bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nordic Mantle Cell Lymphoma (MCL) Project: Prolonged Follow-Up of 86 Patients Treated with BEAM/BEAC + PBSCT Confirms That Addition of High-Dose Ara-C and Rituximab to CHOP Induction + In-Vivo Purging with Rituximab Increases Clinical and Molecular Response Rates, PCR-Neg. Grafts, Failure-Free, Relapse-Free and Overall Survival.
Authors: Geisler Christian H. , Elonen Erkki , Kolstad Arne , Laurell Anna , Andersen Niels S. , Pedersen Lone B. , Jerkeman Mats , Nordstroem Marie , Lauritzen Grete F. , Ralfkiaer Elisabeth , Aakerman Maans , Sundstroem Christer , Langholm Ruth , Karjalainen-Lindsberg Marja-Liisa 
Published: October 2019

Abstract
Methods: In the Nordic Lymphoma Group MCL Project newly diagnosed stage II-IV MCL patients < 66 years receive induction treatment and peripheral-blood stem-cell (PBSC) harvest, followed by BEAM/BEAC with PBSC support. In the MCL1 Protocol, the induction was maxi-CHOP x 3 (CTX 1200 mg/m2, doxorubicin 75 mg/m2, VCR 2mg D1, prednisolone 100 mg D1-5). Stem-cells were mobilised by maxi-CHOP + G-CSF. Because of the high failure rate in MCL1 (Figure 1) the MCL2 protocol was activated adding 2 series of high-dose Ara-C (3g/m2 BID D1-2) and 2 standard doses of rituximab (R) (375 mg/m2) to the induction program. Stem cells were mobilised by Ara-C + G-CSF + rituximab D1 + D9 for in-vivo purging. In both protocols patient-specific molecular markers were sought established before treatment start, and stem-cells and follow-up blood and bone-marrow samples assessed for MCL by PCR or flow cytometry.
Results: Table 1
Compared Results of the Nordic Lymphoma Group MCL1 and MCL2 Protocols
NORDIC MCL PROTOCOL # MCL1 (1997–2000) MCL2 (2000-) P value Supported by the Nordic Cancer Union No. of Pts included/eval. for response 42/42 120/88 Response pretransplant 31/42 86/88 0.002 CR/resp pretransplant 11/31 51/86 0.04 No. transplanted 27 86 Eval. for response posttransplant 27 82 CR/Response posttransplant 25/27 76/82 NS Molecular response posttransplant 5/13 38/42 0.0003 PCR-neg. stem-cell products (of tested) 2/16 22/25 0.00005 3-year failure-free survival (104 pts eval.) 24% 68% 0.0001 3-year relapse-free survival (RFS) 45% 76% 0.04 3-year molecular RFS survival ND 67% 3-year overall survival 60% 85% 0.02
Posttransplant maintenance treatment: In MCL2, patients in clinical stable response but molecular relapse are offered R 4 std. doses. So far, isolated molecular relapse occurred in 11 pts. of whom 10 received R: Four became PCR neg., one did not respond and later relapsed, five are not yet evaluable. Conclusion: By comparing MCL1 results with preliminary results of the still ongoing MCL2 study we conclude that the addition of HD Ara-C and R to the induction treatment significantly increases the
• clinical response rate pretransplant
• molecular response rate
• No. of tumor-cell free grafts
• failure-free, relapse-free and overall survival
Rituximab maintenance treatment can induce 2nd molecular remission, the clinical significance hereof still unknown.
Figure Figure
Preliminary Results of Sibling Donor Immunization with Patient-Derived Id-KLH Vaccine Prior to Reduced-Intensity Allogeneic Stem Cell Transplantation for Multiple Myeloma.
Authors: Bishop Michael R. , Neelapu Sattva , Fowler Daniel H. , Krumlauf Michael , Gress Ronald , Kwak Larry W. 
