bluuebunny/crossref_metadata_2025_split huggingface dataset:
High Dose Therapy (HDCT) with Autologous Stem Cell Transplantation (ASCT) for Non-Hodgkin Lymphoma in the Elderly: Feasibility of a Patient-Tailored Treatment Plan.
Authors: Rupolo Maurizio , Michieli Mariagrazia , Spina Michele , Bernardi Daniele , Berretta Massimiliano , Giacalone Annalisa , Tirelli Umberto 
Published: April 2020

Abstract
HDCT followed by peripheral stem cell (PBSC) rescue is a suitable and effective option for patients (pts) affected by aggressive non-Hodgkin’s lymphoma (NHL) with chemosensitive disease at first relapse. Elderly pts are usually excluded from HDCT programs because of low stem cell collections and low tolerance to intensive chemotherapy. The Comprehensive Geriatric Scale (CGA) is a multidimensional pt evaluation that leads to the identification the therapeutic options. We designed a CGA-driven approach for elderly pts (between 60 and 75 years) affected by aggressive NHL in first relapse. Between October 23, 2000 and August 4, 2003 9 pts with NHL, 60 years of age and older were evaluated for ASCT at the Division of Medical Oncology A, National Cancer Institute, Aviano. Pts are stratified in 3 groups: 1) “frail pts” who do not undergo a HDCT program; 2) pts “at standard risk”, who scored 6 and 8 in the Activity of Daily Living (ADL) and Instrumental Activity of Daily Living (IADL) evaluation, respectively, with a Geriatric Depression Scale (GDS) score &lt;11 and a Mini Mental Status (MMS) score &gt;21 with a good respiratory function and no grade 2 comorbidities, who undergo a HDCT program with BEAM as conditioning regimen; 3) pts at “intermediate risk” who scored at least 5 and 7 in the ADL and IADL evaluation, respectively, with a GDS score &lt;11 and a MMS score &gt;21 and a score of no more than 2 in 1 to 3 comorbidities, who undergo a less aggressive HDCT program with double Melphalan 200 mg/m2 as conditioning regimen. Out of 9 pts 4 underwent to ASCT. The Data are summarized in table 1. CGA has emerged as a mandatory evaluation to guide therapeutic options and establish the prognosis of elderly patients. Stratification of patients into different prognostic groups according to a CGA can render HDCT a feasible and, possibly, effective procedure also in selected elderly patients affected by aggressive NHL.
Table
*Pt died after the first Melphalan transplant (interstitial pneumonia) M/F 6/3 Median age 66 (62–73; 75) Median PS 1 (0–2) # previous lines 1 (1–2) s-IPI 3 (1–4) Histology Large cell 7 Mantle 1 Follicular 1 Stage III 3 IV 6 HCV-positive 2 Salvage treatment ESHAP 3 R-DHAOX 6 Response pre-ABMT CR 6 PR 2 SD 0 PRO 1 CGA Frail 3 Standard risk 5 Intermediate risk 1 CD34+ harvest 4/9 CD34+ 10 6/kg 3.8 (2.3–4.6) ASCT Yes 3/5 standard risk No 3 frail, 1 intermediate risk* Status after transplant 1 CR +15 months 2 Relapses 6, 12 months
Phase I Study of Rituximab-Cyclophosphamide (R-CY) Stem Cell Mobilization and Rituximab-BEAM HDC with ASCT in Patients with Relapsed, Refractory or High Risk Intermediate Grade Non-Hodgkin’s Lymphoma.
Authors: Scigliano Eileen , Grosskreutz Celia L. , Fruchtman Steven M. , Gabrilove Janice L. , Mandeli John P. , Isola Luis M. 
