bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intermediate Dose Intravenous Methotrexate (MTX) Dramatically Reduces the Risk of Secondary Central Nervous System (CNS) Lymphoma.
Authors: Hochberg Ephraim P. , Hammerman Peter , Takvorian Tak , Toomey Christiana , Michaelson James , Rahemtullah Aliyah , Abramson Jeremy S. 
Published: October 2019

Abstract
Secondary CNS lymphoma (SCNSL) is a rare complication of diffuse large B cell non-Hodgkins lymphoma (DLBCL) which is almost universally fatal. Several groups have analyzed risk factors for the development of SCNSL and published risk estimates for both individual anatomic sites of DLBCL as well as combinations of clinical risk factors. Although the rates of SCNSL for all DLBCL patients range from 2.5% to 5% subgroups can be identified with risks as high as 33%. High risk scenarios where CNS prophylaxis is most commonly offered include either a combination of an elevated LDH and more than one extranodal site of disease, or disease involving the bone marrow, testicle, sinus, orbit, or a para-spinal location. The type of prophylaxis used varies widely from intrathecal to high-dose intravenous methotrexate as well as intrathecal use of cytarabine. Despite the advances made in the systemic therapy of DLBCL there is very limited data on the efficacy of these chemopreventive regimens in SCNSL. We undertook a retrospective review at our institution of all patients with DLBCL treated with inpatient intermediate dose methotrexate (3.5 grams per meter squared) followed by leucovorin rescue between 2002 and 2006 for CNS prophylaxis. We found 37 patients. Of 15 patients initially evaluated with diagnostic lumbar punctures (LP), no patient had a positive CSF cytology. The median age of the patients was 59 (26–79). The average IPI was 3. All patients were tested for HIV and 3 were found to be positive. The indications for CNS prophylaxis were primarily an elevated LDH and more than 1 extranodal site of disease (20) but also included patients with bone marrow (9), testicular (3), orbital (5), para-spinal (2) and sinus (6) involvement, with 6 patients having more than one site of involvement. All patients received an anthracycline containing chemotherapy regimen with curative intent. Thirty-six patients received rituximab. Patients received a median of 6 cycles of systemic chemotherapy and 3 courses of MTX given on day 15 of alternating cycles (usually 2, 4 and 6). In addition 2 patients received a single dose of 12 mg of intrathecal methotrexate at the time of their initial LP and 5 patients received intrathecal liposomal cytarabine. We calculated the expected number of cases of SCNSL using the estimates from van Besien et al. Blood ‘98, Hollender et al. Ann Onc ‘02, and Boehme et al. Ann Onc ‘06 as appropriate depending on the sites of disease for each patient. For this population the expected number of cases of SCNSL was 7.98 and the observed number of cases was 1 (p=.002 two-sided binomial probability). In this population of 37 patients with an elevated risk of SCNSL, the use of intravenous intermediate dose methotrexate substantially reduced their risk of this fatal complication.
A Multicenter Phase II Trial of Etoposide, Methylprednisolone, High-Dose Cytarabine, and Oxaliplatin (ESHAOx) for Patients with Refractory/Relapsed Aggressive Non-Hodgkin’s Lymphoma.
