bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I/II Study of Fractionated Radioimmunotherapy (RIT) in Relapsed Low Grade Non-Hodgkin’s Lymphoma (NHL).
Authors: Illidge Tim M. , Bayne Mike C. , Zivanovic Maureen , Du Yong , Lewington Valerie , Peter Johnson W. 
Published: April 2020

Abstract
RIT produces high rates of durable complete responses in “low grade” NHL. Clinical studies have thus far been limited to a single infusion of a radiolabeled anti-CD20 mAb (131I tositumomab or 90Y ibritumomab tiuxetan) in patients with &lt; 25% bone marrow involvement. In this study we have tested the safety and efficacy of 4 weekly infusions of Rituximab followed by 2 fractions of 131I labelled rituximab given 8 weeks apart in relapsed "low grade" NHL and have included patients with higher levels than 25% bone marrow infiltration with lymphoma. Whole body dose (WBD) calculations have been used to allow the total dose given in 2 fractions to be increased in cohorts of 30cGy, 60cGy, 90cGy and 120cGy. A unique anti-rituximab idiotype mAb has been generated enabling serial analysis of serum rituximab concentrations (Cragg et al Blood 2004 Jun 22 Epub). This tool has allowed us to accurately quantify the serum levels of rituximab during the entire treatment schedule. We have also analysed the impact made by induction rituximab, the pre-dose of cold antibody and effects of fractionated RIT on the clearance and biodistribution of the 131I labeled rituximab. Sequential pharmacokinetic analyses have identified wide variation in the effective half-life of 131I-rituximab not only between patients but also within the same patient over the course of the treatment protocol. We found that the mean effective half-life of 131I rituximab increased from 43 hours prior to induction rituximab to approximately 106 hours prior to the second fraction of 131I-rituximab. A strong inverse correlation was found between the patients’ disease burden and the clearance of rituximab, both in the same patient as the tumor burden decreased and between different patients. We have demonstrated that higher cumulative WBD doses can be safely delivered by RIT dose fractionation than can be given with a single dose of anti-CD20, with no grade 3–4 myelotoxicity at the 90 cGy dose level. All 12 patients in the first 3 dose cohorts experienced responses and response durations equal to, or in the majority of cases, superior to that seen with their previous chemotherapy regimen. Data on all 16 patients including 120 cGy dose level will be available at the time of presentation. In conclusion, this fractionated RIT protocol is feasible, efficacious and enables larger WBD doses to be safely delivered than has previously been achieved with non-myeloablative RIT.
The Superior Prognosis of Female Patients with Hodgkin’s Lymphoma Is Related to More Treatment-Induced Leucopenia and Warrants a More Individualized Therapy.
Authors: Klimm Beate , Reineke Thorsten , Haverkamp Heinz , Eich Hans T. , Josting Andreas , Pfistner Beate , Diehl Volker , Engert Andreas 
Published: April 2020

Abstract
Purpose: Several scores have described gender as an important prognostic factor in patients with Hodgkin’s lymphoma (HL), particularly in advanced-stages. However, so far there is no larger analysis to systematically evaluate possible gender-specific factors. The purpose of this analysis was to investigate sex differences with regard to pre-treatment and therapy-related variables and to evaluate their influence on the outcome of HL patients.
Patients and Methods: From 1988 to 1998 the GSHG conducted two generations of clinical trials for early, intermediate and advanced HL (HD4 - HD9). The present analysis comprises 4626 patients of all stages, aged 15 to 75 years, who were enrolled into these multicenter studies and treated according to the GHSG-study protocols.
Results: At a median observation time of 5.5 years, 2050 female and 2576 male patients were suitable for this retrospective analysis. Patients in each group had very similar profiles in terms of age, performance status, stage, histological subtype, clinical risk factors and prognostic factors. Slightly more nodular sclerosis subtypes and mediastinal masses were observed in women. In contrast, more men had a mixed cellularity subtype, older age, advanced stage of disease, and B-symptoms at diagnosis. Acute chemotherapy-related toxicity was distributed almost equally. However, there was more hematotoxicity in females. This difference was most obvious for leucopenia [WHO grade III/IV: 69.9 % versus 55.2 %]. Importantly, there was no higher risk of infections in female patients. Response rates being similar in both groups, however, a lower rate of relapse and death was observed in females.
Univariate analyses revealed significant better outcome in terms of FFTF and OS for females. In multivariate analyses, sex was not identified as an independent prognostic factor, however, lower stages of disease (p&lt;.0001), less B-symptoms (p&lt;.0001), younger age (p&lt;.0001), and leucopenia grade III/IV (p&lt;.0001) were significant variables to which better outcome in females can be related. Particularly, the high prevalence of leucopenia grade III/IV during chemotherapy has a clear impact on better FFTF in females. The smaller proportion of males expressing severe leucopenia also had better outcomes. In addition, when only those patients were included who developed leucopenia grade III/IV within the first two cycles of chemotherapy, the factor maintains its protective role.
Conclusion: In this large retrospective analysis of the GHSG database, a better outcome is observed for female patients compared to male patients with HL. The protective role of severe leucopenia supports the rationale for a more individualized therapy, that may be tailored in a response-adapted manner depending on the individual toxicity profile within the first cycles.
R-DHAOX as Salvage Regimen in Patients (pts) with Relapsed/Resistant Non-Hodgkin[spos]s Lymphoma (NHL).
Authors: Rupolo Maurizio , Spina Michele , Michieli Mariagrazia , Berretta Massimiliano , Abbruzzese Luciano , Mazzucato Mario , Gattei Valter , Tirelli Umberto 
Published: April 2020