Published: October 2019

Abstract
Reduced-intensity allogeneic stem cell transplantation (RIST) results in significant reduction in treatment-related mortality for multiple myeloma (MM) patients (pts); however, success with RIST is limited by a significant risk of relapse. To reduce the risk of relapse, HLA-matched sibling donors were vaccinated with patient-derived idiotype (Id) conjugated to keyhole limpet hemocyanin (Id-KLH) prior to stem cell donation with the goal of transferring tumor antigen-specific immunity. MM pts with HLA-matched siblings underwent plasmapheresis prior to treatment to generate Id-KLH vaccine. After vaccine generation donors received 3 SQ injections of Id-KLH + GM-CSF at 10, 8, and 4 weeks before G-CSF mobilized blood stem cell collection. During vaccine generation and donor immunizaton, MM pts received an induction regimen of EPOCH-F (etoposide, prednisone, vincristine, cyclophosphamide, adriamycin, fludarabine) to achieve a minimal disease state and deplete host T cells in preparation for RIST. MM pts then received a reduced-intensity conditioning regimen consisting of fludarabine (30 mg/m2/d x 4d) and cyclophosphamide (1200 mg/m2/d IV x 4d) followed by allogeneic stem cell infusion. MM pts were then vaccinated with the Id-KLH+GM-CSF at 3, 4, and 6 months post-RIST. Both donors and MM pts were monitored for Id-specific humoral and cellular responses. Five MM pts (ages: 50–60 years; IgG = 4, IgA = 1) and their respective donors have been enrolled onto study. Vaccine was generated from all 5 MM pts. All 5 donors completed vaccinations without significant complications; there were no grade 3 or 4 toxicities. Most common toxicities experienced by donors were erythema, pain, induration and pruritus at sites of injection and diffuse arthralgias. Four MM pts have undergone RIST. There has been one treatment-related death (GVHD) at day +67. Two patients are in CR at 15 and 9 months post-RIST; the third patient is in a PR at 4 months post-RIST. KLH-specific immunity was induced in all of the first 3 donors tested, and Id-specific T cell immunity was induced in 2 of the first 3 donors. In donor-MM pt pair #2 there was evidence that Id-specific T cell immunity was induced in the donor (Figure 1) and passively transferred to the recipient with RIST (Figure 2). Id-specific T cell responses were blocked with HLA Class I and Class II antibodies. These preliminary data confirm that Id-KLH vaccines can be safely and effectively given to normal stem cell donors. More importantly, these data suggest that tumor specific immunity can be induced and passively transferred to the recipient after RIST. Vaccination of donors with tumor-specific antigen represents a tactic to potentially reduce relapse after RIST.
Sensitization of Rituximab-Resistant Ramos RR1 and Daudi RR1 Clones to Various Chemotherapeutic Drugs by a Novel Nuclear Factor-κB Activation Inhibitor.
Authors: Jazirehi Ali R. , Umezawa Kazeo , Bonavida Benjamin 
Published: October 2019

Abstract
Rituximab (chimeric anti-CD20 mAb) has been recently shown to signal NHL B-cell lines (e.g., Ramos and Daudi) and inhibits the constitutively activated NF-κB signaling pathway. This results in the selective downregulation of the anti-apoptotic Bcl-xL expression and sensitization to various chemotherapeutic drug-induced apoptosis (Jazirehi et al., 2004. Submitted). The novel NF-κB factor inhibitor, dehydroxymethyl derivative of epoxyquinomicin (DHMEQ), inhibits NF-κB activity via inhibition of nuclear (translocation) accumulation of p65 (Ariga et al., JBC 277:24625, 2002). This study examined the similarities and differences observed in wild type (wt) parental and rituximab-resistant Ramos and Daudi cells following treatment with either rituximab (20 mg/ml) or DHMEQ (10 mg/ml). In the wt cells, both agents inhibited NF-κB DNA-binding activity, down-regulated Bcl-xL expression and sensitized the cells to drug-induced apoptosis. Rituximab inhibited both the NIK—IκB-α—IKK—NF-κB and the Raf-1—MEK1/2—ERK1/2—AP-1 signaling pathways, while DHMEQ specifically inhibited NF-κB activity. We have generated rituximab-resistant Ramos and Daudi clones by continuous exposure of the cells to step-wise increasing concentrations of rituximab for several weeks and clones isolated by limiting dilution. The CD20+ expressing Ramos RR1 and Daudi RR1 clones were analyzed for their response to treatment with rituximab or DHMEQ. Compared to the wt cells, the resistant clones exhibited hyper-activation of the NF-κB pathway, increased expression of Bcl-xL, and higher resistance to structurally and functionally distinct drugs; their treatment with DHMEQ (15 mg/ml), but not with rituximab, inhibited the activity of the hyper-activated NF-κB, reduced the over-expressed Bcl-xL and sensitized the highly drug-resistant Ramos RR1 and Daudi RR1 clones to various chemotherapeutic drug (CDDP, ADR, VP-16, Taxol, etc.)-induced apoptosis. These findings demonstrate that DHMEQ can reverse the acquired drug-resistance phenotype in both parental and rituximab/drug-resistant NHL B-cell lines when used in combination with subtoxic concentrations of drugs. In vivo, DHMEQ inhibits subcutaneously transplanted prostate cancer xenografts in nude mice (Kikuchi et al., Cancer Res. 63:107, 2003). Consequently, the present findings suggest the potential therapeutic application of DHMEQ in combination with drugs, in the treatment of rituximab/drug resistant B-NHL.
