bluuebunny/crossref_metadata_2025_split huggingface dataset:
Early Response to a Short Course of Induction Chemotherapy Overcomes the Prognostic Role of IPI in Patients with Aggressive NHL. Preliminary Results of the GISL LA05 Trial.
Authors: Di Renzo Nicola , Luminari Stefano , Montanini Antonella , Petrini Mario , Brugiatelli Maura , Gobbi Paolo G. , Stelitano Caterina , Angrilli Francesco , Musso Maurizio , Baldini Luca , Mazza Patrizio , Pennese Elsa , Federico Massimo 
Published: October 2019

Abstract
The achievement of a clinical response to the first part of induction chemotherapy has been considered for predicting survival in patients with aggressive non Hodgkin lymphoma (NHL). In April 2000, the Gruppo Italiano Studio Linfomi (GISL) started the LA05 trial with the aim of assessing different treatment modalities according to response to 4 initial courses of chemotherapy (CT) assessed according to the international response criteria for NHL. Untreated Patients younger than 65 years with histologically confirmed diagnosis of aggressive NHLs were eligible to the study. All stages and all IPI groups were allowed. After 4 courses of CT patients achieving at least a PR >75% were to be treated with two additional courses of CT (group 1); those achieving PR <75% were randomized to receive either additional 4 courses of the same CT or a modified HDS program followed by autologous stem cell support (group 2); patients with SD or PD were to be assigned to salvage programs (group 3). The study CT regimen was ProMECE-CytaBOM; in July 2005, the protocol was amended allowing the use of other CT regimens, including CHOP and MACOP-B, and recommending the addition of Rituximab for B-cell NHL. D The study is still ongoing and we are not yet able to provide data about the efficacy of HDS in patients of group 2. We present the preliminary results of efficacy of the LA05 trial, in particular focused on the outcome of group 1 patients. As of June 2006, 341 patients were enrolled. Eighty percent of cases had DLBCL, 12% PTCL, 5% GIII FL and 3% MCL. Median age at diagnosis was 49 years (range 18–67). Sixty percent had stage III–IV disease and 38% had a bulky mass. IPI was low (0–1) in 52%, intermediate (2) in 22% and high (3+) in 26% of cases. After 4 courses of CT, 265 patients were evaluable for response; one-hundred and seventy patients (64%) achieved a CR or a PR >75%, 49 (19%) achieved a PR <75% and 46 (17%) had SD or PD. The probability of achieving a CR or a PR >75% was 74%, 62% and 42%, for patients with an initial IPI of 0–1, 2 or 3+. At the end of treatment program, a CR was achieved in 57% of cases and a PR in 14%. After a median follow-up of 21 months (range 1–73), the 2-year OS was 69% (IC 95% 62–75), being 85%, 65% and 25% for group 1, 2 and 3 respectively (p<0.001). Two-year OS was 88%, 78% and 78% for patient in group 1 with and IPI of 0–1, 2 and 3+ respectively (p=NS). The achievement of a CR or a PR >75% after the first part of initial CT overcomes the prognostic role of IPI in patients with aggressive NHL.
Toxicity and Risk Factors Contributing to Delayed Methotrexate (MTX) Elimination in Adult/Elderly Patients (pts) Treated with High-Dose Methotrexate Therapy (HDMTX), a 2-Year, Single Center Survey.
