bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic Significance of Multidrug Resistance Gene 1 (MDR1), Multidrug Resistance-Related Protein (MRP) and Lung Resistance Protein (LRP) mRNA Expression in Acute Leukemia.
Authors: Huh Hee Jin , Park Chan-Jeoung , Jang Seongsoo , Seo Eul-Ju , Chi Hyun-Sook , Lee Je-Hwan , Lee Kyoo-Hyung , Seo Jong Jin , Moon Hyung Nam , Ghim Thad
Published: October 2019

The prognostic significance of multidrug resistance (MDR) gene expression is controversial. We investigated whether multidrug resistance gene 1 (MDR1), multidrug resistance-related protein (MRP) and lung resistance protein (LRP) mRNA expression are associated with outcomes in acute leukemia patients. At diagnosis we examined MDR1, MRP and LRP mRNA expression in bone marrow samples from 71 acute leukemia patients (AML 39, ALL 32) using nested reverse transcription polymerase chain reaction (RT-PCR). The expression of each of these genes was then expressed as a ratio in relation to ß-actin gene expression, and the three genes were categorized as being either not expressed (0), weakly expressed (1+), moderately expressed (2+) or strongly expressed (3+). MDR1, MRP and LRP mRNA expression was detected in 23.9%, 83.1% and 45.1%, respectively, of acute leukemia patients. LRP mRNA expression was significantly associated with resistance to induction chemotherapy in acute leukemia patients, and in the AML proportion of these patients, compared to LRP-negative patients (p=0.02 and p=0.03, respectively). MRP and high MDR1 mRNA expression was associated with poorer 2-year survival (P=0.049 and p=0.04, respectively) compared to MRP-negative and non-high MDR1 mRNA-expressing patients, respectively. Patients expressing both MRP and LRP mRNA had poorer outcomes in response to induction chemotherapy and had worse 2-year survival compared to patients not expressing both genes. The present data suggest that MDR gene expression affects CR and survival rates in acute leukemia patients. Thus, determination of MDR gene expression at diagnosis appears likely to provide useful prognostic information for acute leukemia patients.
Unrelated Donor Marrow Transplantation for Acute Lymphoblastic Leukemia in Japan. A Japan Marrow Donor Program Experience between 1993 and 2003.
Authors: Tsuchida Masahiro , Sao Hiroshi , Sakamaki Hisashi , Kawa Keisei , Kanda Yoshinobu , Kato Koji , Hara Masamichi , Ishii Mutsuo , Kikuchi Akira , Okamura Jun , Maruta Atsuo , Takaue Yoichi , Kasai Masaharu , Yabe Hiromasa , Morishima Yasuo , Kato Shunichi , Kodera Yoshihisa
Published: October 2019

From 1993 to 2003, 1223 patients, 0 to 61 year old, with high risk acute lymphoblastic leukemia underwent their first bone marrow transplantation through Japan Marrow Donor Program. Most transplants were performed between HLA serologically matched Japanese pairs with a few exceptions.

Of all, 520 patients underwent transplantation in the first complete remission (1CR: median follow up 488 days), and their probability of 5 year overall survival (OS) by Kaplan Meier analysis was 58.4(standard error; SE 2.8) %. The 281 patients in the 2CR (452 days) showed OS 49.4(3.7) %, 75 at the third or further CR (249 days), OS 29.5(5.9) %, and 333 at relapse or non CR(162 days), OS 16.4(2.6) %. The outcome of the younger tended to be the better except that the oldest group 51–61 year of age did fair. The GVHD prophylaxes were cyclosporine and short term methotrexate (sMTX) in 681 patients, and tacrolimus plus sMTX in 461. Among the 1CR patients, the 5 year OS of 276 patients in cyclosporine group was 52.0% (SE.3.7%) and 217 tacrolimus group showed significantly better OS, 66.5% (SE 5.7%, P=0.03). The grade II to IV, or III to IV acute GVHD developed in 47.3% or 19.1% respectively without any age difference. Acute GVHD grade I might solely favor the patients in 1CR at 5 years or earlier post-transplant, and the survival of those in 2CR was minimally affected by grade 0 to III acute GVHD. On the other hand, the presence of chronic GVHD did not improve the survival rate of the patients in 1CR, whereas the patients in 2CR achieved better survival if they had limited or extensive chronic GVHD. The importance of HLA class I DNA type matching in Japanese population has been published (N Engl J Med. 1998 Oct 22). Patients with ALL did poorly between the pairs with DNA A-locus mismatch in 1CR and 2CR, B-locus mismatch in 2CR, DRB1-locus mismatch in 2CR.

We concluded that, the unrelated donor marrow transplantation in Japan provided as good chance of survival for the patients with ALL as related donors did, despite poorer risk group they belong to. GVHD prophylaxis with tacrolimus might attain better outcome in 1CR patients, and chronic GVHD seemed to improve the OS for the patients in 2CR, but not for 1CR patients.
Expression and Modulation of Carbohydrate-Binding Protein Galectin-3 in Multiple Myeloma Cells by Combined Treatment with GCS-100 and Dexamethasone.
Authors: Chauhan Dharminder , Chang Yan , He Deli , Hideshima Teru , Podar Klaus , Tao Florence , Neri Paola , Schlossman Robert , Schindler Joanne , Carver Bradley , Richardson Paul , Anderson Kenneth C.
Published: October 2019

