bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lyposomal Doxorubicin (Caelyx), Cyclophosphamide - Rituximab (DC-R) Plus GM-CSF as a Salvage Therapy in B-Diffuse Large Cell Lymphoma (B-DLCL) after Autologous Stem Cell Transplantation (ASCT) Failure.
Authors: Olivieri Attilio , Montanari Mauro , Capelli Debora , Scortechini Ilaria , Gini Guido , Trappolini Silvia , Leoni Pietro 
Published: April 2020

Abstract
B-DLCL patients after ASCT failure have a very poor prognosis, salvage chemotherapy or a second transplantation cannot substantially modify the very poor outcome which is characterized by a median overall survival (OS) of 3 months. We recently demonstrated the feasibility of chemoimmunotherapy after ASCT by associating a CHOP-modified schedule+Rituximab and GM-CSF, but often the antracycline retreatment in these patients can be hampered by the risk of severe cardiac damage or by a reduced organ reserve. For this reason we adopted a modified version of this protocol for patients receiving a previous Doxorubicin cumulative dose&gt;300 mg/sm, with the substitution of conventional antracycline with a Lyposomal Pegylated Doxorubicin (DC-R schema); the other inclusion criteria were: diagnosis of B-DLCL CD20+, P.S (WHO)= 0–2, age &lt; 75 years, relapse or progressive disease (PD) after ASCT, measurable disease, absence of severe organ dysfunction and CNS involvement. Seventeen patients were eligible for this salvage protocol; the median age was 47 (28–73) years; the P.S. (WHO) was 0–1 in 11 patients and 2 in six; the disease status after ASCT was: untested relapse in 14 cases and PD in 3 cases. The DC-R + GM-CSF schema (every three weeks) consisting in: R 375 mg/sm day 1 and 15, Caelyx 30 mg/sm and cyclophosphamide 750 mg/sm day 1, GM-CSF 150 mg/day from day 5 until neutrophils recovery. Patients showing disease progression after two courses were excluded while the responders received two more coursesof DC-R+GM-CSF; patients achieving complete remission (CR) after 4 courses did not receive any further treatment. All the17 patients received the planned treatment and were evaluable for response: the overall response rate (ORR) was 58.8% with 10 CR (58.8%), 7 patients showed a PD after 1–2 courses. The toxicity (WHO) consisted in: grade III–IV neutropenia in 11 patients (64.7%) and thrombocytopenia in 2 patients (23.5%), grade I–II infections in 2 patients and grade IV (pneumonia) in one patient. With a median follow up of 15 (1–74) months, 8 out of 10 responders patients are alive and in CR with a median disease-free survival of 24.5 (8–70) months, one patient is alive and in relapse at + 23 months and 1 patients died for infection months after while in CR. Our experience shows that DC-R + GM-CSF is an effective salvage treatment for B-DLCL after ASCT failure; indeed the follow up &gt; 12 months in 5/17 (29.4%) patients in CR suggests a chance of cure.
The Role of Antiviral Treatment in Hepatitis C Virus (HCV)-Related Non-Hodgkin Lymphoma: An Update of a Multicenter Study.
Authors: Vallisa Daniele , Bernuzzi Patrizia , Arcaini Luca , Lazzaro Antonio , Trabacchi Elena , Anselmi Elisa , Arcari Anna Lisa , Moroni Carlo , Berte Raffaella , Malingher Alessandro , Lazzarino Mario , Cavanna Luigi 
Published: April 2020

Abstract
HCV is largely, although not homogenously, diffuse in North-western Europe and U.S.A. It has been shown to play a role both in hepatocellular carcinoma and in B-cell non-Hodgkin lymphoma (B-NHL). Up to now the exact biological mechanisms that could explain the lymphomagenic role of the virus are unknown. We have previously published a series of 13 patients, affected by low grade B-cell NHL and characterized by an indolent course (i.e. doubling time less than 1 year, no bulky disease), who underwent antiviral treatment only with peghilated interferon and ribavirin (peghilated interferon 50–70 microgram weekly, ribavirin 1000–1200 mg daily). Now we report an update of this study. Up to now we were able to evaluate 16 patients with a mean follow up of 15,1± 7,6 months (range 2–28 months). Eight patients experienced complete or good partial haematological response that has lasted up to now with a mean follow up of 16,5 months, among them 3 splenic marginal lymphomas, 2 nodal marginal, 1 follicular lymphoma, 1 plasmocytoid and 1 marginal extranodal lymphoma. Three other patients achieved a long lasting partial response.