Authors: Schwartz Stefan , Martus Peter , Ludwig Wolf-Dieter , Arnold Renate , Ruhnke Markus , Korfel Agnieszka , Kopitzke David , Auton Tim , Thiel Eckhard 
Published: October 2019

Abstract
HDMTX is a well-established regimen used in a variety of neoplasms, including acute lymphoblastic leukemia (ALL) or lymphoma (NHL). Risk factors contributing to a delayed MTX-elimination and toxicity have been studied in pediatric pts with HDMTX (Relling MV, J Clin Oncol 1994, 12: 1667–72). However, data are scarce on risk factors contributing to delayed MTX elimination in adult pts, on toxicities in elderly pts and from pts treated with HDMTX outside clinical trials. We assessed toxicities and risk factors in all non-pediatric pts treated with HDMTX at the Charité in 2003/04. 141 pts (age 16–81y, median 44y) received 614 HDMTX cycles (median dose MTX/m2: 3000mg, range 320–12000mg) for ALL (39), NHL (38), CNS-NHL (36), sarcoma or other solid tumor (28) within (69) or outside (72) clinical trials. In 99/614 (16%) of HDMTX cycles a 15–85% (median 50%) dose reduction was carried out due to renal dysfunction (58), severe toxicity of prior chemotherapy (18) or other reasons (23). Toxicities in 62/614 (10%) HDMTX cycles caused delays of 1–50 days (median 7 days) of scheduled therapy. 61/614 (10%) HDMTX cycles resulted in an increase of serum creatinine values above the upper limit of normal (ULN) (median of 112μmol/L, range 81–386μmol/L). Delayed MTX-elimination (MTX blood level >150μM 24h, >3μM 36h, >1μM 42h, >0.4μM 48h or >0.1μM 68h) occurred in 156/614 (25%) HDMTX cycles. Grade 3/4 toxicities were recorded in 224 (36%) cycles for leukopenia, 127 (21%) cycles for liver toxicity, 116 (19%) cycles for thrombocytopenia, 88 (14%) cycles for fever with neutropenia and 63 (10%) cycles for mucositis/gastrointestinal toxicity. Presence of a 3rd space and comedications with known interference with MTX elimination or nephrotoxic potential were associated with a delayed MTX elimination (p<0.01). Overweight (BMI≥25kg/m2), urine pH<7 at some time after HDMTX and presence of a 3rd space were associated with an increase of serum creatinine values above ULN (p≤0.05). Pts with delayed MTX elimination or an increase of serum creatinine above ULN were older compared to pts with regular MTX elimination (median age 51y vs. 30y and 54y vs. 35y, p<0.01). Pts receiving HDMTX outside clinical trials more frequently experienced delayed MTX elimination (p<0.01). HDMTX frequently causes grade 3/4 hematotoxicity and increases of serum creatinine. Delayed MTX elimination is associated with advanced age and therapy outside clinical trials. Improved supportive care strategies are needed, especially in pts with advanced age, to ensure predictable MTX-elimination and reduce toxicities associated with HDMTX.
Phase II Study of Enzastaurin in the Treatment of Relapsed/Refractory Mantle Cell Lymphoma.
Authors: Morschhausser Frank , Wolf Martin , Seymour John , Tilly Herve , Pfreundschuh Michael , Kluin-Nelemans Hanneke , Raemaekers John , van’t Veer Mars B. , Milpied Noel , Cartron Guillaume , Pezzutto Antonio , Spencer Andrew , Darstein Christelle , Thornton Donald , Dreyling Martin , Reyes Felix 
Published: October 2019

Abstract
Protein kinase C beta (PKCβ), a pivotal enzyme in B-cell signaling and survival, has been identified as a therapeutic target in B-cell malignancies. Recent studies show that PKCβ is overexpressed in a majority of patients (pts) with mantle cell lymphoma (MCL). Other studies implicate overactivation of the PI3K/AKT pathway in the pathogenesis of MCL. Enzastaurin, an oral serine/threonine kinase inhibitor, suppresses signaling through PKCβ and the PI3K/AKT pathway to induce tumor cell apoptosis, reduce proliferation, and suppress tumor-induced angiogenesis. The primary objective of this phase II, single-arm, multicenter trial was to determine the rate of freedom from progression (FFP) for ≥3 cycles (1 cycle = 28 days). Secondary