal track-derived hormones involved in the short- and long-term regulation of food intake and energy balance. PYY, synthesized mainly by endocrine cells of the terminal ileum and colon, is released into the systemic circulation in response to a meal and participates in signalling the end of the meal at the hypothalamus. PYY exerts its pro-satiety actions possibly through an Y2 receptor-mediated mechanism. Ghrelin, secreted predominantly from X/A-like endocrine cells of the oxyntic glands of the stomach, is primarily secreted in the fasting state, with plasma concentrations falling within one hour of a meal. Its role in food intake and energy balance is opposite to that of PYY, as it exerts orexigenic effects through activation of the hypothalamic neuropeptide Y-Y1 (NPY-Y1) pathway. We evaluated the secretion of PYY and ghrelin at diagnosis and during chemotherapy in children with ALL. Ten patients aged 2-7years were included in this perspective study. All patients were treated following the same protocol (HOPDA97)1. A physical examination was performed and blood chemistries were evaluated by standard techniques. Preprandial PYY and active ghrelin levels were determined by specific radioimmunoassays (Linco Research, Inc., USA). Measurements were performed at diagnosis prior to chemotherapy and at several time points prior to each next cycle of chemotherapy for up to 18 months (6–10 measurements per patient). Baseline PYY levels were 213.2±85.3pg/ml, increased significantly to 283.9±72.9pg/ml after the induction and consolidation phase of chemotherapy, and returned progressively to pre-treatment levels at the 6th cycle of the maintenance phase. Baseline active ghrelin concentrations at diagnosis were low (32.6±8.6pg/ml), fluctuated throughout the study period and stabilized at significantly higher levels (57.4±31.6pg/ml) after the 8th cycle of maintenance phase of chemotherapy. These data suggest that in children with ALL and anorexia-cachexia the levels of PYY decrease with time, as the leukemic burden is eliminated. In contrast, active ghrelin levels are relatively low at diagnosis, remain low during the early cycles of chemotherapy, but normalize with the elimination of the leukemic burden, paralleling the body weight gain trajectory.
Maternal Hemoglobin Concentration during Pregnancy and Risk of Infant Leukemia.
Authors: Peters Antoinette M. , Blair Cindy K. , Verneris Michael R. , Neglia Joseph P. , Heerema Nyla A. , Robison Leslie L. , Ross Julie A. 
Published: October 2019

Abstract
Little is known about the etiology of childhood leukemia. Elevated birth weight (> 4000 g) is gaining acceptance as a risk factor, particularly for children diagnosed < 2 years of age, but the underlying biological or physiological explanation for this association has yet to be defined. At least three recent studies have demonstrated a positive association with childhood leukemia and maternal anemia during pregnancy. Physiologic anemia of pregnancy, which results from normal plasma volume expansion, is thought to produce optimal blood viscosity for the low flow area of the placenta and is associated with the highest average birth weights in the offspring. We therefore hypothesized that maternal physiologic anemia of pregnancy would have a positive association with infant leukemia. To test this hypothesis, we utilized data from a case-control study conducted by the Children’s Oncology Group (COG) that consisted of 240 incident cases of acute infant leukemia (< 12 months of age) diagnosed between 1996 and 2002 and 255 controls obtained by random digit dialing. Maternal blood counts were obtained by medical record abstraction. Information regarding the patients’ diagnoses and cytogenetic/molecular abnormalities were obtained from COG institutions. Physiologic anemia of pregnancy was defined as a hemoglobin concentration of < 11 g/dL in the second or third trimester of pregnancy (WHO classification). Anemia earlier in pregnancy is more frequently due to nutritional deficiencies and can be associated with poor fetal outcomes and thus was excluded. Maternal hemoglobin values from the second or third trimester were available for 178 case and 180 control mothers. Data were analyzed using unconditional logistic regression. We found no evidence that physiologic anemia of pregnancy was associated with birth weight of > 4000 g (odds ratio (OR) 1.05, 95% confidence interval (CI)=0.55–1.99) Overall, the OR for physiologic anemia of pregnancy and risk of infant leukemia was 0.85 (95%CI=0.53–1.37). The association remained non-significant when cases were divided into acute myeloid leukemia (AML) (n=63) and acute lymphocytic leukemia (ALL) (n=115) with ORs of 0.64 (95%CI=0.32–1.30) and 0.98 (95%CI=0.58–1.66), respectively. The association was also not significant when cases were stratified by MLL gene abnormality status (OR=0.77; 95%CI=0.42–1.40 and OR=0.88; 95%CI=0.45–1.73, for cases with (n=92) and without (n=62) an MLL gene abnormality, respectively). These associations remained non-significant when the data were adjusted for birth weight, maternal race, and birth order. More stringent criteria for anemia also did not modify the results. We found no evidence for an increased risk of infant leukemia in the offspring of mothers with physiologic anemia of pregnancy. This work was supported by NIH R01 CA79940 and the Children’s Cancer Research Fund.