The only one relapse (marginal nodal lymphoma) occurred about one year after the end of treatment, hematological relapse happened together with viral relapse, the lymphoma reappeared as highly chemo resistant high grade lymphoma, and two months later the patient died. Interestingly complete and good partial responses were more likely to be seen in viral genotype 2 (p=0.035) and were strictly related to the decrease of viral load under treatment (p=&lt;0.001). Toxicity causes the stop of the treatment in 3 patients; however one of them was able to achieve complete hematological response. Time to achieve hematological response was quite long (mean 8± 4,5 months).
This kind of experience strongly provides a role for antiviral treatment in patients affected by HCV related low grade B-cell NHL. Especially viral genotype 2 infection may be considered a good prognostic marker for hematological response as well as decrease of viral load under treatment. Toxicity in our hands was however significant and further experiences are warranted in order to better modulate antiviral therapy doses.
Prospective Randomized Comparison of High Dose AraC and Autologous Peripheral Blood Stem Cell Transplantation as Late Consolidation for Patients ≤60 Years with Standard Risk AML.
Authors: Ganser Arnold , Krauter Jürgen , Hoelzer Dieter , Ottmann Oliver , Martin Hans , Lübbert Michael , Finke Jürgen , Heit Wolf , Fiedler Walter , Kanz Lothar , Schlimok Günter , Kirchner Hartmut , Raghavachar Aruna , Brossart Peter , Brugger Wolfram , Heil Gerhard 
Published: April 2020

Abstract
484 patients aged ≤60 years with de novo (n=385) or secondary (n=99) acute myeloid leukemia (AML) were treated with risk-adapted therapy. Patients with t(8;21), inv(16) or normal karyotype and good response (GR) to induction I (≤5% blasts in day 15 BM) were considered standard risk (SR), all others as high risk (HR). Induction I consisted of standard dose araC, idarubicine and etoposide (IVA-I). Patients with GR to IVA-I continued with IVA-II on day 21 as double induction. Patients with bad response (&gt;5% blasts in day 15 BM) received FlAG/Ida as second cycle. Double induction was followed by early consolidation with intermediate dose araC. As late consolidation, SR patients with normal karyotype and an HLA-matched sibling received matched related donor (MRD) transplantation. The remaining SR patients were randomized between high dose araC (HD-araC; 12 x 3g/m2)/daunorubicine or an autologous peripheral blood stem cell transplantation (autoPBCSCT) with PBSC mobilized after early consolidation. 90% of SR patients (n=250) achieved complete remission (CR) in contrast to 58% of HR patients (n=234) (overall CR rate 75%). 4% of the SR patients died during induction. At 70 months, overall survival (OS) was significantly better for SR (51%) than for HR patients (28%). Within the SR group, relapse free survival at 50 months was not different between patients with normal karyotype (n=165), inv(16) (n=30) or t(8;21) (n=30). 55 SR patients were randomized to receive HD-araC and 59 to autoPBSCT. Distribution of the main characteristics were well balanced (age, performance status, cytogenetics, FLT3 mutation status, de novo or secondary AML). At 63 months, OS was 62% for patients treated with autoPBSCT and 59% for those receiving HD-araC (p=0.91, intent-to-treat). Median duration of neutropenia (&lt;500/μl) was 8 days for autoPBSCT and 20 days for HD-araC (p&lt;0.05). This corresponded to a significantly higher rate of septicemia (20% vs. 10%) and pneumonia (13% vs. 3%) after HD-araC. The duration of thrombocytopenia was 22 days after HD-araC and 11 days after autoPBSCT (p&lt;0.01). 14 patients died in the HD-araC group (4 in CR and 10 from relapse) and 14 patients died after autoPBSCT (1 in CR and 13 from relapse). In patients with normal karyotype, OS at 67 months for the SR patients receiving MRD transplantation (n = 37) was 61% with no significant difference to HD-araC or autoPBSCT. In conclusion, OS is similar in SR AML patients after autoPBSCT, HD-araC or MRD transplantation. In SR patients without an HLA-identical sibling donor, autoPBSCT instead of HD-araC is recommended for late consolidation due to the reduced treatment related toxicity.