Authors: Sym Sun Jin , Kang Hye Jin , Nam Seung-Hyun , Kim Hoyoung , Kim Seok Jin , Eom Hyeon Seok , Kim Won Seog , Suh Cheolwon 
Published: October 2019

Abstract
Etoposide (E), methylprednisolone (S), high-dose cytarabine (HA), and cisplatin (P) (ESHAP) combination is commonly used salvage regimen for non-Hodgkin’s lymphoma (NHL). Oxaliplatin (Ox), a new platinum derivative, showed substantially different cytotoxic activity and adverse effects from both cisplatin and carboplatin. In addition, single-agent oxaliplatin was reportedly active in patients with NHL. We conducted to investigate the efficacy and toxicity of ESHAOx combination, substituting oxaliplatin for cisplatin in ESHAP combination, for relapsed/refractory aggressive NHL patients. Main eligibility criteria included aggressive NHL and failure to achieve a complete remission or recurrent disease after previous chemotherapy. ESHAOx consisted of E, 40 mg/m2 on days 1 to 4; S, 500 mg on days 1 to 5; HA, 2 g/m2 on day 5; and Ox, 130 mg/m2 on day 1, every 3 weeks. Eligible patients were scheduled to receive a maximum of 6 cycles, and high dose chemotherapy and hematopoietic stem cell rescue allowed. Responses were evaluated every 3 cycles. All patients gave written informed consent before study entry. Between May 2006 and January 2007, 27 patients were enrolled. Nineteen (70%) patients with relapsed, 8 patients with refractory, and 10 (37%) patients with IPI 3–5 were included in this study. A total of 102 cycles were administered for a median number of 4 (range 1–6 cycles) per patient. There were 8 (30%) complete responses and 9 (33%) partial responses, producing an overall response rate of 63% (95% CI, 45–81%). Most common grade 3/4 toxicity of the courses was myelosuppression with including neutropenia (55%) and thrombocytopenia (33%). Non-hematologic toxicity was very favorable. No significant renal and neurotoxicity was demonstrated. There was one treatment-related death due to neutropenic sepsis. The results of ESHAOx combination showed highly antitumor activity and favorable toxicity profile, suggesting it can be used as salvage regimen for relapsed/refractory aggressive NHL patients.
Denileukin Diftitox (ONTAK) Plus CHOP Chemotherapy in Patients with Peripheral T-Cell Lymphomas (PTCL), the CONCEPT Trial.
Authors: Foss Francine , Sjak-Shie Nelida , Goy Andre , Jacobsen Eric , Advani Ranjana , Smith Mitchell , Komrokji Rami , Pendergrass Kelly , Bolejack Vanessa , Watts Karen , Acosta Mark 
Published: October 2019

Abstract
PTCL are an aggressive group of lymphomas comprising a number of histopathologic subtypes for which CHOP chemotherapy has been the standard first-line regimen at many centers. Denileukin diftitox (Dd) is a recombinant DNA-derived cytotoxic protein composed of diphtheria toxin fragments A and B and the full length sequence of human interleukin-2 (IL-2). Dd targets T-cells expressing the intermediate and high-affinity IL-2 receptor. Because the mechanism of action of Dd is distinct from traditional cytotoxic chemotherapy and Dd has exhibited minimal myelosuppression, we evaluated the safety, tolerability, and efficacy of combining Dd with CHOP as first-line therapy for patients with PTCL according to the REAL classification. (Pts with mycosis fungoides or Sezary syndrome were not included.) Dd was administered at 18 mcg/kg/day on Days 1 and 2 followed by CHOP on Day 3, and G-CSF support starting Day 4, every 3 weeks for up to 6 cycles. Evaluation of response is performed after every 2 cycles of treatment.
Results: Forty-one pts, 18 male/23 female, have been enrolled to date, with a median age of 52. Ten pts are not evaluable for response: 5 discontinued due to an adverse event (AE) prior to assessment of response; 3 due to lack of measurable disease at baseline; and 2 are too early to evaluate. For the 31 response-evaluable patients, the overall response rate is 90%, with 71% (22/31) CR or CRu, 19% (6/31) PR, 6% (2/31) SD, and 3% (1/31) PD. Ten of 28 responders (36%) have progressed, with a median duration of response of 13 months.
PTCL subtype No. of Patients No. evaluable Responses ORR PTCL-nos 20 15 3 CR, 5 CRu, 4 PR, 2 SD, 1 PD 80% Angioimmunoblastic 10 9 3 CR, 5 CRu, 1 PR 100% Anaplastic large cell 6 4 2 CR, 2 CRu 100% Enteric T-cell 2 1 1 CRu 100% Hepatosplenic 1 0 n/a n/a Nasal/nasal type T/NK cell 1 1 1 CRu 100% Subcutaneous panniculitic T-cell 1 1 1 PR 100%
Toxicities have generally been grade 1–2, were transient, and caused few dose modifications. The most common have been fatigue (62%), nausea (44%), anemia (38%), sensory neuropathy (33%), hypoalbuminemia (33%), elevated ALT (30%), dyspnea (28%), thrombocytopenia (30%), leukopenia (28%), fever (25%), elevated AST (25%), lymphopenia (25%), and hyperglycemia (25%). Forty-three percent (17/40) of patients experienced one or more grade 3–4 hematological toxicities and 40% (16/40) of patients experienced one or more grade 3–4 non-hematological toxicities. Five patients discontinued the study due to AEs, all occurring prior to Cycle 2, for: infusion-related anaphylaxis; elevated LFTs; port-related staph sepsis; pneumonia; and a death possibly resulting from tumor lysis syndrome and rhabdomyolysis.