Galectins belong to the family of mammalian lectins sharing an evolutionary conserved sequence in their carbohydrate recognition binding (CRD) domains and exhibit a characteristic affinity for beta-galactoside-sugars. Based on their structure and CRD, galectins have been categorized into three different categories: 1) Prototype (Gal-1, 2, 5, 7, 10, 11, 13, and 14), 2) Chimera type (Gal-3), and 3) Tandem repeat type (Gal-6, 8, 9, and 12). In particular, Galcetin-3 (Gal-3) is associated with growth, differentiation, adhesion, RNA processing, and apoptosis (Apoptosis, 2005, 10: 267–75). Previous studies show that Gal-3 is expressed on tumor cell surface and mediate the transformation and metastasis of tumor cells in vivo(Apoptosis, 2005, 10: 267–75). Here, we show that Gal-3 is differentially expressed in multiple myeloma (MM) cell lines and purified patient cells, as determined by both western blotting and polymerase chain reaction (PCR). Importantly, Gal-3 shares structural similarities with the anti-apoptotic protein Bcl-2: both proteins are rich in proline, glycine, and alanine amino acid residues in their NH-2-terminal domains and contain anti-death motif Asp-Trp-Gly-Arg (NWGR) in their C-terminal domains (Proc Natl Acad Sci USA, 1996, 93: 6737–42). Gal-3, like Bcl-2, is therefore a potential therapeutic target. In this context, modified citrus pectins (MCP) have been reported to bind and inhibit Gal-3-induced human umbilical endothelial cell migration and micro vessel tube formation (Am J Pathol.2000, 156:899–909) as well as block tumor growth and metastasis (J Natl Cancer Inst. 2002, 94:1854–62). GCS-100 is a MCP currently under clinical development. Here we show that GCS-100 binds to human recombinant Gal-3. In MM cells, GCS-100 triggers apoptosis and enhances anti-tumor activity of the conventional agent Dexamethasone. We examined whether GCS-100-, Dex- or GCS-100 + Dex-induced MM cell death modulates Gal-3 or Bcl-2 expression. Treatment of MM.1S cells with either GCS-100 or Dex alone does not alter Gal-3 or Bcl-2 expression. However, combined treatment of MM cells with sub-toxic concentrations of GCS-100 and Dex markedly attenuates Gal-3 expression, without any changes in Bcl-2 levels, suggesting that alterations in Gal-3 are specific. Previous studies showed that Gal-3 inhibits mitochondrial pro-apoptotic protein cytochrome-c (cyto-c), and our results show that GCS-100 + Dex triggers the release of cyto-c from mitochondria to cytosol. Together, these data suggest that the combination of GCS-100 + Dex overcomes the inhibitory effect of Gal-3 on cyto-c, thereby inducing apoptosis. Since Gal-3 is widely expressed in MM cells, its inhibition may augment the anti-tumor activity of therapeutic regimens.
The Effect of Repeated Administration of Cyclophosphamide on CYP2B1 and 2B2 in Rat.
Authors: Afsharian Parvaneh , Terelius Ylva , Lundgren Stefan , Hassan Moustapha
Published: October 2019

Cyclophosphamide is used in high doses as a part of the conditioning regimen prior to stem cell transplantation. It is usually given for two or four consecutive days, primarily to facilitate engraftment of donor cells. Cyclophosphamide is a prodrug that is activated in liver by a 4-hydroxylation reaction catalyzed by cytochrome P450 (CYP) enzymes. Several studies have shown that cyclophosphamide induces its own metabolism, which affects its pharmacokinetic parameters after repeated dose (Chang TK, Yu L et al. Cancer Res1997; 57:1946–54 and Schuler U, Ehninger G et al. Cancer Chemother Pharmacol1987; 20:248–52). In the present study, we aimed to investigate the effect of repeated doses of cyclophosphamide on the CYPs in rat. mRNA, protein, and enzyme activity levels were investigated. Animals received (200 mg/kg, i.v.) at time 0, 20, 48 h. Additionally another group of animals was treated at 0, 6, 20, 26, 48 and 54 h. At each time point three animals were killed 30 min after the administration (Xie H, Afsharian P et al. Xenobiotica2005; 35:239–51). mRNAs of CYP2B1 and 2B2 were significantly induced up to 458- and 8.3-fold at 6h, 983- and 102-fold at 26 h, and 342- and 33-fold at 54 h. CYP2B protein levels were increased and their peaks was observed at 20 and 48 h. Microsomal activity of CYP2B was determined at three different concentration of cyclophosphamide (1, 0.5, 0.1 mM) by measuring the formation rate of 4-hydroxy-cyclophosphamide (4-OH-CPA). The microsomal activity increased as reflected in an increase in cyclophosphamide 4-hydroxylation at all concentrations used using microsomes from rats treated at 6, 20 and 48 h. A significant increase of 4-hydroxylation of cyclophosphamide (0.1 mM) by 2.9-, 4.4- and 4.2- fold, respectively compared to the control rats. However, a decrease in the hydroxylation rate was observed using microsomes from rats treated at 26 and 54 h and in all concentrations used that might due to hepatotoxicity effect of cyclophosphamide when administered in short time period of repeated dose. A significant (p<0.05) decrease in CPA concentration and a significant (p<0.05) increase in its metabolite (4-OH-CPA) level in plasma were observed with repeated administration of CPA. In conclusion, an induction effect on CYP2B and a substantial up regulation of its mRNA expression were observed after repeated administration of CPA. This information can have a high clinical importance when a dosing schedule for cyclophosphamide considering the polymorphism of CYPs in cancer patient.
Results of Phase II Study of Lenalidomide (L) {Revlimid®} in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL).
Authors: Chanan-Khan Asher Alban , Miller Kena C. , DiMiceli Laurie , Padmanabhan Swaminathan , Lawrence David , Bernstein Zale P. , Takeshita Kenichi , Spaner David , Wallace Paul , Byrne Catriona , Crystal Cynthia , Czuczman Myron S.
Published: October 2019

Introduction: Lenalidomide (L) is a compound in a new group of drugs called ImiDs® which have Immunomodulatory properties and with anti-tumor activity reported in multiple myeloma and MDS. Although the exact mechanism of action of L is unknown, they are reported to affect the tumor microenvironment through modulation of critical cytokines such as TNF-a, VEGF and IL-6. These cytokines also play an important role in pathogenesis of CLL. Based on these properties we have investigated and previously reported on the anti-leukemic activity of thalidomide in CLL. We subsequently conducted a phase II study with L, to evaluate its clinical activity in pts with relapse (rel) or refractory (ref) CLL. Here we present the results of this study.