Aldehyde Dehydrogenase Expression in Primitive Human Hematopoietic Progenitor Cells with Side Population Characteristic and in Samples from Patients with Acute Myeloid Leukemia.
Authors: Meissauer Ute , Hoffmann Joerg , Scharenberg Christian , Neubauer Andreas , Brendel Cornelia 
Published: October 2019

Abstract
High activity of the detoxifying enzyme aldehyde dehydrogenase (ALDH) has been attributed to primitive hematopoietic stem cells in the murine and human system. ALDH activity can be measured by a functional assay employing BODIPY-aminoacetaldehyde (BAAA) as a fluorescent intracellular substrate. High ALDH activity within hematopoietic stem cells is associated with CD34 and AC133 surface expression.
Given the co-expression of these markers in acute myeloid leukemia (AML), we sought to investigate whether ALDH-activity can be detected in early blood stem cell disorders and in primitive hematopoietic progenitor cells with the side population phenotype. Employing a commercial Aldefluor™ -kit thirteen peripheral blood and bone marrow samples from patients with AML were stained for ALDH activity. Four samples exhibited a clearly distinctive positive staining pattern when compared to the inhibitor control, i.e. 16–91% of AML blast cells were considered as ALDH positive. The staining pattern was similar to marrow samples from healthy donors or peripheral blood sample controls from G-CSF-mobilised healthy stem cell donors.
In addition we investigated ALDH activity in primitive bone marrow side population (SP) cells from healthy individuals. Although the ALDH substrate BAAA is actively extruded out of cells and especially SP stem cells by an ABC-transporter-activity, we established a co-staining method for Hoechst 33342 and BAAA by inclusion of specific ABC-transporter inhibitors.
Both SP cells and ALDH-positive cells appeared as a clear distinctive population with some overlap between both populations. Quantitative RT-PCR of different sorted stem cell samples confirmed that SP cells had higher ABCG2-expression than ALDH positive cells and ABCG2-expression was higher in ALDH positive cells compared to the total cell fraction or granulocytes.
We conclude that ALDH is expressed in some but not all AML blast cells. This is in accordance with the cytogenetic heterogeneity of this disease and may have therapeutic implications because of the detoxifying activity of the ALDH enzyme. In addition ALDH activity can also be found on a minor population of very primitive marrow progenitor cells. Whether high ALDH activity is a feature of the leukemic stem cell requires further investigation.
Results of Randomized Study on Dexrazoxane Administration in Children with De Novo Acute Leukaemia.
Authors: de Berranger Eva , Thebaud-Leculee Estelle , Wickaert Isabelle , Vaksman Guy , Mazingue Francoise , Francart Charles , Dalle Jean-Hugues , Nelken Brigitte 
Published: October 2019

Abstract
Anthracyclins and anthracenediones represent major drugs for both myeloid and lymphoblastic acute leukemia. Among their efficient mechanisms, these drugs induce free radical production responsible of cardiac toxicity. Even though toxicity is mainly dose related, there is an inter-individual sensitivity, and then it appeared very important to develop drugs able to protect cardiomyocytes. Dexrazoxane was developed in this goal in adult patients where its efficiency was demonstrated both to protect heart and to respect anticancer therapy results. We conducted a prospective single bind randomized study using dexrazoxane associated with first-line therapy in pediatric acute leukemia.