Conclusion: The combination of Dd plus CHOP has a generally manageable safety profile and to date has exhibited promising clinical activity in PTCL.
HIV-Associated NK/T-Cell Lymphomas: A Review of 93 Cases.
Authors: Castillo Jorge , Pantanowitz Liron 
Published: October 2019

Abstract
Introduction: NK/T-cell lymphomas (NKTCL) are being reported with increased frequency in HIV-infected patients in the HAART era. However, there has been no comprehensive review of these emerging HIV-associated lymphomas. We present, to our knowledge, the first comprehensive review of the epidemiology, clinical and pathologic features, therapeutic options, and outcome in HIV-associated NKTCL.
Methods: A total of 93 cases of NKTCL in HIV-infected individuals were identified in a literature review using PubMed and cited articles from 1996 until March 2007. Data regarding epidemiology (country), demographics (age, gender), clinical features (presentation, tumor location), HIV status (CD4, AIDS-defining illness, coinfections), lymphoma (WHO/EORTC subtype, immunophenotype, Ann Arbor stage), treatment, and outcome were extracted.
Results: Cases were reported worldwide (USA, Europe, South America, Asia), with a 15x increased incidence compared to the general population. Patients were of median age 38 years (range 1–63) at presentation, exhibited a 4:1 male predominance, and had a median CD4 count of 184 cells/mm3. Up to 54% had a prior AIDS-defining illness. The most common clinical findings were lymphadenopathy, B symptoms, erythroderma and pruritus. All subtypes were noted including Peripheral T-cell (n=36), Cutaneous T-cell including Mycosis fungoides (n=25), Anaplastic Large Cell (n=13), Adult T-cell Leukemia/Lymphoma (n=8), NK cell (n=4), and other lymphomas (2 AILD, 2 Enteropathy-associated, 1 PEL, 1 Intravascular). Most expressed CD45RO and CD3 antigens, CD4>CD8, CD30 in a subset (n=23), and EBV was detected in 20 cases (mainly extranodal PTCL, cutaneous ALCL, and NK cells). Most (74%) were extranodal (50% involving skin) and 26% nodal. Staging (60 patients) overall showed stage I (27%), II (3%), III (17%), and IV (53%).There was no standard therapeutic approach, with 46% given one modality, 17% multimodal treatment, and 12% were untreated in reported cases. HAART was rarely used. Death occurred in 55% of patients and median overall survival (83 patients) was 1.1 years from the time of diagnosis.
Conclusions: NKTCL afflicted HIV-infected persons are likely to be young males with AIDS who have a CD4 count under 200 cells/mm3 at presentation. They are also prone to present with extranodal disease, skin involvement, and at an advanced stage. Although a standard treatment approach is still required, the prognosis of HIV-associated NKTCL remains poor. The role of HAART needs to be further explored.
Pax5 Activates Oncogenic Transcription Factors of the Ets Family by Repressing the mir-15a/16-1 microRNA Cluster.
Authors: Chung Elaine Y. , Cozma Diana , Yu Duonan , Dews Michael , Wentzel Erik A. , Chang Tsung-Cheng , Mendell Joshua T. , Thomas-Tikhonenko Andrei 
Published: October 2019

Abstract
We have recently demonstrated that Pax5 promotes B-lymphomagenesis by upregulating key components of B-cell receptor signaling [Cozma et al, J Clin Inv, 117 (8), 2007]. Gene regulation by Pax5 often involves complex formation with other oncogenic transcription factors of the Ets family, namely Myb and Ets1. We determined that expression of these proteins themselves depends on the presence of Pax5, as seen in human diffuse large B-cell lymphomas with Pax5 knockdown and murine lymphomas with epigenetic silencing of Pax5 [Yu et al, Blood, 101:1950–1955, 2003; Johnson et al, Nat Immunol, 5:853–861, 2004]. Upon reconstitution with the Pax5 gene, Myb and Ets1 levels increase sharply. This occurs with little increase in steady-state mRNA levels, suggesting post-transcriptional regulation, possibly by microRNAs. To test this hypothesis, we compared miRNA profiles of Pax5-deficieint and sufficient cells and discovered that several miRNAs are indeed repressed by Pax5. Among them is the miR-15a/16-1 cluster whose predicted targets include both Myb and Ets1. Consistent with this prediction, forced expression of miR-15a/16 brings down Myb and Ets1 protein levels. This is accompanied by impaired Pax5 function and overall suppression of B-lymphomagenesis. Thus, Ets family members (along with previously identified bcl-2) are key targets of the miR-15a/16 locus, a tumor suppressor in chronic lymphocytic leukemia.