Patients and Methods: CLL pts with rel or ref disease were eligible. L was given at 25mg PO QD x 21 days followed by 7 days rest on a 28 day cycle. Absolute lymphocyte counts (ALC) were measured at Day 0, 7 and 30. Response was assessed at day 30 and monthly thereafter using the NCI-WG 1996 criteria. Pts with stable disease (SD) or better response were continued on therapy for a maximum of 12 months while those with progressive disease (PD) were to receive rituximab (R) (375mg/m2) added to L. Pts were considered evaluable for response if they completed at least 2 months of treatment. Target enrollment is 29 patients.

Results: Twenty nine pts, median age of 64 years (range: 47–75) were enrolled. All pts are available for toxicity and 17 out of 29 pts available for response evaluation. Three pts on treatment are too early for response assessment while 9 pts are off study (2 withdrew consent and 5 got < 2 months of therapy due to toxicity). Response is reported based on evaluable pts. Complete remission (CR) was noted in 2/17 (11.7%) pts while partial remission (PR) was noted in 9/17 (52.9%) pts. Additional 5/17 (29.4%) pts, currently on treatment, achieved stable disease (SD). ORR (CR+PR) in the intent to treat population is 42.3% (11/26, excluding pts currently too early for response assessment). To date only 1 pt has PD after 3 months of L and is on LR per protocol. Toxicity: Flare reaction (tender swelling of lymph nodes and/or rash) was the most common SE noted in almost all pts. Other important SE were tumor lysis syndrome (n=2); grade 3/4 hematologic toxicities (n=7) and febrile neutropenia (n=3).

Conclusion: This is the first study to report the clinical activity of L in pts with CLL. Our findings are encouraging and provide evidence of the anti-CLL activity of L. Although some of the pts did achieve a CR, longer follow-up will determine the durability of responses noted to date. Update results of this study along with toxicity profile of L in CLL will be presented at the meeting.
Patient Characteristics in CD 20+ and CD 20− Adult Acute Lymphoblastic Leukemia (ALL): A Single Institution Analysis.
Authors: Gladney Sara P. , Heffner Leonard T. , Langston Amelia , Holden Jeannine , Phillips Carol , Winton Elliott , Flowers Christopher R. , Lechowicz Mary Jo , Lonial Sagar , Waller Edmund , Khoury Hanna J.
Published: October 2019

Targeted therapy is increasingly incorporated into the chemotherapy regimens of adult ALL. While the prognosis of BCR/ABL + (Philadelphia) ALL is well recognized; the significance of CD 20 postivity is unknown. We report the characteristics of 76 patients treated at Emory University between January 1999 and March 2005, divided into 2 groups based on CD 20 expression, as determined by flow cytometry. The CD 20+ patients presented with a higher WBC count and LDH, and lower platelet counts (table). In the CD 20+ group, 65% had pre B cell ALL and 8% had high grade B cell leukemia/lymphoma, whereas the CD 20- group consisted of 30% pre B cell ALL, 24% T cell ALL, and 10% had high grade leukemia/lymphoma. Of the 35 Ph+ ALL patients, 27 were CD20+ (20%) and 18 CD20- (51%). Patients were treated on clinical trials L20, ALL2, and more recently with the Hyper-CVAD regimen (n=32). Only 5 of the CD 20+ patients received rituximab in addition to chemotherapy. With a median follow-up of 320 days, 46% of patients in each group are alive, 35% and 38% relapsed in the CD 20+ and CD 20- group, respectively. In summary, we found that CD 20+ ALL patients present with higher WBC count and LDH, and a lower platelet count; although, due to our small sample size, these differences were not significant. Further follow up is needed to provide mature results on survival and remission.

CD 20+ CD 20- p= Total numbers 26 50 Median Age (yrs) 45.2 (18–74) 44 (19–76) NS Median WBC (103/μl) 29.1 10 0.09 Median Platelet (103/μl) 35 65 0.11 Median LDH (IU) 894 500 0.05 Normal Cytogenetics 13 (50%) 21 (42%) NS Ph+ ALL 7 (26%) 18 (35%) NS CR within 60 days 20 (77%) 27 (54%) NS Primary Refractory 2 (8%) 6 (12%) 0.7 Relapse 9 (35%) 19 (38%) NS Alive at last follow up 12(46%) 23 (46%) NS Expired by d270 8 (36%) 11 (25%) NS
Simultaneous Detection of Major Fusion Transcripts in CML, ALL and AML Leukemias in a Multiplex Bead-Array Assay.
Authors: Ye Fei , Mire Brad , Wolf Ila , Lahey Cora , Hadd Andrew G.
Published: October 2019

INTRODUCTION: Accurate sub-classification of leukemia-associated chromosome translocations is essential for precise risk-stratified diagnosis and improvement of treatment outcomes. We have developed a rapid assay system to detect the nine most common chromosomal translocations covering three different leukemia disease groups: CML, ALL and AML. The purpose of our study was to confirm clinical detection of twelve translocation markers.