Published: April 2020

Abstract
The addition of rituximab to mobilization regimens does not adversely affect collection of adequate numbers of CD34+ PBSC and may decrease tumor cell contamination. Prior administration of rituximab may sensitize lymphoma cells to chemotherapy, but its use with high dose chemotherapy has not been studied. In this study, eligible patients had intermediate grade NHL either primary refractory, relapsed or in CR1 with a high or intermediate/high risk IPI score. Five patients with a median age of 38 years (28–53) have been treated. All patients had rituximab previously. At transplant, 4 patients had relapse, chemosensitive to salvage in 3 patients, and untested in 1 patient. One patient had primary refractory disease, chemosensitive to salvage. Stem cell mobilization was rituximab 375mg/M2 followed by CY 2gm/M2/day for 2 doses and filgrastim 10ug/kg/d. Collection started when the CD34 count was ≥12/ul. High dose chemotherapy consisted of rituximab 375mg/M2 on day −8, carmustine 300mg/M2 on day −7, etoposide 200mg/M2/d on days −6 to −3, cytosine arabinoside 200mg/M2 on days −6 to −3 (8 doses) and melphalan 140mg/M2 on day −2. Patients received filgrastim post transplant and standard antibiotic prophylaxis. All patients are alive 11 to 306 days post transplant (median follow up 4.5 months). The median CD34+ cell dose collected was 8 x 106/kg (1.1 to 17.6). One patient had an inadequate CD34+ cell dose and required bone marrow harvesting which yielded 0.72 x 106/kg CD34+ cells. Engraftment of neutrophils and platelets occured at a median of 11 days post transplant. Infectious complications included febrile neutropenia in one patient following mobilization and in 4 patients following R-BEAM. Transient grade I–II (common toxicity criteria) hepatic enzyme elevation occurred in 2 patients following R-CY. Following R-BEAM, 3 patients developed grade II–IV LFT elevation without evidence of VOD, which resolved in two patients prior to discharge. The patient with grade IV hepatic toxicity had abnormal liver enzymes prior to study and known intrahepatic lymphoma. This patient continues to have grade III elevation of GGT 306 days post transplant with no evidence of infectious hepatitis or lymphoma (PET negative). One patient developed moderate hemorrhagic cystitis. One patient developed bilateral pulmonary infiltrates of unkown etiology (BAL negative for organisms) which resolved. R-CY was well tolerated as a mobilization regimen and led to adequate stem cell collection. R-BEAM HDC resulted in frequent elevations of LFTs. Further studies of rituximab with HDC warrant caution regarding hepatotoxicity.
High-Dose Sequential Chemotherapy (HDSC) in Support of Autologous Stem Cell Transplantation (ASCT) in Patients with Relapsed/Refractory Hodgkin Lymphoma (HL) and Non-Hodgkin Lymphoma (NHL).
Authors: Oyan Basak , Koc Yener , Ozdemir Evren , Kansu Emin 
Published: April 2020

Abstract
Background and aim: High-dose chemotherapy followed by ASCT is currently the standard treatment in achieving long-term survival in patients with relapsed or refractory HL and NHL. The aim of the present study is to assess the role of HDSC and ASCT in attaining high survival rates in patients with relapsed or refractory lymphoma.
Patients and Method: From 2000 to 2004, 42 patients with relapsed/refractory HL or NHL with a median age of 42 years (M:F=28:14) were treated with HDSC and ASCT. Only patients who were sensitive to salvage chemotherapy were eligible for the protocol, consisting of 3 phases. Phase I consisted of cyclophosphamide (4.5 g/m2) followed by G-CSF (10 mcg/kg/d) and PBSC collection. Phase II consisted of etoposide (2 g/m2) with G-CSF support of at 5 mcg/kg/d. The transplant phase consisted of mitoxantrone (60 mg/m2) and melphalan (180 mg/m2) followed by APBSC infusion.
Results: NHL patients had diffuse large cell (n=16), anaplastic large cell (n=4), mantle cell (n=2), follicular (n=2), small lymphocytic (n=2) and peripheral T cell (n=2) histology. Patients with HL had mixed cellular (n=7) and nodular sclerosing (n=7) histology. The rationale for ASCT was first relapse in 17 (41%) patients, more than one relapse in 14 (33%) patients, primary refractory disease in 10 (24%) patients and high risk disease in 1 (2%) patient. Prior to HDSC, 69% and 31% of the patients were in CR and PR, respectively. Patients received a median of 5.3x106/kg CD34+ cells. Median times to achieve neutrophil and platelet engraftments were 14 and 24 days, respectively. Transplant related mortality rate was 7% (n=3). At a median follow-up of 26 months (range, 1–48), 10 patients relapsed and 12 patients died. Causes of mortality were; veno-occlusive disease (n=1), infection (n=3), progression/relapse (n=6), congestive heart failure (n=1) and secondary AML (n=1). Five patients developed congestive heart failure (severe in one patient), mainly due to high cumulative doses of anthracyclines during the previous therapies. The estimated 3-year disease-free survival (DFS) and overall survival (OS) were 66.7% and 69.2% in HL patients and 75% and 77.4% in NHL patients, respectively. Regarding DFS and OS, there was no statistically significant difference between HD and NHL. Currently, 30 (71%) of patients are alive, of which 28 (67%) patients are in complete remission.
Conclusion: HDSC followed by APBSCT is an effective therapy in patients with relapsed/refractory NHL or HD, with an acceptable mortality rate.