Interplay between Pax5, Myb/Ets1, and miR-15a/16-1. (A) Upregulation of Myb and Ets 1 in tumors over-expressing Pax5ER fusion, as compared to control GFP-only neoplasms. (B) Down-regulation of Myb and Ets1 in Pax5 tumors engineered to over-express the miR-15a/16-1 cluster. All panels depict Western blotting. Interplay between Pax5, Myb/Ets1, and miR-15a/16-1. (A) Upregulation of Myb and Ets 1 in tumors over-expressing Pax5ER fusion, as compared to control GFP-only neoplasms. (B) Down-regulation of Myb and Ets1 in Pax5 tumors engineered to over-express the miR-15a/16-1 cluster. All panels depict Western blotting.
FLT3-ITD but Not FLT3-TKD Mutations Have Major Prognostic Impact in Normal Karyotype AML.
Authors: Schneider Stephanie , Schneider Friederike , Dufour Annika , Mellert Gudrun , Zellmeier Evelyn , Braess Jan , Bohlander Stefan K. , Feuring-Buske Michaela , Buske Christian , Fritsch Susanne , Heinecke Achim , Sauerland Maria C. , Hoster Eva , Unterhalt Michael , Berdel Wolfgang E. , Wormann Bernhard J. , Buechner Thomas , Hiddemann Wolfgang , Spiekermann Karsten 
Published: October 2019

Abstract
Background: Approximately 45% of AML patients have a normal karyptype (NK-AML) and an intermediate clinical prognosis. As only 20–42% of these patients show long-term survival, it is important to identify prognostic markers to distinguish patients’ outcome more precisely. Mutations in the FLT3 gene such as internal tandem duplications (ITD) in the juxtamembrane domain and point mutations in the tyrosine kinase domain (TKD) are the second most common abnormalties in AML patients. For FLT3-ITD it is well known that patients have an unfavourable prognosis. Up to now there are not enough reliable data to determine the prognostic impact of FLT3-TKD mutations.
Patients and Methods: We have investigated the prevalence of FLT3-TKD mutations in a cohort of 803 cytogenetically normal AML (NK-AML) patients and its possible prognostic significance. At diagnosis the mutation status of FLT3 (ITD and TKD) and the NPM1 gene were analyzed by routine molecular techniques.
Results: The median age of all patients was 60 years and the median observation time of survivors 23.2 months. Results of the mutation status’ of FLT3-ITD, FLT3-TKD and NPM1 were available in 757/803 (94.3%), 683/803 (85.1%) and 696/803 (86.7%) patients, respectively. FLT3-ITD, FLT3-TKD and NPM1 mutations were found in 222 (29.3%), 46 (6.7%) and 354 (50.9%) of all analyzed patients, respectively. We could not detect any influence of the FLT3-TKD mutation on OS (p= 0.753), RFS (p= 0.229), EFS (p= 0.835), CR (p= 0.168) and on d16 blast count (p= 0.696). In most patients FLT3-ITD and TKD mutations were mutually exclusive, although a minority of 8/674 patients (1.2%) carried both mutations. FLT3-TKD mutations were more frequently found in patients with NPM1 mutations compared to NPM1-negative patients (9.04% vs. 3.74%; p= 0.008). In contrast to FLT3-ITD mutations FLT3-TKD mutation had no prognostic impact in NPM1 positive AML cases.