MATERIALS AND METHODS: The liquid bead array assay combined multiplex RT-PCR with signal readout in a 96-well plate format. RNA fusion transcripts of leukemia-associated chromosome translocations were reverse transcribed into cDNA and amplified by multiplex PCR using biotin-modified primers. An endogeneous control gene, GAPDH, was co-amplified in each sample and concurrently analyzed. A single-tube bead array contained 11 marker specific oligonucleotide probes with sequences complimentary to the fusion transcript splice junction for the following markers: b2a2, b3a2 for CML; e1a2, E2A-PBX1, TEL/AML1 and MLL/AF4 (e10/e4, e9/e5) for ALL; PML/RARa (long and short forms), AML1-ETO and inv(16) (A and D types) for AML. Biotinylated amplified products were hybridized to the array without intervening purification steps. After incubation with streptavidin-conjugated fluorophore, the reaction mixtures were analyzed by the Luminex platform.

RESULTS: RNA samples from translocation-positive cell lines and IVT products were detected with less than 10% CVs in approximately five hours. Long and short forms of PML-RARa and A and D types of inv(16) were specifically resolved. The assay can detect two MLL/AF4 subtypes: MLL/AF4 (e10/e4) or MLL/AF4 (e9/e5). Eighty-seven leukemia patient samples (RNAs extracted from peripheral blood and bone marrow) were screened and all translocations were correctly detected. A software system for selective readout based on disease class was implemented.

CONCLUSIONS: This multiplex array-based assay can be an effective and reliable tool in the clinical screening of leukemia patients for the presence of specific fusion transcripts with important diagnostic and prognostic implications.
Expression of Inhibitor-of-Apoptosis Protein (IAP) Livin in Pediatric Acute Lymphoblastic Leukemia (ALL) Cells.
Authors: Dasgupta Anindya , Gu Lubing , Alvarado Carlos S. , Zhou Muxiang , Findley Harry W.
Published: October 2019

Livin (ML-IAP, KIAP, BIRC7) is a recently identified member of the IAP family of anti-apoptosis proteins, and expression has been reported in melanoma, some types of carcinoma, and neuroblastoma. Additionally, we have detected expression of livin in leukemic cells from pediatric ALL cell lines and primary ALL cells. Livin was detected by RT-PCR in all 9 ALL lines tested, although expression varied markedly among lines: 3 of 9 lines showed strong expression of livin (equal to or greater than the melanoma line G361, which served as a positive control), while the remaining lines had a faint band. These livin-positive lines included both B-cell precursor ALL (BCP-ALL, 7 lines) as well as T-ALL (2 lines). We confirmed livin protein expression (by immunoblot) in 3 lines with high levels of livin RNA (EU-1 and REH, BCP-ALL; and CCRF-CEM, T-ALL); two other lines (EU-3 and EU-4, BCP-ALL) with low levels of livin RNA showed much less protein expression. These results are similar to those we have previously reported for neuroblastoma, which also shows variability in expression of livin among different cell lines. Similarly, livin was detected in primary ALL cells from all four patients tested to date (including three BCP-ALL and a T-ALL case) at either diagnosis or relapse. Again, livin expression varied significantly among cases; one of the two cases with elevated livin was in relapse, while the other two cases (at diagnosis) showed only faint expression. Livin expression in normal bone marrow mononuclear cells was also low (relative to G361 cells and high-expressing ALL cells). When resistance to doxorubicin was compared for lines with elevated livin vs those with low livin expression, increased resistance was noted in the former lines. To further evaluate the effect of livin on drug resistance, EU-4/ALL cells with low endogenous livin were stably transfected with a livin expression plasmid. A significant increase in resistance to doxorubicin was noted for livin-transfected cells at concentrations above 1ug/ml in a 48 hr cytotoxicity assay. Taken together, these results suggest that elevated livin expression contributes to drug resistance in some cases of pediatric ALL. We are currently evaluating the mechanism by which elevated livin expression protects leukemic cells from doxorubicin.
Hairy Cell Leukemia and Secondary Lymphoproliferative Disorders.
Authors: Chang Monique , Kujawa Jennifer , Garrison Michael , Hindenburg Alexander
Published: October 2019

Prolonged immunosuppression is generally associated with an increase in incidence of lymphoid cancers. Transplant recipients, primary or genetic immunodeficiencies and patients with the acquired immunodeficiency syndrome (AIDS) have a known increased incidence of lymphoproliferative disorders. Patients who develop hairy cell leukemia (HCL) also have impaired immune function at the T-cell level that is present before definitive therapy. The lack of T-cell responsiveness is due to a decrease in memory T helper cells, abnormal activation of spleen T lymphocytes that behave like tumor infiltrating cells, and selection of oligoclonal T-cell populations with a very restricted and skewed T-cell repertoire. Inadequate antigen presentation may also play a role due to monocytopenia and lack of CD 28 on T-cells. Treatment with purine analogs, particularly pentostatin and cladribine, targets both resting and proliferating lymphocytes. This further impairs immune function by producing a prolonged reduction of normal lymphocytes, mainly CD4 cells, for as long as two years. There are reports of lymphoproliferative disorders as a second malignancy after treatment for HCL. However, it is not clear if treatment with purine analogs can induce second malignancies due to immune suppression. We reviewed the literature for cases of secondary lymphoproliferative disorders in patients treated with and without purine analogues for HCL. Purine analogues do not appear to have an increased risk for a secondary lymphoproliferative disorder. However, a preexisting immunosuppressed state may exist that antecedes the treatment of HCL and predisposes some patients to secondary lymphoproliferative disorders.