Patients and Methods: From Dec’00 to Sept’03, 16 patients (pts) were enrolled and randomized for receiving or not dexrazoxane (1000mg for 50mg of anthracyclines or anthracenedione doxorubicin dose equivalent) with chemotherapy. Cardiac function was evaluated by echocardiogram before induction and after each chemotherapy course of either CLG-EORTC 58951 trial arm VHR or French acute myeloid leukemia trial LAME01 and each year after treatment completion. The cardiologist operator did not know if child received dexrazoxane or not. The cumulative equivalent doxorubicin dose was 310mg/m2 for EORTC 58951 VHR group and 460mg/m2 for LAME01. The primary end-point was cardiac function evolution. The secondary end points were OS, EFS and the respect of initial therapy schedule.
Results: 16 pts (9M/7F), median age 8.5y (range: 2.4 – 16.1) were enrolled. Initial diagnoses were AML: 11 and ALL: 5. Five AML pts and 3 ALL pts received dexrazoxane. Median follow-up was 28.5 months (10–47). 12 pts were alive, 6 in each arm of study. One pt relapsed in arm with dexrazoxane and 3 in the other arm. Two pts died of disease and 2 from infection equally dispatched in the 2 study arms. Mean left ventricular shortening fraction was 39.4+/−1.9% and 35.6+/−1.2% in pts without dexrazoxane and 40.2+/− 2.2% and 38.7+/− 2% in pts with dexrazoxane before chemotherapy and 1 year after diagnosis. All these values were comparable. Mean duration between day1 of each chemotherapy course was the same in different arms of study.
Discussion and conclusion: Dexrazoxane may be used safely in children receiving anthracycline. No difference in OS and DFS appear in our study. Median follow-up was probably too short for distinguishing any cardiac alteration and patient number was low. In addition, shortening fraction may be not the better cardiac indicator and wall stress could be more efficient. Further investigations are on-going.
Comparison of Two Induction Regimens, High Dose Cytarabine /Mitoxantrone vs Hyper-CVAD, for Adult Acute Lymphoblastic Leukemia/Lymphoma.
Authors: Jeong Woondong , Liu Delong , Katragadda Sreedhar , Shi Qiuhu , Ahmed Tauseef , Seiter Karen 
Published: October 2019

Abstract
Seventy-three consecutive adult patients with newly diagnosed ALL and lymphoblastic lymphoma were treated with either high-dose cytarabine /mitoxantrone (Ara-C/Mito) or Hyper-CVAD between January 1994 and January 2005 at the Westchester Medical Center. The regimens were chosen according to investigators’ preferences. The two induction regimens were either Ara-C 3 g/m2/d for 5 days and mitoxantrone 80 mg/m2 on day 2 (52 patients) or Hyper-CVAD regimen (21 patients) containing four cycles of Hyper-CVAD alternating with four cycles of high-dose methotrexate and Ara-C. All patients who were in CR received consolidation and maintenance therapy after induction. In Ara-C/Mito group, 45 (87%) of 52 patients achieved a complete remission (CR), 2 (4%) had resistant disease and 5 (9%) had died during remission induction in median follow-up of 48 months (range, 0.5 – 109 months). In Hyper-CVAD group, 16 (76%) of 21 patients achieved a CR, 4 (19%) had resistant disease and 1 (5%) had died during remission induction in median follow-up of 12months (range, 0.5 – 43 months). The difference of CR rate between the two groups was not statistically significant. (p=0.31). The overall survival (OS) of AraC/Mito group was 21 months (95% confidence interval [CI], 13 – 38 months), with a 3-year and 5-year OS of 36%, and 30%, respectively. In Hyper-CVAD group, OS was 26 months (95% CI, 26 -NR ), with a 3-year OS of 40%. The difference of OS between the two groups was not statistically significant (p=0.24). In Ara-C/Mito, median CR duration was 34 months (95% CI, 13-) and in Hyper-CVAD, median CR duration was not reached. In a combined multifactorial analysis of the two groups for prognostic factors, Age (<35) was the only favorable factor toward OS (p=0.03). Other prognostic factors including cytogenetics, cell type, WBC, LDH, were not statistically significant.
In conclusion: Ara-C/Mito and Hyper-CVAD appear to be comparable in terms of CR rate, toxic death, and OS in this single institution retrospective analysis. It will be interesting to compare the two induction regimens in a large multicenter randomized study.