Immunotherapy with Rituximab after Peripheral Blood Stem Cell Transplantation for Multiple Myeloma.
Authors: Massumoto Celso Mitsushi , Junior Edilson Pinheiro , Baiocchi Otávio C.G. , Pinheiro Ronald , Alves Adelson 
Published: April 2020

Abstract
Introduction: autologous stem cell transplantation is a potentially curative or may augment the time to progression in Multiple Myeloma (MM) patients. The immunotherapy with rituximab may help control the minimal residual disease after high dose chemotherapy. Twenty percent (20%) of Multiple Myeloma patients express the CD20+ protein and can be target for immunotherapy.
Objective: The aim of this study was to evaluate the use of rituximab after autologous stem cell transplantation for Multiple Myeloma.
Patients and Methods: eight patients (4 male) with a median age of 53 (range 43–59) years diagnosed with MM. All of them had received at least one previous regimen were enrolled in the protocol study. All patients signed the consent form. Patients in relapse received a salvage regimen with C-VAD n=2 (cyclofosfamide 4 g/m2 e vincristine 0.4 mg/d (d 1–4), doxorrubicin 0.9 mg/m2 (d1-4) e dexametasone 40 mg (d1-4; 9-12; 17–22) or cyclofosfamide (1OO mg/kg, n=7) followed by stem cell harvesting. The preparative regimen was Busulfan 12 mg/kg and cyclofosfamide 120 mg/kg or Melphalan 200mg/m2. Rituximab at a dose of 375mg/m2 weekly x 4 was given every 6 months for 2 years after SCT. The clinical characteristics of the patients are shown on Table 1.
Results: the median time to ANC and platelets engraftment was 11 (range 8–12) and 26 (range 17–35) days. Patients have been in CR at a median time of 11 months follow-up. Minor Rituximab-associated toxicities were seen:rigor, fever and short of breath that were controlled with acetaminophen and diphenidramine.
Conclusion: the Rituximab given after autologous stem cell transplantation is safe in Multiple Myeloma patients and may prolong time to disease progression. A randomized study is required to evaluate the role of rituximab after ASCT.
Table 1 - Clinical Characteristics of Patients
Patients Age/gender Status Pre- BMT Status Post- BMT Salvage Tx Prep. regimen ANC/Platelets X1000 MM3/ml Follow-up (months) FRC 57/M PR PR C-VAD BU+MEL 12/28 EXPIRED MB 52/F CR1 CR1 C-VAD BU+MEL 12/60 EXPIRED AM 52/F PR PR C-VAD BU+MEL 9/26 EXPIRED IM 54/M PR CR Cyx2 BU+MEL 12/21 ALIVE GAD 50/F PR CR Cyx2 BU+MEL 12/35 ALIVE SCM 59/M CR CR Cyx2 BU+MEL 10/17 ALIVE MAD 63/F CR CR C-VAD MELPHALAN 12/25 ALIVE JFC 51/M CR CR C-VAD BU+MEL 12/18 ALIVE
Autologous Bone Marrow Transplantation for Follicular Lymphoma in First Remission: Long Term Follow up of Two Sequential Trials with Standard Dose and High Dose CHOP Induction.
Authors: Freedman Arnold S. , Gribben John G. , Neuberg Donna , Li Sigui , Kim Helen , Mauch Peter , Nadler Lee M. 