Secondary Lymphoproliferative Disorders in Patients Treated for Hairy Cell Leukemia (HCL) Prior Treatment for HCL Non Hodgkin’s Lymphoma Hodgkin’s Lymphoma Waldenstrom’s Macroglobulinemia Multiple Myeloma Purine Analogues 16 3 2 1 Other Systemic Therapies 7 2 0 1 No Systemic Therapy 10 0 0 0 Unknown 3 1 0 0
Cytogenetics of Hispanics and Whites with Childhood Acute Lymphoblastic Leukemia in California.
Authors: Aldrich Melinda C. , Zhang Luoping , Wiemels Joseph L. , Ma Xiaomei , Loh Mignon , Selvin Steve , Feusner James , Smith Martyn T. , Buffler Patricia A.
Published: October 2019

Epidemiologic studies of childhood leukemia have made limited use of tumor genetic characteristics, which may be related to disease etiology. We characterized the cytogenetics of 543 childhood leukemia patients (0–14 years of age) enrolled in the Northern California Childhood Leukemia Study, an approximately population-based study comprised primarily of Hispanics (42%) and non-Hispanic whites (41%), and compared the cytogenetic profiles between these two ethnic groups. Subjects were classified by immunophenotypes, conventional cytogenetic characteristics, and fluorescence in situ hybridization findings. The abnormalities most frequently observed among all patients were pseudodiploidy and high hyperdiploidy (51–67 chromosomes) (27% and 25%, respectively). No ethnic differences in the frequency of 11q23/MLL rearrangements were observed between Hispanics and non-Hispanic whites. Among B lineage ALL patients without 11q23/MLL rearrangements, the percentage of TEL-AML1 translocations was significantly lower in Hispanics (13%) than in non-Hispanic whites (24%; P = 0.01). This is the first large study to compare frequencies of cytogenetic events of primarily Hispanic and non-Hispanic white childhood leukemia patients. Our data suggest some cytogenetic characteristics likely differ between non-Hispanic whites and Hispanics. The mechanistic basis for the two-fold variation in frequency of TEL-AML1 may be due to ethnic-specific risk factors or genetics and should be explored further. Owing to the heterogeneity of leukemia in children, it is possible that cytogenetic subgroups may have distinct etiologies and risk factors which otherwise would be overlooked with the broad leukemia subtypes (e.g. ALL, AML) presently used in epidemiologic analyses.
Associations of Birthweight and Maternal Fertility Problems with Childhood Cancers.
Authors: Dorak M. Tevfik , Hammal Donna M. , Pearce Mark S. , McNally Richard J.Q. , Parker Louise
Published: October 2019

Higher birthweight, maternal history of miscarriage and low birth order have been associated with increased risk of childhood leukaemias and some solid tumours. No study has investigated these factors together and differences in disease etiology between girls and boys have been generally overlooked. In a retrospective case-control study, 732 childhood (≤15 yr) cancer cases from the population-based Northern Region Young Persons’ Malignant Disease Registry (NRYPMDR) whose hospital birth records could be accessed and 3723 controls matched for date and hospital of birth were compared. We examined maternal reproductive history and birthweight for gender-specific associations using conditional logistic regression. In univariate analysis, maternal history of miscarriage showed an association with all cancers (OR = 1.29; 95% CI = 1.05 to 1.62, P = 0.02). In individual cancer groups, this association was significant for acute lymphoblastic leukaemia (ALL) (n=225, OR = 1.56; 95% CI = 1.07 to 2.27, P = 0.02), and marginally significant in osteosarcoma and neuroblastic tumours (neuroblastoma and ganglioneuroblastoma). There was no significant association with birth order. Being first born was a weak risk factor for ALL in boys only (OR=1.3, 95% CI = 0.8 to1.8). In boys but not in girls, the risk of ALL increased with birthweight (OR = 1.06 per 100 gr increase; 95% CI = 1.01 to 1.11, P = 0.01). When birthweights were normalized using UK standards for gestational age and gender, the associations were not more marked. A multivariate model for ALL confirmed the independence of associations with miscarriage history and birthweight. Gestational age was not a risk marker and did not explain the associations with birth weight and miscarriage history. Consideration of gender unravelled significant associations of maternal reproductive history and size at birth with childhood cancer markedly different between girls and boys. Most notably, associations with birth weight and miscarriage and the weak association with being first-born in childhood ALL were all stronger in males. The findings for birthweights normalized for gestational age suggested that size at birth rather than in utero growth trajectory is of etiologic importance in childhood ALL.
Epidemiology of Fungal Infections in Hematological Malignancies in Italy: SEIFEM-2004 Study (Sorveglianza Epidemiologica Infezioni Fungine Nelle Emopatie Maligne).
Authors: Pagano Livio , Caira Morena , Candoni Anna , Offidani Massimo , Martino Bruno , Liso Vincenzo , Picardi Marco , Bonini Alessandro , Chierichini Anna , Fanci Rossella , Caramatti Cecilia , Invernizzi Rosangela , Gallamini Andrea , Mitra Maria Enza , Melillo Lorella , Allione Bernardino , Fianchi Luana , Falcucci Paolo , Valentini Caterina Giovanna , Van Lint Maria Teresa , Girmenia Corrado , Nosari Anna Maria
Published: October 2019

Background: To evaluate the incidence and the outcome of fungal infections in patients (pts) affected by hematological malignancies (HM).

Methods: A retrospective study, conducted over 1999–2003, in pts with HM, admitted in 18 Italian Hematology divisions in tertiary cares or university hospitals, who developed proven or probable fungal infections.