Increased Expression of Insulin-Like Growth Factor I Is Associated with Ara-C Resistance in Leukemia.
Authors: Abe Shori , Harigae Hideo , Funato Tadao , Kameoka Junichi , Takahashi Shinichiro , Kaku Mitsuo , Sasaki Takeshi 
Published: April 2020

Abstract
Cytosine arabinoside (Ara-C) is one of the most common drugs used in the treatment of acute myeloid leukemia (AML). Therefore, the resistance to Ara-C is a major obstacle to improvement of the cure rate of AML. However, the molecular mechanism for Ara-C resistance has not been fully understood. In order to investigate the mechanism involved in Ara-C resistance, the gene expression profile of Ara-C-resistant human K562 leukemia cells (K562/AC cells) was compared with that of the Ara-C-sensitive K562 parental cells by using a cDNA microarray platform. Correspondence analysis demonstrated that the insulin-like growth factor I (IGF-I) gene was significantly upregulated in K562/AC cells. The increased expression of IGF-I in K562/AC cells was confirmed by quantitative RT-PCR (RQ-PCR). We then studied the biological significance of IGF-I upregulation in Ara-C resistance. First, K562/AC cells were treated by suramin, a nonspecific growth factor antagonist. The treatment with suramine reduced viability and induced apoptosis of K562/AC cells. Furthermore, the addition of IGF-I neutralizing antibody exhibited the same effect as suramine. Moreover, the IC50 of Ara-C sensitive K562 parental cells was increased by the addition of exogenous IGF-I ligand. These results strongly suggest that IGF-I-IGF-I-R pathway is directly involved in Ara-C resistance. Next, the activation status of phosphatidylinositol 3-kinase (PI3-kinase)/Akt pathway, which is the downstream of IGF-I-IGFI-R signal, in K562/AC cells was examined. Western blot analysis showed that the phosphorylation level of Akt is higher in K562/AC cells than K562 sensitive cells. In addition, LY294002, the specific inhibitor for PI3-kinase reduced the survival of K562/AC cells. Since activation of PI3-kinase/Akt pathway has been shown to exhibit an anti-apoptotic effect in tumor cells, it is possible that IGF-I induces Ara-C resistance by escaping from apoptosis through PI3-kinase/Akt pathway in an autocrine or paracrine fashion. Finally, the expression level of IGF-I was examined in 27 clinical samples by RQ-PCR. The results showed that IGF-I expression level was higher in leukemic cells in refractory or relapsed AML patients, who received Ara-C combined chemotherapy, than that at diagnosis. These results suggest that the inhibition of the IGF-I-IGF-I receptor pathway is a valuable therapeutic approach to overcome Ara-C resistance in AML.
Reversal of Rituximab-Resistant AIDS-B-NHL Clone to Chemotherapeutic Drug-Induced Apoptosis by Bortezomib and DHMEQ.