endpoints included objective response rate (complete + partial) and toxicity. Pts with previously relapsed/refractory MCL, with no more than 4 prior regimens of therapy, received 500 mg enzastaurin orally, once daily, until disease progression or unacceptable toxicity. A total of 60 pts (18 female; 42 male), median age of 66 years (range: 45–85), median international prognostic index of 2 (range: 0–5), and an Eastern Cooperative Oncology Group performance status of 0–2 were enrolled. All pts had CD20 + MCL and failed multiple prior therapies (median = 2, range: 1–5). Most pts had received CHOP-based chemotherapy and/or rituximab. All enrolled pts received at least 1 dose of enzastaurin and were included in the safety and efficacy analysis. Three pts discontinued due to adverse events possibly related to study drug (diarrhea, renal impairment, and syncope). There were no drug-related deaths or grade (Gr) 4 toxicities. No drug-related bone-marrow toxicities, except Gr 3 anemia (1 pt), were reported. There was 1 case each of drug-related Gr 3 diarrhea, dyspnea, vomiting, hypotension, and syncope. Fatigue (Gr ≤2) was the most common toxicity (n = 5). No objective tumor responses were recorded. 22 of 60 enrolled pts (36.7%, 95% CI: 24.5%–48.9%) were FFP for ≥3 cycles. Six of these pts, who had failed prior chemotherapy and/or immunotherapy, achieved stable disease for ≥ 6 months. One pt was FFP for 22 months, and 2 pts are still on treatment for 8+ and 12+ months, respectively. Although no objective tumor responses occurred, 6 pts were FFP for 6 to 22 months. Oral enzastaurin was well tolerated for extended durations, suggesting it may be used as continuous or maintenance therapy after induction therapy and warrants further investigation in MCL.
The VIP-ABVD Regimen Is Not Superior to the CHOP 21 for the Treatment of Non Epidermotropic Peripheral T Cell Lymphoma. Final Results of the “LTP95” Protocol of the GOELAMS.
Authors: Gressin Remy , Peoch Michel , Deconinck Eric , Casassus Philippe , Desablens Bernard , Senecal Delphine , Quitet Philippe , Vilque Jean Pierre , Foussard Charles , Eghbali Houchingue , Jaubert Jerome , Tournilhac Olivier , Lucas Virginie , Delwail Vincent , Choufi Bachera , Thyss Antoine , Huguet Francoise , Maloisel Frederic , Richard Bruno , Milpied Noel-Jean , Colombat Philippe 
Published: October 2019

Abstract
Introduction: There is non consensus today for the treatment of PTCL. The five years OS with the CHOP regimen is estimated to 40%. A five years OS of 65% have been expected with an alternating VIP/ABVD regimen in a cohort ot 58 patients (pts) retrospectively studied by the same institution in Grenoble FRANCE (results presented at the french haematology society in 2000).
Aim of the study and methods: To confirm the superiority of the VIP/ABVD in first line for pts with PTCL. We have compared the 2 years EFS of pts receiving 8x CHOP21 or 6 alternating VIP/ABVD in a random manner. The VIP/ABVD regimen consisted of an alternance of three VIP regimen (VP16 100 mg/sqm D1 to D3; Ifosfamide 1000 mg/sqm D1 to D5 and Cisplatinum 20 mg/sqm D1 to D5) and three ABVD (Adriblastin 50 mg/sqm, Bleomycin 10 mg/sqm, Vinblastin 10 mg/sqm and Deticene 375 mg/sqm D1 and D14). A 40 grays IF irradiation was systematically used for AA stage I-II and on the tumoral sites larger than 5 cm to complete the treatment plan.
Results: 100 pts were included and 88 retained after a centralized pathologic review. 57 pts were diagnosed as PTCLu, 15 LAI, 10 T and 4 NTNB anaplasic, 1 angiocentric and 1 NK type. 45 pts received the CHOP and 43 the VIP/ABVD.
53/88 pts (60%) achieved a CR (34) or PR&gt;75% (19). With a median Fup of 26.5 months EFS and OS are respectively 40% at 2 years and 40% at 4 y. There is no difference between the two groups. Two factors but not the IPI score have significantly influenced the survivals: histologic types (anaplasic vs no anaplasic) and AA stage (I–II vs III–IV).