Results: The population included 11,802 pts: 3,012 AML (25.5%), 1,173 ALL (9.9%), 596 CML (5%), 1,104 CLL (9.4%), 1,616 MM (13.7%), 3,457 NHL (29.3%), 844 HL (7.2%). Pts who underwent HSCT were included in a different analysis. A fungal infection occurred in 538 pts, with an incidence of 4.6%; in particular we registered 346 episodes sustained by moulds (incidence 2.9%) and 193 by yeasts (1.6%). The incidence rate depends upon underlying malignancy (12.3% in AML, 6.5% in ALL, 2.7% in CML, 0.6% in CLL, 0.5% in MM, 1.6% in NHL, 0.9% in HL). Among moulds, the etiological agents were Aspergillus (310 episodes, incidence 2.8%), Mucorales (13 pts, 0.1%), Fusarium (15 pts, 0.1%), and other rare fungi (7 pts, 0.1%). Among yeasts we registered septicemia due to Candida (175 pts, 1.6%). Other yeast infections were caused by Cryptococcus (8 pts, 0.1%), Tricosporon (7 pts, 0.1%) and other rare agents (2 pts). We did not observed an increase of A.terreus infections while the number of episodes sustained by A.flavus increased from 1999 to 2003 (RR 2.10; IC95% 0.8–5.49; p-value 0.117). The overall mortality rate was 1.8%. Among 538 pts with fungal infection 39% died for this complication, with differences between aspergillosis (42%), zygomycosis (63%), fusariosis (53%) and candidemia (33%). There was not variation in mortality rate during the study period; comparing these pts with those observed in our previous studies during the period 1987–1988 we observed a significant reduction of death due to aspergillosis (RR 1.90; IC 95% 1.17–3.09), but no differences in mortality rate due to Candida.

Conclusions: Our study confirms the general trends already described: infections due to moulds are more frequent than those caused by yeast. Aspergillus remains the main etiologic agent, followed by Candida. The other agents (Mucorales, Fusarium, Trichosporon) remain rare. AML represents the most frequently involved category. The mortality rate due to aspergillosis is actually about 40%, with a remarkable decrease when compared to past years; as for candidemia, we observed a reduction in the incidence, but not in the mortality rate.
Clinical Significance of the Philadelphia Chromosome Positive Pediatric Acute Lymphoblastic Leukemia in Chinese.
Authors: Ye Qidong , Gu Long-Jun , Tang JingYan , Xue Huiliang , Chen Jing , Pan Ci , Chen Jing
Published: October 2019

Objective To explore the incidence, clinical characteristics and prognosis of childhood acute lymphoblastic leukemia (ALL) with t(9; 22).

Methods All of the clinical characteristics of the 325 childhood ALL patients from November, 1998 to November, 2003 were analysised. The statistics was done by SPSS 10.0.

Results There were 129 cases of high-risk ALLs in 325 Childhood ALL patients, with 95 males and 34 females. BCR-ABL fusion gene was found in 16 cases by RT-PCR, accounting for 4.9%. All of them were m-BCR-ABL. There were 12 males and 4 females among 16 Ph positive ALLs. The mean age at diagnosis was 8.54±3.36 (3.5 to 12.5) years, 50.0% of which were older than 10 years. The percents of patients who had initial WBC count more than 100×109/L, myeloid antigen coexpression, hypodiploidy, and ALL-L2 were 37.5%, 53.8%, 33.3%, and 62.5%, respectively. By comparison, the percents of age (older than 10 years), initial WBC count (more than 100×109/L), myeloid antigen coexpression, prednisone poor response (PPR), and CR over 35 days in the Ph positive ALLs were higher than that in the negative ALLs. No statistic difference was found in sex and L2 proportion between them. Moreover, no difference was found between Ph positive ALLs and negative high-risk ALLs in the mentioned parameters, except for the myeloid antigen coexpression. Four-year event-free survivals (EFS) and disease-free survivals (DFS) were 77.4% and 79.4, respectively, in Ph negative ALLs, but were 33.0% and 47.7%, respectively, in Ph positive ALLs (P<0.01). In Ph negative high-risk ALLs, the four-year EFS and DFS were 51.2% and 54.6%, respectively, both of which had no statistic difference between Ph positive cases. Only one Ph positive child received allogeneic BM transplantation, who remained in EFS at the time of this analysis.

Conclusion The percent of t(9; 22) in Chinese childhood ALLs had no difference with the report abroad. There were statistic differences between Ph positive and negative childhood ALLs in age, initial WBC count, early response to therapy, and four-year EFS and DFS, but no difference was found between Ph positive ALLs and Ph negative high-risk ALLs, except for the immunophnotype. Aggressive treatment, such as high-dose chemotherapy with allogeneic BM transplantation should be considered for these patients to improve survival.

Event-free survival curves for children with acute lymphoblastic leukemia Event-free survival curves for children with acute lymphoblastic leukemia
Efficacy of Chemotherapy Regimen Containing Pirarubicin on 111 Patients with High-Risk, Relapse and Refractory Acute Leukemia.
Authors: Huang Fen , Meng Fan Yi
Published: October 2019

Objective: To evaluate the efficacy of chemotherapy regimen containing pirarubicin on the patients with high-risk, relapse and refractory acute leukemia.

Methods: 184 patients with high-risk, relapse and refractory acute leukemia were recruited and randomized to experiment group (111) and control group (73). The experiment group included 64 acute non-lymphocytic leukemia (ANLL) patients, 39 acute lymphocytic leukemia (ALL) patients and 8 mixed leukemia patients, and all received one of the following regimen: TA, VTP, VTLP or TAVP (T: pirarubicin, V: vincristine, P: prednisone, L: L-asparaginase). The patients in the control group received routine chemotherapy without pirarubicin.

Results: the complete remission rate (CR) was significantly higher in pirarubicin-treated group than in control group either for all the patients (64.4% vs 43.8%, p<0.05) or for ANLL patients (68.1% vs 36.2%, p<0.05). At the same time bone marrow suppression was severer in pirarubicin-treated group than in control group (p<0.05).