Abstract
Rituximab is active as single agent in relapsed CD20-positive NHL. Second line chemotherapeutic regimens in NHL are mainly based on cisplatin (DDP) and are most frequently employed as cytoreductive regimens for high dose chemotherapy and for peripheral blood CD34-positive (PBSC) harvesting. On the basis of preclinical and clinical studies, the substitution of DDP with oxaliplatin (OXDDP) in regimens like DHAP can result in a lower toxicity and higher activity. We studied the tolerability and efficacy of R-DHAOX regimen in the treatment of relapsed and refractory NHL. From November 2002 until June 2004, 33 pts affected by relapsed/refractory NHL were treated with R-DHAOX regimen (Rituximab 375 mg/m2, e.v. day 1, Desametazone 40 mg e.v. days 1–4, Oxaliplatin 130 mg/m2 e.v. day 2 and Cytarabine 2000 mg/m2 e.v. twice a day, day 3). The median age was 51 yrs (range 19–74). Twenty-one pts were in first relapse, 7 pts &gt;1 relapse and 5 pts refractory to the first line. The results are summarized in table 1. These data suggested that the R-DHAOx regimen is a novel combination in salvage therapy for relapsed/refractory NHL. It has clinically significant activity with an acceptable toxicity profile, even in HIV-positive pts. R-DHAOX permits adequate stem cell harvest with G-CSF mobilisation and in our experience no delay in engraftment occurred. Supported by ISS and AIRC grants. Table 1
°30 pts evaluable; ^5 HIV-positive pts, 1 HCV-positive pts, 22 elegible for ASCT M/F 21/12 PS 1 (0–2) Median age 51 (19–74) HIV-positive 10 HCV-positive 1 Histology Lymphocytic 2 Follicular 8 (24%) Mantle 2 Diffuse large cell 18 (55%) Burkitt 1 Large cell CD30+ 2 Stage II 1 III 6 (18%) IV 26 (79%) s-IPI 0–1 10 (30%) &gt;1 23 (70%) # previous lines 1 (1–2) Dose reduction 65 (55%) Toxicity Neutropenia G3/G4 22 (66%) Anemia G3/G4 8 (24%) Thrombocytopenia G3/G4 21 (64%) Mucositis G3/G4 2 Neurotoxicity G3/G4 1 Response° CR 8 (27%) PR 13 (43%) SD 1 (3%) PRO 8 (27%) Day of PBSC peak +14 (12–18) CFU-GM x10 4 /kg 93 (10.9–230) CD34+ 10 6 /kg 7 (0.65–20) # apheresis 1 (1–2) High dose chemotherapy^ 15 (68%)
GD2 Peptide Mimotope DNA Vaccines for Anti-Neuroblastoma Immunotherapy.
Authors: Fest Stefan , Hilt Kerstin , Huebener Nicole , Zeng Yan , Strandsby Anne , Weixler Silke , Gaedicke Gerhard , Riemer Angelika , Foerster-Waldl Elisabeth , Jensen-Jarolim Erika , Lode Holger N. 
Published: April 2020