Conclusion: The VIP/ABVD is not superior to the CHOP regimen for the treatment of PTCL. The combination Ann Arbor stage and the histologic pattern is the best predictive factor of the survivals. New innovative approach are mandatory to improve the prognostic of PTCL.
Imatinib Mesylate (Gleevec®) Is Active in Relapsed/Refractory Waldenstrom’s Macroglobulinemia: Planned Interim Results of WMCTG Clinical Trial 05-140.
Authors: Treon Steven P. , Soumerai Jacob D. , Patterson Christopher J. , Hunter Zachary R. , Villarreal Rose , Ghobrial Irene M. 
Published: October 2019

Abstract
Waldenstrom’s macroglobulinemia is a B-cell disorder characterized by the infiltration of lymphoplasmacytic cells (LPC) in the bone marrow (BM), along with an IgM monoclonal gammopathy. Characteristic of WM is an increased number of mast cells (MC) which are found in association with LPC, and stimulate LPC growth through several TNF-family members including CD40L, APRIL and BLYS (Ann Oncol17:1275; Blood104:917A). As such, we have targeted MC in WM. One important growth and survival factor for MC is stem cell factor (SCF), which signals through CD117. Imatinib mesylate blocks SCF signaling through CD117, and induces apoptosis of WM BM MC and LPC, both of which highly express CD117 (Blood2004; 104:314b). As such, we performed this Phase II study of imatinib mesylate in patients with relapsed and refractory WM. Intended therapy consisted of imatinib mesylate which was initiated at 400 mg po qD over the first month, and subsequently dose escalated to 600 mg po qD for up to 2 years. Dose de-escalation to 300 mg po qD was permitted for toxicity. Thirteen patients were enrolled and are eligible for evaluation at interim analysis. Median age was 64 (range 53–80 years), and median prior therapies was 2 (range 1–5). Nine and four patients had relapsed and refractory disease, respectively. Following a median of 3 months of therapy, median serum IgM levels for all evaluable patients declined from 3190 (range 763–8130 mg/dL) to 2095 (range 695–7340 mg/dL) at best response (p=0.009). On an intent to treat analysis, 6/13 (46.2%) of patients attained a ≥25% decrease in serum IgM. Responses were prompt, and occurred at a median of 2.5 months. Overall, therapy was well tolerated with ≥grade 2 toxicities as follows: anemia (n=4); edema (n=3); hyperglycemia (n=2); leukopenia (n=2); thrombocytopenia (n=1); neutropenia (n=1); and resulted for 4 patients in dose modification (n=4) or treatment cessation (n=3). The interim results of this study demonstrate that imatinib mesylate is an active and well-tolerated salvage therapy for WM.
NF Kappa B as a Therapeutic Target in AML.
Authors: Jenkins Christopher , Pepper Chris , Mills Ken , Burnett Alan 
Published: October 2019

Abstract
NF Kappa B is an inducible transcription factor that regulates the expression of a large number of genes essential for the normal immune and inflammatory responses. However, inappropriate NF Kappa B expression has been implicated in a number of malignancies. In this study, a two fold increase in NF Kappa B1 expression in AML samples, as compared to normal cell populations was shown by Affymetrix gene array. In addition, constitutive activation of the p65 protein component of NF Kappa B was demonstrated by ELISA in 70% of nuclear extracts derived from primary AML samples. In comparison there was no constitutive activation in the normal marrow samples tested. Elevated levels of AML nuclear p65 were inverse correlated with the proportion of cells undergoing spontaneous apoptosis, indicating that increased basal activation of NF Kappa B confers a cytoprotective effect on primary AML blasts. This data strongly suggest that NF Kappa B is a potential therapeutic target in AML. Consequently, the effects of the novel NF Kappa B inhibitor, LC1, were investigated in AML cells in-vitro. Leukemic cells were treated with LC1, at a range of 0.002 – 20mM, and the LC50 values for each sample were determined by MTS assay. The AML cell lines NB4, HL60 and U937 were also evaluated in the same way and demonstrated LC50 values of 2.98, 7.5, and 5.9 μM respectively. K562 cells were remarkably resistant to LC1, and were also shown to have the lowest NF Kappa B expression by Affymetrix gene array. Primary diagnostic AML (n=48) samples were analysed and an LC50 range of between 0.61μM and >100μM was detected with a median of 6.9μM. Annexin V and cell cycle analysis confirmed increased apoptosis as the mode of cell death. A time- and dose-dependent reduction in nuclear p65 NF Kappa B protein levels by LC1 was proven by ELISA. This preceded the induction of apoptosis, demonstrating that the inhibition of nuclear p65 NF Kappa B was not simply a result of cell death. The levels of NF Kappa B expression were correlated with the LC1 in-vitro LC50 response, demonstrating a significant inverse relationship. In addition, the downstream consequences of LC1-induced NF Kappa B inhibition were shown with a decrease in cytokine expression as demonstrated by cytokine array. The potential for synergy between LC1 and the conventional chemotherapeutic agent Ara-C and the proteasome inhibitor Velcade were also measured. Synergy was demonstrated in 60% of cell samples with Ara-C, and 80% with Velcade. This study suggests that LC1 is a potentially useful novel agent for the molecular therapy of acute myeloid leukemia.