Conclusions: chemotherapy regimen containing pirarubicin is more effective than routine regimen without pirarubicin in the management of high-risk, relapse and refractory acute leukemia, especially in ANLL patients, although it induce severer but tolerable bone marrow suppression.
sVEGFR3 but Not VEGF-C Plasma Level Is Increased in Non-Hodgkin Lymphoma.
Authors: Wrobel Tomasz , Mazur Grzegorz , Biedron Monika , Jazwiec Bozena , Pyszel Angelika , Kuliczkowski Kazimierz
Published: October 2019

BACKGROUND: Non-Hodgkin’s lymphomas (nHL) may spread via blood vasculature or lymphatics. Vascular endothelial growth factor (VEGFs) family of glycoproteins is essential for angiogenesis and lymphangiogenesis. VEGF-C enhances lymphangiogenesis and promotes metastasis via lymphatic vessels. VEGF-C stimulates lymphangiogenesis by binding VEGFR-2 and VEGFR-3 receptors on lymphatic endothelial cells Elevated serum levels of proangiogenic cytokines (i.e. VEGF) are the independent prognostic factor in nHL. Data concerning the role of lymphangiogenesis in nHL are very limited. Salven et al. showed low VEGF -C mRNA in lymphoma cells. The role of lymphangiogenesis in lymphoma dissemination remains to be determined. The aim of the study was to assess plasma levels of VEGF-C and sVEGFR3 in nHL patients. before chemotherapy and after achieving complete remission (CR).

MATERIAL AND METHODS: Plasma samples from 39 adult (18 females and 21 males) patients with B-cell nHL taken at diagnosis and in CR were measured by ELISA to evaluate VEGF-C and sVEGFR-3 levels (Bender Medsystems and R&D Systems respectively). In addition plasma samples from 25 healthy volunteers were evaluated as the control. Statistical analysis was performed using U Mann-Whitney test (p<0,05).

RESULTS: There was no significant differences in VEGF-C levels between untreated nHL group, nHL in CR and the control (166,9±221,8 vs 217±294,4 vs 161,2±118 pg/ml respectively). In untreated nHL patients sVEGFR3 level was significantly higher than in the control (19434±8990 vs 13949±5417 pg/ml respectively; p=0,007). In CR sVEGFR3 decreased but was still significantly higher than in healthy control (18163±9108 vs 13949±5417 pg/ml respectively; p=0,038).

CONCLUSION: Similarly to previous studies we demonstrated that VEGF-C plasma levels were not increased in nHL. There are several observation that in human tumors VEGFR3 is involved both in lymphangiogenesis and angiogenesis. Increased VEGFR3 in nHL may reflect intensity of blood and lymphatic endothelium proliferation.
Expression of VEGF-C and Its Receptor VEGFR-3 in Diffuse Large B-Cell Lymphomas.
Authors: Pazgal Idit , Boycov Olga , Shpilberg Ofer , Okon E. , Bairey Osnat
Published: October 2019

Vascular endothelial growth factor (VEGF)-C and its receptor tyrosine kinase VEGFR-3 are critical regulators of lymphangiogenesis. Their expression has been observed in a variety of solid tumors and was associated with lymph node metastasis in patients. The aim of this study was to evaluate whether aggressive lymphatic malignant cells express VEGF-C and its receptor VEGFR-3 and whether the expression correlates with intratumoral microvessel density, and patient outcome. Pathological specimens were taken at diagnosis from 29 diffuse large B-cell lymphoma (DLBCL) patients (11 men, 18 females, mean age 70 years) who were diagnosed between the years 1997–2001. The specimens were evaluated by immunohistochemical staining to determine the expression of VEGF-C and VEGFR-3 and the microvessel count (by factor-VIII-related antigen). All lymphoma specimens demonstrated positive staining for VEGF-C and VEGFR-3 with high intensity staining in 50% and 68% of the specimens respectively. The mean microvessel count was 58 (range 23–120) and blood vessels in all specimens demonstrating positive staining for both VEGF-C and VEGFR-3 (strong in 25% and 58% respectively). We found a significant correlation between high serum levels of β2 microglobulin and high VEGFR-3 staining. High intensity staining was found in 77% of the patients with high β2 microglobulin compared to 44% of the patients with normal β2 microglobulin level (p=0.03).

The patients who expressed high intensity VEGFR-3 staining had worse survival. In the 13 patients who lived more than 5 years, only 46% of them demonstrated high intensity staining while 85% of patients that lived less than 5 years demonstrated such staining (p=0.01). The median event free survival (EFS) was 21 months. A significantly higher proportion of the patients with low EFS (lower than 21 months) demonstrated high intensity staining for VEGFR-3, (p=0.01)

These results suggest that DLBCL tumors express both VEGF-C and its receptor (VEGFR-3) and that this signaling pathway may be associated with patient’s prognosis.

Figure Figure
Identification of Subtype-Specific Genomic Alterations of Acute and Lymphoma Types of Adult T-Cell Leukemia/Lymphoma.
Authors: Oshiro Aya , Tagawa Hiroyuki , Oshima Kouichi , Karube Kennosuke , Uike Naokuni , Tashiro Yukie , Utsunomiya Atae , Masuda Masato , Morishima Yasuo , Nakamura Shigeo , Seto Masao
Published: October 2019

Background: Adult T cell leukemia/lymphoma (ATLL) is a human T-lymphotropic virus type-I mediated neoplasm and four major clinical subtypes are recognized; i.e., smoldering, chronic, lymphoma and acute types. Among these subtypes, acute and lymphoma types are fetal disease with poor prognosis. Although these two subtypes represent different clinical features, detailed analysis for genomic/genetic differences has not been sufficiently investigated.

Purpose: To investigate genomic aberrations of these subtypes, we performed array-based comparative genomic hybridization (array CGH: 2308 BAC clones spotted in duplicate) for 66 cases of ATLL (17 cases of acute and 49 cases of lymphoma subtypes). To determine target genes in recurrently amplified regions, quantitative real-time PCR (RQ-PCR) was conducted.