Authors: Vega Mario , Jazirehi Ali , Bonavida Benjamin 
Published: April 2020

Abstract
The mechanisms underlying the failure of B-NHL cancer patients to respond to treatment with rituximab, alone or in combination with chemotherapy, are not known. In efforts to address this issue, we have generated rituximab-resistant clones of the AIDS NHL cell line, (2F7RR). Recent findings have demonstrated that treatment of the wild type (wt) 2F7 with rituximab sensitized the tumor cells to various chemotherapeutic drug-induced apoptosis. Chemosensitization was the result of rituximab-mediated inhibition of the p38 MAPK signaling pathway and the selective inhibition of the anti-apoptotic Bcl-2 gene product (Vega et. al., Oncogene23:4993, 2004). Analysis of one clone, 2F7RR1, revealed that the cells have diminished surface CD20 expression and failed to respond to CDC and to apoptosis following cross-linking. In addition, the cells were resistant to rituximab-mediated chemosensitization. In contrast to wt2F7, molecular analysis of the 2F7RR1 clone revealed that rituximab failed to inhibit p-Lyn, p38-MAPK, BclXL, and Bcl-2. In addition, rituximab failed to inhibit the transcription factors NF-κB, YY1, SP-1, and STAT3. Noteworthy, 2F7RR1 exhibited higher resistance to drug-induced apoptosis compared to wt2F7 and showed overexpression of Bcl-2. Previous findings with the wt2F7 demonstrated that Bcl-2 was responsible for chemoresistance. Accordingly, we examined whether inhibition of Bcl-2 in 2F7RR1 can reverse chemoresistance. Since Bcl-2 is under the transcriptional regulation of NF-κB, we examined the effect of the NF-κB inhibitors Bortezomib and DHMEQ (DHMEQ was a kind gift from Dr.K. Umezawa Keio University, Japan) (Kikuchi, et al., Cancer Review, 2003, 63:107). The findings revealed that treatment of 2F7RR1 with these inhibitors resulted in the reversal of resistance to a number of chemotherapeutic drugs (examples: taxol, vincristine, ADR, CDDP, VP16, etc.). The chemo-sensitization by Bortezomib and DHMEQ was equivalent and the combination treatment of each of these inhibitors with the drug was synergistic. These studies present evidence that rituximab and drug-resistant tumor cells may be sensitized to chemotherapeutic drug-induced apoptosis via inhibition of NF-κB or Bcl-2. These findings also suggest that Bortezomib and DHMEQ may be clinically relevant in the treatment of rituximab and drug-resistant AIDS-B-NHL.
Microarray Analysis of Differentially Expressed Genes in Response to Retrovirally Mediated Overexpression of MDR1.
Authors: Maier Patrick , Herskind Carsten , Li Li , Laufs Stephanie , Zeller Jens W. , Fleckenstein Katharina , Wenz Frederik , Fruehauf Stefan 
Published: April 2020

Abstract
An important strategy for improving cancer therapy is the protection of healthy cells against therapy-induced damage. In this context gene therapy can complement radio- and chemotherapy in the treatment of tumours. Retroviral overexpression of P-glycoprotein (P-gp), the product of the MDR1 (multidrug resistance 1) gene, can deliver such a protective effect. P-gp possesses two relevant functions: its detoxifying effect acts as an efflux pump and could be important in high-dose chemotherapy, the anti-apoptotic effect of overexpressed P-gp could protect normal cells in tumour radio- or chemotherapy. The protection of haematopoietic stem cells in lymphoma, myeloma or solid tumor therapy is a promising candidate for this approach. However, little is known which other gene expressions might be influenced by MDR1-overexpression. Therefore we analyzed differentially expressed genes in the human lymphoblastoid cell line TK6 transduced with onco-retrovirus SF91m3 encoding MDR1 using the GeneChip Human Genome U133 Plus2.0 (Affymetrix). 61 annotated genes showed a significant change in expression (p&lt;10−4) in MDR1 overexpressing compared to control transduced (overexpression the neomycin resistance gene) and untransduced cells. We found that genes coding for detoxifying and exocytotis proteins (e.g. ABCB4, ALDH1A, unc13) were up-regulated. Furthermore several proapoptotic genes were down-regulated (e.g. Casp1, Casp4) with concomitant increased expression of antiapoptotic genes (e.g. Akt3). The differential expressions for several genes were verified with real-time PCR. The results confirmed the dependence of these gene regulations on MDR1 overexpression. The influence of MDR1/P-gp overexpression on apoptotic signalling and cell survival was further corroborated by reduced apoptosis rates in response to irradiation in SF91m3 transduced cells compared to the control cell lines. Our genomics results support the findings from other studies that overexpression of MDR1 confers protection against apoptotic stimuli. The multidrug resistance phenotype does not seem to be only due to high P-gp expression but also to other metabolic proteins. Our results could have important implications for MDR1-gene therapy in patients receiving chemotherapy regimens in combination with radiotherapy.