AraC/Mito vs Hyper-CVAD Regimen N Med F/U CR CR duration OS 3yr OS 5yr OS NR: median not reached. M: month AraC /Mito 52 48m 87% 34m 21m 36% 30% Hyper-CVAD 21 21m 76% NR 26m 40% NR p=0.31 p=0.24
Burkitt’s Lymphoma in Korea: Clinical Manifestations and Efficacy of Modified CALGB 9251 Regimen (BNHL).
Authors: Lee Danbi , Kim Shin , Ko Ock Bae , Koo Ja Eun , Chong Young Pill , Huh Jooryung , Suh Cheolwon 
Published: October 2019

Abstract
Background: Clinical manifestations of sporadic Burkitt’s lymphoma of Asia including Korea has not been well informed. When Korean patients with Burkitt’s lymphoma were treated following the protocol proposed by the Cancer and Leukemia Group B (CALGB) 9251, grade 4 mucositis was reported in every patient. Thus, we had modified CALGB 9251 protocol and named BNHL.
Aims: This study was aimed to show the clinical manifestations and to evaluate efficacy and toxicity of BNHL in patients with Burkitt’s lymphoma in a Korean single center.
Methods: Between January 1998 and July 2005, 25 patients who were diagnosed as Burkitt’s lymphoma at Asan Medical Center were available to evaluate the clinical features. Among 25 patients, 12 patients treated with BNHL were available. In BNHL protocol, we reduced the dose of methotrexate (1,500 → 1,000 mg/m2/day on Day 1) and etoposide (80 → 50 mg/m2/day on Day 4 and 5) in cycle 2, 4, and 6, and the dose of methotrexate (1,500 → 1,000 mg/m2/day on Day 1) in cycle 3, 5, and 7 from the protocol of CALGB 9251.
Results: Median age was 50.4 years (range: 17–77) and 15 patients were male. Among 25 Burkitt’s lymphoma, 20 patients had extranodal involvement, and 9 patients had 2 or more extranodal involvements. Extranodal sites were bone marrow, GI tract, genitourinary organ, bone, and lung, in decreasing order. Among total patients, 16 were in stage III or IV, and 9 were in stage I or II. Twelve patients had B symptoms, and 16 patients had high or high intermediate score of age adjusted international prognostic index (IPI). For 12 patients treated with BNHL, median follow-up duration was 13 months (range: 3–20 months). Among patients treated with BNHL, 9 patients achieved CR, and 3 patients achieved PR. The event free survival (EFS) rate at 1 year was 54% (95% CI, 39–69%) and median EFS was not reached. Among 9 patients who achieved CR, 2 patients were relapsed. Three patients died as a result of treatment-related complications (2 patients) or progressive disease (1 patient). Median overall survival (OS) was not reached yet, and 1-year OS rate was 64% (95% CI, 50–78%). All patients treated with BNHL had hematologic toxicities of grade 3 or 4 neutropenia/thrombocytopenia. Grade 3 or 4 non-hematologic toxicities were; mucositis (67%), infection (58%), hepatic toxicity (42%), peripheral neuropathy (25%), and azotemia (25%).
Conclusions: Korean patients with Burkitt’s lymphoma had worse age-adjusted IPI score than that in western countries. Extranodal involvements were more frequent. Despite these poor risk factors, BNHL modified from CALGB 9251 showed satisfactory efficacy and acceptable toxicities in Korean Burkitt’s lymphoma.
Mechanisms Controlling Selective Death of Leukemia Stem Cells in Response to Parthenolide.
Authors: Guzman Monica L. , Li Xiaojie , Corbett Cheryl , Hassane Duane C. , Jordan Craig T. 