Results: Array CGH: Comparison of genome profiles revealed that lymphoma type shows more frequent gain and loss than those of acute type. The numbers of respective genomic gain and loss regions of lymphoma type were 9.7 and 9.8 on average. The numbers of genomic gain and loss regions of acute type were 4.2 and 4.5 on average. Gain of 1q, 2p, 4q, 7p and 7q, and loss of 10p, 13q, 16q and 18p were characteristic to lymphoma type whereas gain of 3p and 3q was specific to acute type. Recurrent high-level amplifications were found at 1p35, 6p25, 7p22.2, 7q21–q22, 7q31–q36 and 14q32 in lymphoma type. However, such genomic amplifications were not found in acute type.

RQ-PCR: CARMA1 (7p22 locus), which encodes signaling proteins associated with development of B and T cells, was a possible target of the 7p22 amplification in lymphoma type. The extremely higher expression of BCL11B (14q32 locus) which is a key regulator of both differentiation and survival during thymocyte development, was found in acute type irrespective of the 14q32 amplification. However, no overexpression of BCL11B was found in lymphoma type with high copy number gain, indicating that BCL11B is not the target gene for 14q32 amplification in the lymphoma type.

Conclusion: Array-CGH revealed that patterns of genomic aberrations between acute and lymphoma types were different. Quantitative gene expression analysis also implicated distinct mechanism of aberrant gene expressions between acute and lymphoma types. Combination of array-CGH and quantitative gene expression analysis provided evidence that the acute and lymphoma types are developed via distinct genomic/genetic pathways.
A Pilot Study of Physical Activity Level and Mood among Long-Term Lymphoma Survivors.
Authors: Habermann Thomas M. , Janney Carol A. , Clark Matthew M. , Rummans Teresa A. , Sloan Jeff S. , Cerhan James R. , Geyer Susan M. , Thomas Randall J.
Published: October 2019

It has been well-documented in cardiac patients and in the general population that physical activity improves physical and mental health. Physical activity could also improve the health and quality of life of long-term lymphoma survivors, but little is known about physical activity in this group of patients. Using the Mayo Tumor Registry, we identified eligible patients who were 16 years or older at diagnosis, U.S. residents, first diagnosed with Hodgkin or non-Hodgkin lymphoma from 1984–1998, diagnosed and/or initially treated at Mayo Clinic Rochester, and survived for 5 to 20 years (N=2,485). In October of 2004, we mailed a 23-page survey to 95 randomly selected patients; 7 were found to be ineligible (deceased or too ill). Of the 88 remaining patients, we were able to find a correct address for 82, and 57 completed a survey for a 70% participation rate. Physical activity was self-reported using the Godin (1985) Leisure-Time Exercise Questionnaire. Of the 54 patients with complete data for this report, the mean age at completion of the questionnaire was 60.8 years (26.1–86.7). The mean time since diagnosis was 12.0 years (6.3–19.9), and 52% survived more than 11 years. The histologies included 22 (39%) Hodgkin lymphoma, 21 (38%) diffuse large B-cell lymphoma, 3 (5%) follicular lymphomas, 1 (2%) high-grade lymphoma, 5 (9%) peripheral T-cell lymphomas, and 4 (7%) other. Regular fitness was reported by 21% of the respondents. This is lower than a recent report of adults aged 50 years and older, where approximately 40% of those free of chronic disability were attaining recommended daily physical activity levels. It is also lower than the expected 30% in patients with disabilities from the Behavioral Risk Factor Survey (Brown DR et al., Med Sci Sports Exerc2005;37:620–9). In addition, although not statistically significant, there were effect sizes observed suggesting that sedentary responders had higher levels of depression, higher anxiety levels, more distress, and lower quality of life (QOL) compared to physically active respondents. These finding need to be verified in a larger sample to obtain better estimates. In conclusion, levels of physical activity were lower than general population samples. These results also suggest that physical activity level may be related to improved mood and QOL in this population.
A Novel Functional Role for Soluble CD27 in the Pathogenesis of Waldenstrom’s Macroglobulinemia.
Authors: Ho Allen W. , Leleu Xavier , Hatjiharissi Evdoxia , Tournilhac Olivier , Xu Lian , O’Connor Kelly , Manning Robert , Santos Daniel , Chemaly Mariana , Branagan Andrew , Hunter Zachary , Patterson Christopher , Anderson Kenneth C. , Treon Steven P.
Published: October 2019

The tumor necrosis factor (TNF) receptor family member, CD27, is a transmembrane co-stimulatory molecule present on primed T and B lymphocytes that also secrete a soluble form (sCD27). Recent evidence has suggested that interactions between CD27 and its TNF-like ligand, CD70, play a critical role in regulating B-cell activation and survival, though the detailed mechanism(s) by which this occurs remain unclear. Waldenstrom’s Macroglobulinemia (WM) represents a lymphoplasmacytic lymphoma characterized by a monoclonal IgM gammopathy and possesses a mast cell component that may contribute to its pathogenesis (Blood 104; 646a). Using ELISA assays, we observed that WM patients displayed significantly higher levels of sCD27 in their sera (median 7.45, range 0–19.42 U/ml) versus healthy donors (median 0, range 0–2.78 U/ml; p=2.5 x 10−7). CD27 was expressed in 7/7 patients using RT-PCR analysis, but was expressed on the cell surface of tumor cells in 5/12 patients using flow cytometric analysis. Conversely, CD70 expression was widely expressed on both tumor cells (6/6 patients) and mast cells (10/11 patients) using flow cytometric analysis. In order to define the functional role of sCD27 in WM, we cultured BCWM.1 (CD27−CD70+) WM cells, and LAD1 (CD27−CD70+) mast cells with sCD27 (0.1–50 ug/mL), and observed no effect on proliferation or induction of apoptosis. Culture of LAD1 cells with sCD27 did, however, result in marked upregulation of the TNF family ligands CD40L (CD154) and a proliferation induction ligand (APRIL), which previous work in our laboratory had implicated as mast cell proliferation and survival factors in WM. Taken together, these studies suggest a novel functional role for sCD27, and imply a pivotal role in the pathogenesis of WM.