High Incidence of Myelodysplasia and Secondary Leukemia in the UK MRC Pilot Study of Autografting in Chronic Lymphocytic Leukemia.
Authors: Milligan Donald , Kochethu Geothy , Dearden Claire , Matutes Estella , MacConkey Christopher , Catovsky Daniel 
Published: April 2020

Abstract
In the MRC CLL Pilot Study of autografting conducted between 1996 and 2001 115 newly diagnosed patients were treated with a median of 6 cycles of fludarabine (range 3–8). In addition 26 patients received further treatment, mainly the addition of cyclophosphamide to fludarabine, CHOP or alemtuzumab, in order to achieve either CR, nPR or PR. Progenitor cells were mobilised with cyclophosphamide 2g/m2 and G-CSF. Sixty-five patients were autografted with cyclophosphamide and TBI conditioning or BEAM (20%). The median CD34 cell dose for transplanted patients was 2.6x106/Kg (range 0.75–3.9). Ten patients have subsequently developed AML/MDS at a median 3.5 years after starting treatment (range 2.5–7 years). Eight patients had undergone an autograft and 2 had received fludarabine alone and not proceeded to transplant. The actuarial risk of developing MDS/AML post autograft was 12.4% at 5 years (CI 0.7–24%). At the time of diagnosis of MDS/AML all the patients had either complex cytogenetics or/and deletion of chromosomes 5 or 7. These abnormalities were not detectable by FISH on the pre-transplant harvested material. Analysis of potential risk factors (age, stage of disease, previous treatment, cell dose, conditioning type) demonstrated only age as a possible factor (p&lt;0.05). This frequency of post transplant MDS has been reported in low grade lymphomas but not previously in autografts for CLL. We hypothesise that this patient population may be particularly at risk of secondary MDS/AML and that potential causative factors are fludarabine, a low cell dose and transplant conditioning.
Probability of developing MDS/AML after Tx Probability of developing MDS/AML after Tx
A Gene Polymorphism within the Kinase Domain of BCR-ABL and Its Effects on Sensitivity to Tyrosine Kinase Inhibitors.
Authors: Crossman Lucy C. , O’Hare Thomas , Lange Thoralf , Willis Stephanie G. , Stoffregen Eric P. , Corbin Amie S. , O’Brien Stephen G. , Heinrich Michael C. , Druker Brian J. , Middleton Peter G. , Deininger Michael W.N. 
Published: April 2020

Abstract
Background: Point mutations that impair drug binding are the most important mechanism of acquired resistance to imatinib. Mutations within the ATP binding loop (P-loop) of BCR-ABL are associated with a poor prognosis in patients on imatinib. We have identified a single nucleotide polymorphism at position 247 (numbering according to ABL-B) that leads to the replacement of lysine by arginine. In CML patients, either the lysine or arginine allele of amino acid 247 becomes part of the BCR-ABL fusion gene. Due to its close proximity to the P-loop, we decided to investigate the allele frequency of K247R and whether the presence of the arginine allele affected sensitivity of Bcr-Abl to Abl kinase inhibitors.
Patients and Methods: We investigated the frequency of the arginine allele of K247R in 157 patients with CML and 213 healthy blood donors by conventional sequencing, restriction enzyme digestion and single strand conformational polymorphism analysis. We used Abl autophosphorylation and substrate phosphorylation assays, immunoblotting and cellular proliferation assays to examine the influence of K247R upon imatinib and dasatinib sensitivity.