The IGF1-R Inhibitor AEW541 Is a Potent Anti-Myeloma Agent That Overcomes Drugs Resistance, and Has Synergistic Activity with Other New Drugs.
Authors: Maiso Patricia , Ocio Enrique M. , Garayoa Mercedes , Pearson Mark A. , Pandiella Atanasio , Miguel J.F. San 
Published: October 2019

Abstract
Multiple myeloma (MM) represents an incurable disease for which development of new therapies is required. Here we report the effect on myeloma cells of AEW541, a new small molecule, belonging to the pyrrolo[2,3-d] pyrimidine class, identified as inhibitor of the IGF-1R in vitro kinase activity. AEW541 showed a potent antimyeloma activity (IC50 <4.5 μM) on MM cell lines both sensitive (MM1S, U266, OPM2, RPMI8226) and resistant (MM1R and U266LR7) to conventional chemotherapeutic agents. In fresh cells from five MM patients a marked antitumor activity was confirmed. AEW541 showed a synergistic effect with dexamethasone and lenalidomide, while it was additive with melphalan and bortezomib. Moreover the triple combination of AEW541, bortezomib and dexamethasone showed even higher anti-MM activity. Gene expression profiles of MM1S cells identified a total of 967 genes to be significantly deregulated (transcriptional changes in gene expression of 2-fold or greater) by treatment with AEW541. The classification of these genes according to functional categories indicated that 3.5% were involved in apoptosis/responses to stress and 13% in the control of cell cycle/proliferation. By Western analyses, we observed that AEW541 affected genes involved in cell cycle and cell death pathways. AEW541 blocked cell cycle progression, and this was accompanied by p27, up-regulation and pRb, CCND1, CCNA and CCNE downregulation. AEW541 induced cell death through an increase in the mitochondrial outer membrane permeability and provoked DNA fragmentation. AEW541 induced apoptosis and at late time points, also activated caspases 8,9 and 3. The pan-caspase inhibitor Z-VAD-FMK only slightly decreased the sensitivity to AEW541. In addition, AEW541 stimulated a caspase-independent pathway, through the release of AIF and Endonuclease G from the mitochondria. It is therefore conceivable that both caspase dependent and independent pathways are activated by AEW541 in MM cells, although the effect of AEW541 on cell cycle arrest is an earlier and more potent event. Finally, AEW541 was able to overcome the protective effect that confers IL-6, IGF-1 and BMSCs to myeloma cells in a dose dependent manner. All these data indicate that AEW541 could be a useful drug for the treatment of MM patients, particularly in combination with other novel agents such as bortezomib or lenalidomide together with dexamethasone.
Pharmacogenetics of Response to Glucocorticosteroids in Adults with Acute Lymphoblastic Leukemia.