Vascular Endothelial Growth Factor (VEGF)-Induced Endothelial Cell Migration Requires Urokinase Receptor (uPAR) for Integrin Redistribution.
Authors: Prager Gerald W. , Breuss4 Johannes M. , Brunner4 Patrick , Binder4 Bernd R. 
Published: October 2019

Abstract
VEGF activates endothelial cells to migrate and invade surrounding tissues, an initial event in the angiogenic process. For invasion, the coordinated localized formation of a proteolytic repertoir is necessary. Focusing the urokinase receptor towards the leading edge of migrating cells provides such armor and inhibition of uPA binding to its receptor inhibits invasion of endothelial cells. In addition integrins continuously have to form focal contacts at the leading edge. Thus the spatial proximity between the localized proteases and the matrix seems to be essential for matrix degradation. In order to allow cell locomotion integrins have to release their ligands when they reach the trailing end and are subsequently endocytosed and redistributed to newly formed focal adhesions in a repetitive process.
We here describe a new role of uPAR in regulating integrin redistribution. We have previously reported that stimulation of human endothelial cells by VEGF (50ng/ml) via its receptor flk-1 induces pro-uPA activation, when bound to uPAR. Subsequently a uPA/PAI-1/uPAR-complex is formed, which thereafter is endocytosed via a LDL-R family member. We now show that by this process beta-1 integrins are co-internalized in clathrin coated vesicles via a uPAR dependent mechanism. Subsequently, endocytosed uPAR recycles to focal adhesions where it co-localizes with integrin alpha-v/beta-3. Disrupting this chain of events, either by (1) RAP - a specific inhibitor of the LDL-R family - or by (2) uPAR depletion (using uPAR−/− cells or cleaving the GPI-anchor of uPAR by PI-PLC), beta-1 integrins are no longer internalized after VEGF stimulation. Under the same circumstances the migratory response of endothelial cells toward VEGF is impaired in vitro as shown by video-based migration assays and in vivo as demonstrated by matrigel angiogenesis assays. Next, we generated synthetic peptides interfering with uPAR/integrin interaction, which inhibit not only VEGF-induced integrin redistribution, but also diminish VEGF-induced endothelial cell migration, significantly.
These data suggest that in VEGF-induced cell migration uPAR plays a central role not only in focusing proteolytic activity, but also in initial integrin redistribution. Interference with this process could be a therapeutic target for diseases depending on VEGF-induced angiogenesis.
Improved Clinical Outcome and ADAMTS13 Activity Following Cyclosporine Therapy in Patients with TTP.
Authors: Cataland Spero R. , George James N. , Kraut Eric H. , Bourgeois Tran T. , Ferketich Amy K. , Kennedy Melanie S. , Caligiuri Michael A. , Wu Haifeng M. 
Published: October 2019

Abstract
Patients with a clinical diagnosis of TTP presenting to The Ohio State University were enrolled and treated on a prospective trial of concurrent plasma exchange (PE) and adjuvant immunosuppression.
Patients: Between April 2003 and August 2004, 15 patients were entered and followed on this study. The median age was 46 years (range, 19–59), 11/15 were female, 7/15 were African American, and 9/15 were obese (body mass index >30 kg/m2). Nine patients had been previously treated for TTP.
Method : All patients with TTP were treated initially with concurrent PE and corticosteroids. Daily exchanges of one plasma volume using cryosupernatant plasma were performed with concurrent prednisone at a dose of 1 mg/kg/day. PE was continued until a clinical remission was achieved as defined by: 1) normal platelet count 2) normalization of LDH for 2 consecutive determinations, and 3) improvement or stabilization of renal or neurologic abnormalities. After criteria for remission were achieved patients had 2 additional procedures performed every other day and the prednisone tapered over the next 4 weeks. Patients with exacerbations (defined as the need to reinstate PE within 30 days discontinuation) of TTP had prednisone discontinued and began oral cyclosporine (CSA) at a dose of 2–3 mg/kg/day orally concurrent with the resumption of PE. After achieving a second remission, PE was tapered as described previously and CSA was continued for a total of 6 months of therapy. Serial measurements of ADAMTS13 activity and inhibitor assays were obtained prior to the initiation of PE and at regular intervals during follow-up.