Conclusions: In our study in a large cohort of 803 NK-AML patients we could not detect any prognostic impact of FLT3-TKD mutations. Although FLT3-ITD and TKD mutations have both transforming potential in vitro and in vivo mouse models, the clinical impact of both mutations shows striking differences. Further studies with FLT3-PTK inhibitors will clarify the pathogenetic relevance of these mutations in AML.
Prevalence and Prognostic Impact of KIT Mutations in Acute Myeloid Leukaemia with Inv(16). A Retrospective Study.
Authors: Cairoli Roberto , Beghini Alessandro , Ripamonti Carla B. , Grillo Giovanni , Nadali Gianpaolo , Di Bona Enrico , Colapietro Patrizia , Nichelatti Michele , Bertani Gianbattista , Ravelli Erika , Cuneo Antonio , Ottaviani Emanuela , Pioltelli Pietro , Ferrara Felicetto , Lazzarino Mario , Rossi Giuseppe , Rodeghiero Francesco , Pizzolo Giovanni , Martinelli Giovanni N. , Morra Enrica 
Published: October 2019

Abstract
Introduction Several studies have recently pointed out the adverse impact of KIT mutations (mutKIT) on relapse incidence (RI) and overall survival (OS) in AML pts with t(8;21). By contrast, the prognostic significance of mutKIT in pts with inv(16) remains unclear. Purpose of this study is to evaluate the prevalence and the prognostic impact of mutKIT in inv(16)(p13q22).
Patients and Methods Fifty adults with inv(16) AML at diagnosis (median age 46.6 yrs, range: 17–88; M/F: 30 /20), were centrally analyzed for mutKIT in exon 2, 8, 10, 11 and 17. Mutations were detected using sequencing and other sensitive assays such as ARMS (amplification refractory mutation system) PCR for D816Y and D816H and enzymatic digestion with HINFI for D816V and with Tsp509I for N822K.
Results Data showed a prevalence of KIT mutation of 34% (17/50 pts). Among the mutKIT cases, we detected mutations in exon 17 (n=12), exon 8 (n= 4) and exon 10 (n=1). There was no difference between the mutKIT vs the unmutated (KIT-) patients in the median of WBC count at presentation (WBC 13.9 x109/L, range 4.4 to 277.5 vs 19.4 x109/L, range 2.5 to 130; Mann-Whitney U test: p = 0.649). Of the 42 patients (age < 60 years) who received intensive chemotherapy, 13 resulted mutKIT upon mutational screening. Complete remission (CR) was achieved in 13/13 (100%) mutKIT vs 27/29 (93%) KIT- patients (Fisher’s exact test: p > 0.999). At a median follow-up of 26 months (range: 2–144), 9/13 (69%) mutKIT and 8/27 (29%)KIT- pts relapsed;the Kaplan-Meier plots revealed KIT mutations to be a significant factor adversely affecting RI (log-rank test: p = 0.017) but not OS (61% in mutKIT vs 75% in KIT-;log-rank test: p = 0.331).
Conclusion KIT mutations are associated with a greater probability of relapse following CR, without affecting OS, in AML pts with inv(16) aged <60 years.
The Prognostic Significance of Complex Karyotype in Philadelphia Chromosome-Negative (Ph−) Acute Lymphoblastic Leukemia (ALL) in Adults Is Related with Risk Group.