Published: October 2019

Abstract
Studies have shown that human acute myelogenous leukemia (AML) originates from a rare population of leukemic stem cells (LSCs). LSCs are found in nearly all AML subtypes and are sufficient to initiate and maintain leukemic growth in both long-term cultures and NOD/SCID mice. Since conventional chemotherapy drugs typically target actively cycling leukemic blast cells, the quiescent LSC population is likely to be drug resistant. Recently, we have described agents that can selectively kill LSC while sparing normal hematopoietic stem cells (HSC), thus demonstrating that quiescent LSC can be effectively destroyed. In particular, the sesquiterpene lactone parthenolide (PTL) is active as a single agent and can induce robust LSC-specific apoptosis. Therefore, we sought to further elucidate the mechanisms that result in leukemia-specific death. To this end, we have shown that PTL inhibits NF- κB and activates p53 in AML cells. Moreover, we have found that AML cells are highly-oxidized relative to their normal less-oxidized counterparts as determined by dihydrofluorescein diacetate (H2DCF-DA) fluorescence. Although PTL treatment was found to increase the basal oxidative load of both normal and leukemic cells, these increases were ultimately associated with only leukemia-specific death. High levels of reactive oxygen species are associated with genotoxic stress. Therefore, we hypothesized that PTL-mediated increases of the oxidative load in AML cells would be sufficient to produce genotoxic stress in AML cells, but not normal cells. We thus examined pathways involved in sensing and responding to oxidative and genotoxic stress. These studies demonstrate that upon PTL treatment, AML cells phosphorylate p53 on serine 15, and increase transcription of several downstream p53 pro-apoptotic genes, including GADD45, Bax, and p21. In addition, we detected phosphorylation of ATM on serine 1981, γ-H2AX, and phosphorylation of Chk2 on threonine 68. Importantly, these events are not observed in normal hematopoietic cells treated with PTL. These findings suggest a DNA damage/repair response to PTL in AML cells, and that normal cells appear to be resistant to this mechanism. Collectively, these data indicate that oxidative stress and DNA damage pathways may be a central component of PTL-induced apoptosis. We propose a model whereby AML cells exist in a physiological state in which PTL is able to preferentially invoke genotoxic stress in AML. Based on empirical evidence, we suggest that AML LSC also exist in such a state, and that PTL mediated inhibition of NF- κB and induction of stress leads to selective apoptosis of malignant cells, sparing normal cell populations.
Clinical Significance of Monoclonality by Flow Cytometry in Histologically Negative Bone Marrow in Patients with Diffuse B Cell Non Hodgkin’s Lymphoma.
Authors: Lahav Meir , Lucianski Michael , Radnay Judith , Shapiro Hava , Gronich Naomi , Manor Yosef , Lishner Michael 
Published: October 2019

Abstract
Bone marrow (BM) involvement in diffuse large B cell non Hodgkin’s lymphoma (DLBCL) results in stage IV staging and has negative impact on survival. Up to 40% of patients with DLBCL have BM involvement by routine histology of marrow biopsy. The identification of lymphoid monoclonality is widely used in diagnosis of lymphoma, by flow cytometric and molecular methods. The clinical significance of monoclonality by these methods has not been systematically addressed in clinical setting. An International Workshop of response criteria in non Hodgkin’s lymphoma recommends that histologically normal marrow with small clonal population detected by flow cytometry should be considered normal until there are clinical studies that demonstrate a different outcome for this group. Recently it was reported that clonality detected by PCR amplification carries worse prognosis in patients with DLBCL. In our institution bone marrow biopsies of all patients with lymphoma are routinely evaluated by flow cytometric analysis since 1993. We evaluated the clinical course of all our patients with DLBCL diagnosed or followed up between 1993 and 2004 and compared the clinical course of patients with histologically positive marrow, histologically and cytometry negative marrow and histologically negative marrow and monoclonal lymphoid population detected by flow cytometry. Monoclonality was defined as ration of light chain expression kappa: lambda>3:1 or lambda: kappa > 2:1 in at least 2% of the gated population. Selected cells were analyzed by two or three color combinations: CD5 versus CD19, CD20 versus CD10 and kappa chain versus lambda chain occasionally with the addition of CD19 or CD20. Among 110 patients, 80 had negative marrow histologically and on cytometry (BM-FC-), 16 were positive on both parameters (BM+FC+) and 14 were histologically negative and cytometry positive (BM-FC+). All three groups were similar in parameters as age, performance status, hemoglobin and LDH levels. BM-FC- and BM-FC+ were similar in IPI scores. BM-FC- patients had significantly longer survival time that BM+FC+ and BM-FC+ patients. There was no significant difference in survival of BM+FC+ and BM-FC+ patients.
We conclude that the clinical outcome of patients with DLBCL with histologically normal bone marrow and monoclonality on flow cytometry is similar to those with histologically positive marrow. These results may imply that lymphoid monoclonality on flow cytometry should be regarded as bone marrow involvement and treated as such.