Results : ADAMTS13 data is available for the first 6 patients treated with PE + prednisone. A summary of clinical outcomes and ADAMTS13 activity may be found in Table 1. Of the patients suffering exacerbations after initial therapy with PE + prednisone, ADAMTS13 data is available from the first 2 of 5 patients treated with PE + CSA and is shown in Figure 1.
Clinical Responses and ADAMTS13 Activity
Inhibitor Remission Exac. Relapse Med. ADAMTS13-Pre Med. ADAMTS13-Remission Med. Remission (mo) * samples tested to date **median ADAMS13 PE+Pred. 5/6* 14/15 7/15 2/15 5% (range, 2-7%)** 5% (range, 2-7%)** 1(range, 1-9 ) PE+CSA 2/2* 5/5 0/5 0/5 Figure 1 Figure 1 6 (range, 3-10)
Conclusions : In this prospective study, no patients had significant improvement in ADAMTS13 activity despite achieving remission with PE and corticosteroids. These data showing persistently low ADAMTS13 activity at the time of remission may have contributed to the high rate of exacerbations in this group of patients. In the analysis of the first 2 patients treated with concurrent PE and CSA, there was clear and sustained improvement in ADAMTS13 activity that began after the discontinuation of PE and correlated with the clinical remission of TTP.
Figure Figure
Patterns of Care in a Random Population-Based Sample of Patients Diagnosed with CLL.
Authors: Davis Thomas A. , Clegg Limin X. , Stevens Jennifer L. , Harlan Linda C. 
Published: October 2019

Abstract
Over the past decade new drugs have significantly altered the treatment paradigm for patients with Chronic Lymphocytic Leukemia (CLL). Fludarabine, rituximab and alemtuzumab have established efficacy in CLL, but the patterns of disease presentation and course, and clinical intervention in general practice has not been captured. The Division of Cancer Control and Population Sciences (DCCPS) of NCI has conducted a population-based study of a stratified random sample of patients diagnosed with CLL in 1998 (n=470) who resided in the geographic areas covered by the Surveillance Epidemiology and End-Results program. Patients were followed through Dec, 2001. Logistic regression analyses were performed to study the potential factors that associated with the likelihood of receiving chemotherapy, therapeutic antibodies and/or splenectomy. Cox Proportional Hazards regression models were used to study the risk factors associated with survival time. Stages at diagnosis were 33%, 17%, 16%, and 33% for RAI 0, I/II, III/IV, and unstaged respectively. Early RAI stage was associated with younger age, private insurance, and non-Hispanic white race. Bone Marrow biopsy was performed at diagnosis in approximately 60% of patients, more frequent in patients with advanced stage. Therapy was given to 46% of patients during the follow up period, ranging from 12% for stage 0 to 80% for stage III/IV. 15%, 21% and 5% of patients received fludarabine, alkylating agents, and antibodies, respectively. Splenectomy was performed in 2.8% of stage I/II and 5.4% of stage III/IV cases. The multivariate analysis of receipt of therapy found stage, race/ethnicity, Charlson Comorbidity Score, and education were significantly associated with treatment. The average time from diagnosis to treatment was 3.1 months. Only 1.1% of patients participated in clinical trials. The most frequent reasons for therapy were symptoms, lymphadenopathy and elevated lymphocyte count (in 10–19% of patients stage 0 and III/IV respectively). Men were slightly more likely to be treated, more often with systemic therapy. Women were more likely to receive splenectomy. Blacks received therapy more often than whites or Hispanics even after adjusting for stage at diagnosis, comorbidity score, age, gender, marital status and education. In an analysis of survival, increasing age, advanced stage, minority race, being unmarried and treatment all were significantly associated with death. These data reflect an expected distribution of presentation and treatment for CLL in 1998. Notable, however, are the frequency of treatment based purely on lymphocyte count or lymphodenopathy, the frequency of antibody therapy when none were approved for this indication, the frequency of splenectomy and the impact of race on treatment and outcome.
Identification of Molecular Predictors of Response to ZARNESTRA™ (Tipifarnib, R115777) in Relapsed and Refractory Acute Myeloid Leukemia.