Published: April 2020

Abstract
High dose therapy and autologous stem cell transplantation (ASCT) has been employed as salvage therapy for patients (pts) with relapsed follicular non-Hodgkin’s lymphoma (FL). Recently, the randomized European CUP trial demonstrated that following 3 cycles of CHOP, ASCT significantly improved both disease free and overall survival when compared to continued CHOP in pts with relapsed FL. In an attempt to improve the results of high dose therapy in FL, we undertook 2 sequential studies for pts with FL in first remission. In the first study, 77 pts with previously untreated advanced stage FL (median age 43), received 6–8 cycles of standard dose CHOP (SD-CHOP) + involved field radiotherapy followed by high dose chemoradiotherapy and anti-B cell purged autologous bone marrow transplantation (ABMT). Following SD-CHOP induction, 27 of 77 pts (36%) were in CR and 50 in a minimal disease state (&lt; 2 cm masses, &lt; 20% BM involvement). At BM harvest, 36 pts had histologic evidence of BM involvement. In the second trial, 19 pts with advanced stage disease (median age 44) were treated with 4 cycles of dose intensified CHOP (HD-CHOP) (cyclophosphamide 1.5 g/m2 day 1 and 2) with G-CSF support followed by high dose chemoradiotherapy and anti-B cell purged autologous ABMT. Following HD-CHOP, 13 of 19 pts were in CR. At BM harvest, 7 of the 19 HD-CHOP pts had histologic BM involvement. Following ABMT, there were 2 acute in-hospital deaths in the pts receiving SD-CHOP induction and none in the pts who received HD-CHOP induction. Nine late deaths in remission were observed in the SD-CHOP pts including 6 from MDS/AML, and 2 late deaths in the HD-CHOP pts. Thirty-three pts who received SD-CHOP remain alive without relapse, with a median follow up of 12 years. Ten pts who received HD-CHOP induction remain alive without relapse, with a median follow up of 9.1 years. For pts receiving SD-CHOP induction, the DFS and overall survival at 10 years are 42% (90% CI: 33%–52%) and 64% (90% CI: 55%–73%), respectively. For pts who received HD-CHOP induction, the DFS and overall survival at 10 years are 59% (90% CI: 38%–79%) and 75% (90% CI: 57%–93%), respectively. The impact of BM treatment and DFS was examined. Pts with known bcl-2 translocations for whom post-BM purging samples were available for pcr examination were analyzed. Following ABMT, pts who were reinfused with pcr negative BM had a significantly better DFS than the pts who were reinfused with pcr positive BM. This study suggests that a subset of pts with FL experience long term remission following ABMT in first remission.
Selective and Efficient Gene Delivery of CD40-Ligand by a Fiber-Modified Adenovirus Vector with Specific Antibody to Human Leukemia and Myeloma.
Authors: Kato Kazunori , Hirai Sachie , Masuta Yukari , Kuroishi Aiko , Nakamura Kiminori , Hamada Hirofumi 
Published: April 2020

Abstract
The use of adenovirus vector for cancer gene therapy is limited by their low transduction efficiency for lymphoma, leukemia and myeloma. We previously reported that highly efficient gene delivery of CD40-ligand by a modified adenovirus vector with the integrin-binding motif, RGD, in the H1 loop of the fiber knob (AxCAhCD40L-F/RGD) could induce phenotypic alteration followed by T cell immune response to autologous leukemia cells. But the utility of adenovirus with RGD-motif is still limited by their lack of specificity on tumor cells. Recent studies revealed a novel strategy of targeting adenovirus using a bispecific single-chain antibody (scFv) specific for adenovirus and target molecules on tumor cell surface. However, this approach should permit the production of high quantities of active bispecific scFv for in vivo use. To target adenovirus to hematopoietic tumor cells efficiently, we herein constructed a modified adenovirus vector that contained a synthetic immunoglobulin G-binding domain (termed Z33) in H1 loop of the fiber knob. A recombinant adenovirus encoding EGFP, lacZ (as reporter gene; Ax3CAZ3-F/Z33 or Ax3EGFP-F/Z33) or CD40L (as a therapeutic gene; Ax3CD40L-F/Z33) with Z33-modified fiber were tested for gene transfer efficiency into human tumors such as lymphoma, leukemia and myeloma cells. By the treatment with various antibodies specific for CD20 (Rituximab), CD40, CD38, CCR2 or CXCR4 that are expressed on leukemic cells, we achieved 3 to 10-fold enhancement of gene expression in lymphoma/leukemia (Ramos, Daudi or THP-1) and myeloma cells (MM1S, IM-9 or KMS5) compared with control IgG-treated tumors. We also examined specific gene delivery to freshly isolated leukemia B cells from patients that also contains normal lymphocytes. By using antibody to CD20 or CD40, we could selectively deliver CD40L gene with Ax3CD40L-F/Z33 into leukemia B cells (&gt;50% at 300 pu/cell), but not in T and monocytes, followed by the induction of immune costimulatory molecules that are important in anti-leukemia immune response. Overall, our results indicated that combination of Z33-modified adenovirus vector and tumor specific antibody can be used as a modality for the gene therapy of leukemia and myeloma.
Development of Novel Multigene Lentiviral Vectors.