Results: We found that frequency of the arginine allele of K247R was 1.6% in patients with CML and 0.2% in the controls (P = 0.11). In one patient analysis of CD3+ and CD33+ obtained at the time of complete cytogenetic response revealed the presence of K247R in both cell compartments, consistent with a polymorphism. Three out of 5 patients with the arginine allele of K247R expressed in BCR-ABL failed to achieve a major cytogenetic response to imatinib, suggesting reduced drug sensitivity. However, in vitro assays showed no alteration in sensitivity to imatinib or dasatinib compared to “wild type”.
Conclusions: K247R is a rare polymorphism within the kinase domain of Abl. There is no evidence that K247R is more frequent in CML patients, and the presence of K247R does not affect drug sensitivity. It is important that clinicians are aware that K247R does not reflect a kinase domain mutation, and that its presence does not signal a need to change therapeutic strategy unless there are other signs of inadequate response to drug therapy.
Characterization of Gene Expression Associated with Cyclophosphamide Resistance in Chronic Myeloid Leukemia (CML).
Authors: Bao Fei , Nordberg Mary L. , Polk Paula , Sun Amanda , Murray David , Andersson Borje S. , Munker Reinhold 
Published: April 2020

Abstract
Cyclophosphamide (CP) is one of the alkylating agents collectively referred to as oxazaphosphorines that are used to treat many types of cancers including myeloid leukemia. Tumor cell drug resistance is an important factor for clinical treatment failure. The mechanisms of drug resistance are multifactorial and incompletely understood. KBM-7 human CML cell line was established from blast cells from a patient in the terminal phase of CML. In the CP resistance model, the B5-180 sub-line was isolated following exposure to the in vitro active CP analog 4HC. B5-180 cells were cross-resistant to busulfan and γ-radiation. Total RNA was extracted and hybridized to Affymetrix Genechip HG-U95Av2 arrays. Each array contains 12,386 probes corresponding to approximately 9000 known human genes. Each cell line was arrayed in triplicate. Quantitative RT-PCR, Fluorescence In-Situ Hybridization (FISH) and cytogenetic analysis were performed in both cell lines. Both the KBM-7/B5 parental line and B5-180 resistant sub-line expressed high-levels of BCR-ABL transcripts by real-time RT-PCR. FISH and cytogenetic analysis revealed multiple copies of t(9;22) translocation and other additional chromosomal abnormalities such as trisomy 8, and abnormalities of chromosome 18 in both cell lines. Gene array identified 794 gene transcripts that were more than twofold (range from 2-fold to 2675-fold) over-expressed or under-expressed in the resistant line relative to the parental line. ALDH1A1 (aldehyde dehydrogenase 1 family) showed the most differential expression between sensitive and resistant cell lines, ALDH1A1 was upregulated more than 2000-fold in the resistant sub-line. ALDH-2 (aldehyde dehydrogenase 2 family mitochondrial) was also expressed substantially higher in the resistant line. This finding is consistent with the established fact that elevated ALDH activity is an important factor in the resistance of B5-180 cells to 4HC. The remaining differentially expressed genes encode proteins with a wide variety of biochemical functions, which include 44 apoptosis and 7 anti-apoptosis-related genes, 56 genes related to cell cycle and cell growth, 6 DNA repair genes, 13 genes involved in hemopoiesis and B-cell activation. We also tested the expression of the hematopietic transcription factor PU-1 and PUB, a novel PU-1 binding factor. Interestingly, the expression of PU-1 was decreased and PUB increased in the resistant clone. In conclusion, we have identified a large number of differentially expressed genes in a CP resistant cell line derived from CML blast crisis by microarray technology. Our results suggest that CP resistance is a complex phenotype that involves multiple genes and a variety of mechanisms. Real-time RT-PCR analysis and further characterization of selected genes associated with CP resistance as well as the response in vitro to tyrosine kinase inhibitors are currently under investigation.