Authors: Jamroziak Krzysztof , Balcerczak Ewa , Szemraj Zofia , Salagacka Aleksandra , Grzybowska-Izydorczyk Olga , Cebula Barbara , Szemraj Janusz , Mirowski Marek , Robak Tadeusz 
Published: October 2019

Abstract
Glucocorticoids are crucial components of standard chemotherapy regimens used for the treatment of adult acute lymphoblastic leukemia (ALL). However, little is known on significance of the inherited genetic background for response to steroids in adult ALL. We hypothesized that functional single nucleotide polymorphisms (SNPs) in genes important for steroid pharmacokinetics and pharmacodynamics may contribute to sensitivity or resistance to steroids. In this study we investigated whether analysis of common functional SNP in drug transporter P-glycoprotein gene (MDR1 or ABCB1), phase I cytochrome P450A metabolizing enzymes genes (CYP3A4 and CYP3A5) and glucocorticoid receptor gene NR3C1 can be useful to predict response to induction chemotherapy and survival of adult ALL patients. Sixty-two uniformly treated adult ALL patients were investigated for 6 common SNPs affecting steroid pathway including MDR1 exon 26 C3435T, CYP3A4*1B, CYP3A5*3, CYP3A5*6, NR3C1 bcl I and NR3C1 N363S polymorphisms. Genotypes were identified using direct sequencing or restriction fragment length polymorphism (RFLP) method. In the genotyped cohort 60% patients achieved complete remission after first induction chemotherapy. The analysis of the prognostic impact of the genotyped SNPs on treatment response showed that carriers of the glucocorticoid receptor NR3C1 gene 363S allele had a significantly greater probability of achievement of complete remission as compared to the non-carriers, odds ratio(OR)=1.23, 95% confidence interval (95%CI) = 1.02 −1.47, p=0.042). None of the analyzed polymorphic variants showed significant impact on probability of progression-free and overall survival of the included patients. In conclusion, we found that glucocorticoid receptor NR3C1 gene N363S polymorphism contributes to the response to steroids in patients with adult ALL. Inherited functional polymorphisms in pharmacokinetic pathways of anti-leukemic drugs should be considered as determinants of response potentially useful for individualization of chemotherapy of adult ALL of in the future.
Oxidative Stress in Red Blood Cells, Platelets and Polymorphonuclear Leukocytes from Patients with Myelodysplastic Syndrome.
Authors: Fibach Eitan , Ghoti Hussam , Amer Johnny , Winder Asher , Rachmilewitz Eliezer 
Published: October 2019

Abstract
Myelodysplastic syndrome (MDS) is characterized by refractory cytopenias due to ineffective hematopoiesis. Some patients with severe anemia require multiple blood transfusions and develop iron overload. Consequently, reactive oxygen species (ROS) are generated concomitant with a decrease in cellular antioxidants such as reduced gluthatione (GSH). The generated oxidative stress contributes to cell damage, apoptosis and ineffective hematopoiesis.
Using flow cytometry, we measured the oxidative state of RBC, platelets and PMN in 14 low-risk MDS patients and 25 normal donors. The results indicate that the majority of the patients had higher ROS in RBC (2.79-fold) and platelets (2.91-fold) and lower GSH in their RBC (3.4-fold) and platelets (2.1-fold) than normal (p<0.005). As for PMN, there were no significant differences in ROS, although GSH was significantly (p<0.1) lower in MDS compared with normal donors. The oxidative stress in MDS cells could be ameliorated by a short in vitro treatment with the iron-chelators deferrioxamine and deferiprone, or with the anti-oxidant N-acetylcysteine. These results suggest that the decrease in transfusion requirements with increase in platelet and PMN counts in MDS patients treated with deferrioxamine may be due to indirect antioxidant effect of the iron chelator and suggest that treatment with a combination of iron-chelators and anti-oxidants might be more effective.
ROS generation and GSH content in MDS blood cells ROS generation and GSH content in MDS blood cells Effect of iron chelations and an antioxidant on the oxidative status of MDS cells Effect of iron chelations and an antioxidant on the oxidative status of MDS cells