Authors: Chinnasamy Nachimuthu , Milsom Michael , Neuenfeldt James , Shaffer James , Margison Geoffrey P. , Fairbairn Leslie J. , Chinnasamy Dhanalakshmi 
Published: April 2020

Abstract
Lentiviral vectors are efficient in transducing dividing and non-dividing cells. Many gene transfer applications require vectors that express more than one protein which include but not limited to therapeutic gene plus a selectable marker gene, multiple genes encoding different subunits of a complex protein or multiple independent genes that cooperate functionally. Previous strategies in constructing multigene lentiviral vectors by other groups included splicing, multiple internal promoters, internal ribosome entry site (IRES), and fusion proteins. In this study we explored the feasibility of expressing homeobox B4 (HOXB4), O6-methylguanine-DNA-methyltransferase (MGMT), and enhanced green fluorescent protein (EGFP) under the control of a single promoter with the use of IRES sequence from encephalomyocarditis (EMCV) virus and/or foot and mouth disease virus (FMDV) 2A cleavage factor in a HIV-1 based self-inactivating lentiviral vector. In bicistronic vectors the small FMDV 2A sequence can be used efficiently as an alternative to IRES. In case of tricistronic vectors the 2A sequence can be used in combination with IRES to obtain simultaneous expression of three cDNAs under the control of a single internal promoter. Monocistronic, bicistronic and tricistronic vectors were constructed and a three-plasmid expression system was used to generate vesicular stomatitis virus glycoprotein pseudotyped lentiviral vector particles. Viral titers were measured by quantification of HIV p24 gag by ELISA. The relative efficiency of transgene expression in transduced cells by various vectors was compared by appropriate methods including fluorescence microscopy, flow cytometry, immunocytochemistry, biochemical assay, and western blotting. All the multigene vectors produced high titer viral particles and were able to simultaneously express two or three transgenes in transduced cells. However, the expression of EGFP from monocistronic vector as measured by mean fluorescence intensity was 3–8 times and 10–20 times higher than that of bicistronic and tricistronic vectors respectively. Notably expression of second gene encoded by the bicistronic vector containing FMDV 2A was 2–3 fold higher than that of IRES-based vector. Expression of MGMT in monocistronic and bicistronic constructs was also 4 to 20 times higher than tricistronic vectors. The FMDV 2A cleavage factor efficiently mediated the generation of the expected cleavage products from the artificial fusion protein. These vectors can be used in a wide range of applications including the expression of: multiple subunits of a functional protein, tumor antigen and co-stimulatory molecule(s), multiple tumor antigens for immunotherapy applications, and co-expression of selectable marker gene/s with therapeutic gene/s.
Activation-Dependent Expression of an Interleukin-2 Transgene Mediated by Transduction with a Lentiviral Vector Enhances T Cell Functions.
Authors: Sun Qi , Chorney Karen , Stine Carol , Lucas Kenneth G. 
Published: April 2020

Abstract
Adoptive T cell immunotherapy (ATCI) is an evolving strategy that explores antigen-specific T cells manipulated ex vivo as therapeutic agents. Although the concept of ATCI has been tested clinically, with success in the treatment of post-transplant EBV induced lymphoproliferative disease, one of the major obstacles hindering its application to other malignancies is the procurement of tumor-specific T cells that possess potent anti-tumor functions even in the inhibitory environment at the tumor sites. This study aims to genetically engineer enriched viral specific T cells for improved immune functions. A self-inactivating lentiviral vector (SIN) CD69p-IL2 was constructed to encode the transgene interleukin-2 (IL2) under the control of a human CD69 promoter (CD69p), and this vector was tested in ex vivo cultivated EBV-specific T cells. SIN vector allows a high degree of autonomy for the internal promoter, and CD69 expression in the T cells is closely associated with T cell activation. Experiments showed that the SIN vectors efficiently transduced EBV-specific T cells, both CD4 and CD8. Furthermore, the newly cloned CD69p exhibited a higher degree of responsiveness to physiological antigen stimulation than the early promoter from the cytomegalovirus (CMVp). In response to stimulation by EBV-infected B cells, the percentage of IL2 expressing cells was 2 fold higher for the activated CD69p-IL2 transduced T cells than the non-transduced, or the CMVp-IL2 transduced, counterparts. In correlation with the stronger IL2 expression, 3 fold more T cells expressed the anti-viral cytokine interferon-γ (IFN-γ) in the CD69p-IL2 transduced T cells than the CMVp-IL2 transduced, and the IFN-γ expression at the single cell level was 2 fold higher in the former, indicating an enhanced functionality. While the culture supernatant from the CMVp-IL2 transduced T cells contained IL2 at a concentration 2000 fold higher than the non-transduced T cells, the IL2 level in the media from the CD69p-IL2 transduced T cells was comparable to that in the control, suggesting the IL2 expression mediated by the CD69p more relevant to T cell functions than the CMVp. These results may serve as a foundation for the further development and clinical application of specific T cells engineered for enhanced immune functions.