Authors: Raponi Mitch , Lowenberg Bob , Lancet Jeffrey E. , Harousseau Jean-Luc , Stone Richard , Rackoff Wayne , Thibault Alain , Zhang Yi , Atkins David , Wang Yixin 
Published: October 2019

Abstract
The orally available farnesyltransferase inhibitor (FTI) tipifarnib has demonstrated clinical efficacy in hematological disease. In an effort to identify patients with a higher likelihood of response, we have employed microarray technology to identify gene expression markers that predict response to tipifarnib. In an open label, single arm, Phase II study of patients with relapsed or refractory acute myeloid leukemia, tipifarnib was administered at a dose of 600 mg twice daily for the first 21 days of each 28-day cycle. Gene expression profiles from 80 bone marrow samples, collected before drug treatment, were analyzed on the Affymetrix U133A gene chip that contains approximately 22,000 genes. Statistical analyses were performed to identify genes that predict patient outcome following treatment with tipifarnib. Nineteen genes were selected because they showed significant differences in gene expression between the responder group and the non-responder group of patients. Several of these genes are associated with oncogenesis, cell proliferation, and FTI biology. One of the candidate genes, lymphoid blast crisis oncogene (oncoLBC or AKAP13), was over-expressed in patients who were resistant to tipifarnib. A leave-one-out cross validation (LOOCV) showed that the predictive value of this gene provided a sensitivity of 93% in identifying responders and a specificity of 61%, providing an overall diagnostic accuracy of 69%. In addition, supervised analysis identified a combination of 3 gene expression markers that together can potentially be used to predict patient response to the drug with the best overall accuracy of 74%. This 3-gene expression signature provided a sensitivity of 86% and a specificity of 70% in the LOOCV. In both instances, classification of patients using the gene expression signatures demonstrated significantly enhanced overall survival in those predicted to be responders. These data indicate that diagnostic gene expression signatures can potentially double the response rate to tipifarnib from 24% to 48%. The identification of these gene expression markers is an important step towards defining diagnostic signatures that could be used to identify AML patients who are likely to respond to tipifarnib and for understanding pathways that are affected by farnesyltransferase inhibition in AML.
Increasing the Number of Apheresis Collections Increases Lymphocyte Collection and Affects Survival after Autologous Stem Cell Transplantation for Non-Hodgkin Lymphoma.
Authors: Porrata Luis F. , Gastineau Dennis A. , Pineda Alvaro , Winters Jeffrey L. , Moore S. Breanndan , Padley Douglas J. , Bundy Kevin L. , Litzow Mark R. , Micallef Ivana N.M. , Inwards David J. , Ansell Stephen M. , Gertz Morie A. , Lacy Martha Q. , Dispenzieri Angela , Tefferi Ayalew , Elliott Michelle , Hogan William J. , Hayman Suzanne R. , Markovic Svetomir N. 
Published: October 2019

Abstract
Peripheral blood infused total autograft absolute lymphocyte count (A-ALC) correlates with day 15 absolute lymphocyte count and is an independent prognostic factor for survival after autologous stem cell transplantation (ASCT) for non-Hodgkin lymphoma (NHL). Factors to enhance A-ALC collections are not well defined. We hypothesize that the number of peripheral blood apheresis collections (PBAC) directly correlates with A-ALC. 190 consecutive NHL patients who underwent ASCT at the Mayo Clinic between 1993 and 2001 were analyzed. The primary end point of the study was to assess the correlation between the number of PBAC and A-ALC. The secondary end point was to determine if the number of PBAC affected survival post-ASCT. Of the 190 patients, 18 patients underwent 1 PBAC, 23 patients 2 PBAC, 50 patients 3 PBAC, 37 patients 4 PBAC, 50 patients 5 PBAC, and 12 patients had ≥ 6 PBAC. There was no association between the number of PBAC and the number of CD34+ stem cells collected (p= 0.25). A strong association between number of PBAC and A-ALC (Kruskall Wallis test, p <0.0001)(Figure 1) was identified. Using a cut-off of 4 PBAC, superior overall survival (OS) and progression-free survival (PFS) were observed for patients that underwent 4 PBAC or more compared to patients that underwent less than 4 PBAC (86 months vs 18 months, p <0.0001; 76 months vs 10 months, p <0.0001, respectively). Multivariate analysis demonstrated PBAC ≥ 4 is an independent prognostic factor for OS (RR = 0.654, 95%CI: 0.529–0.804, p< 0.0001) and for PFS (RR = 0.682, 95%CI: 0.561–0.826, p< 0.0001) when compared with other significant factors including performance status, lactate dehydrogenase and extra nodal disease. These data suggest that increasing the number of PBAC beyond the minimum number required to meet CD34+ collection targets may result in improved overall and progression-free survival mediated by an increase in autograft absolute lymphocyte count.