Authors: Granada Isabel , Sancho Juan-Manuel , Oriol Albert , Morgades Mireia , Bethencourt Concepción , Parody Ricardo , Hernández-Rivas Jesús-María , Moreno Maria-José , Del-Potro Eloy , Tormo Mar , Rivas Concepción , Sanz Miguel-Angel , Grande Carlos , Bueno Javier , Abella Eugenia , Ortega Juan-José , Ribera Josep-Maria 
Published: October 2019

Abstract
Different from acute myeloblastic leukemia, the prognostic significance of complex karyotype (CK) is not well known in adults with ALL. A recent study showed that CK (≥5 chromosomal abnormalities) confer an increased risk of treatment failure and poor survival (Moorman, 2007). The aim of study was to analyze the possible prognostic influence of CK in Ph- adult (≥15yr) ALL patients treated with risk-adapted protocols from the Spanish PETHEMA Group. The cytogenetic studies were reviewed following the ISCN criteria (2005). CK was defined as the finding of 3 or more structural chromosomal abnormalities. Patients were included in three different trials: ALL-96 for standard-risk (SR) ALL, and ALL-93 or ALL-AR03 for high-risk (HR) ALL. Patients with Burkitt’s ALL were not included in these trials. Patients included: 237. SR: n=44, 25 males, WBC count 12x109/L (SD: 14), 5 patients with CK (11.4%), 39 non-complex karyotype and normal karyotype (non- CK) (88.6%). HR: n= 193, 107 males, WBC count 58x109/L (SD: 77), 25 patients with CK (13%), 168 non- CK (87%). Complete remision (CR), disease free survival (DFS) and overall survival (OS) according to karyotype group and trial are showed in Table: When CK was defined as the finding of ≥ 5 structural chromosomal abnormalities (n=11, SR=3, HR=8), DFS and OS were also significantly shortened in patients with SR ALL and CK (p=0.007 and p=0.001, respectively), but not in patients with HR ALL. Complex karyotype (defined as ≥ 3 or ≥5 structural chromosomal abnormalities) did not have any prognostic relevance in adults with high-risk Ph- ALL, whereas a significant short survival observed in standard-risk patients with complex karyotype.
Regulation of the New CXCR7 Receptor in Plasma Cell Dyscrasias.
Authors: Moreau Anne-Sophie , Leleu Xavier , Jia Xiaoying , Runnels Judith , Pitsillides Costas , Carlson Alicia L. , Ngo Hai T. , Roccaro Aldo M. , Azab Abdelkareem , Azab Feda , Lin Charles P. , Ghobrial Irene M. 
Published: October 2019

Abstract
Background: Multiple Myeloma (MM) and Waldenstrom Macroglobulinemia (WM) are characterized by widespread involvement of the bone marrow (BM) as the result of successful homing, engraftment and growth of tumor cells at that site. The receptor for SDF-1, CXCR4 has already been implicated by us and others in the migration and homing of tumor cells to the bone marrow. Recently, a new receptor for the chemokine SDF-1 has been described, namely CXCR7. To date, it has been implicated in the migration of embryonic cells during neurogenesis in zebrafish. It has been reported to be expressed in cancer cells but its function remains unknown. We have previously shown that disruption of the CXCR4/SDF-1 axis interferes with homing of MM cells to the BM. To better understand the homing and migration of MM and WM tumor cells, we sought to study the expression and function of CXCR7.
Methods: MM (U266, MM1.S, RPMI, OPM2, OPM1, KMS12BM) and WM (BCWM.1 and WSU-WM) cell lines were used. CD19+ and CD138+ cells were extracted from patient bone marrow samples by microbeads selection after informed consent. To determine the expression of CXCR7 on MM and WM cell lines as well as primary samples, we used flow cytometry and RT-PCR analysis. The migration of tumor cells towards SDF-1 was studied using the transwell boyden chamber migration assay. The adhesion of tumor cells to fibronectin using a fluorometric assay. The CXCR7 inhibitor CCX-754 (ChemoCentryx Inc., Mountain View, CA) was used.
Results: CXCR7 was expressed in all cell lines tested except WSU-WM by flow cytometry and RT-PCR. Interestingly, U266 cell line did not express surface CXCR4 and expressed CXCR7 and therefore was used in further experiments to determine the differential role of CXCR7 in SDF-1 related function. Primary WM (n=14) and MM (n=7) cells expressed low intensity CXCR7 by flow cytometry. Use of the above cells in experiments utilizing small molecule antagonists of both CXCR4 and CXCR7 suggested that inhibiting the binding of SDF-1 to one receptor could impact the signaling functions of the other. Experiments are ongoing to clarify the nature of the interaction between these two SDF receptors. Furthermore, adhesion of U266 cells to fibronectin was increased in presence of SDF-1, and inhibited in the presence of CCX-7754. Further analysis to examine CXCR7 and CXCR4 antagonism in adhesion are ongoing.
Conclusion: we showed for the first time CXCR7 expression on MM and WM tumor cells. Our results lead us to conclude that through binding of a shared ligand, CXCR7 and CXCR4 may modulate the biological activity of the other.