Abstract
The tumor-associated antigen disialoganglioside-GD2 is expressed on neuroblastoma and melanoma and is an established target for passive immunotherapy. The aim of this study was to develop an active immunization strategy leading to the induction of a humoral anti-GD2 immune response. However, carbohydrates and glycolipids are T cell-independent antigens (TI) and usually evoke a poor immune response in tumor-bearing hosts.
Here, we describe the identification, characterization and in vivo efficacy of cyclic peptides mimicking the structure of glycolipid GD2, i.e. GD2 mimotopes, in order to overcome T-cell independency. First, GD2 peptide mimotopes were identified by biopanning experiments of a phage-display library displaying circular decapeptides against the human/mouse chimeric anti-GD2 antibody (Ab) ch14.18. Thirteen independent phage clones were isolated which bind to ch14.18 with high specificity. Competitive binding of phages expressing GD2 peptide mimotopes to ch14.18 antibody revealed two superior peptide candidates, mimotope A (MA) and and mimotope D (MD), which were subjected to further evaluation. Second, two plasmid DNA minigene vaccines were generated by overlapping PCR encoding for MA and MD, respectively. The plasmids were based on pSecTag2-A also including a kappa leader sequence, a T-cell helper epitope from HIV-1 gp 120 (T1) and a myc-tag. Minigene expression was demonstrated following transfection of COS-7 cells in western-blots and GD2 mimikry was determined in solid phase ELISA experiments. Third, the efficacy of these mimotope DNA vaccines to induce a tumor protective anti-GD2 immune response was tested in the syngeneic NXS2 model of neuroblastoma expressing ganglioside GD2. The DNA vaccination was accomplished with attenuated Salmonella typhimurium (SL 7207) used as an oral vaccine carrier. Only mice receiving the mimotope DNA vaccines revealed a decrease in primary tumor growth by 50% and a dramatic reduction of spontaneous liver metastases with a mean liver weight of 1g in both groups (MA and MD) in contrast to negative controls (3g). Interestingly, mice immunized with KLH conjugated peptide mimotopes A and D revealed an increased rate of s.c. tumor growth and spontaneous liver metastasis with average liver weights of 5 (MA) and 7 (MD), respecively, suggesting the induction of tolerance using this peptide vaccine approach. Finally the highest anti-GD2 humoral immune response was observed in sera of mice from both GD2 mimotope DNA vaccine groups, consistent with the anti-tumor reponse observed in vivo. Based on these data, we belive that GD2 mimotope DNA vaccines may provide a useful strategy for active immunization against neuroblastoma.
Transfection of Dendritic Cells with In Vitro Transcribed RNA Induces Polyclonal CMV-Specific CD8+ and CD4+ Mediated T Cell Responses.
Authors: Heine Annkristin , Holderried Tobias , Grünebach Frank , Appel Silke , Weck Markus M. , Reichardt Volker L. , Brossart Peter 
Published: April 2020

Abstract
Transfection of dendritic cells (DC) with in vitro transcribed RNA was shown to be a highly efficient method to generate antigen specific T cells, probably due to the induction of a polyclonal T cell response directed against multiple antigens presented on different HLA allels. However, the experimental evidence of this assumption remains to be demonstrated. To accomplish this, we used monocyte derived DC that were electroporated with RNA coding for the CMV pp65 antigen. The induction and expansion of antigen specific CD8+ and CD4+ T cells was assessed using a pannel of peptides derived from this antigen and presented on HLA-A2, -A1, -A11, -A24, -B35 and -B7 in IFN-g ELISPOT, 51Cr-release and proliferation assays. Autologous DC generated from CMV positive healthy donors were pulsed with peptides or transfected with pp65 RNA and utilized as stimulators. Autologous purified CD8+ and CD4+ lymphocytes were used as effector cells. By applying this approach we found that transfection of DC with pp65 RNA induces an expansion of polyclonal CD8+ mediated T cell responses that recognized peptide antigens presented on different HLA molecules. These in vitro generated cytotoxic T cells were able to efficiently lyse DC pulsed with pp65 derived peptides or transfected with the cognate RNA in an antigen specific manner after several in vitro restimulations. Furthermore, this experimental approach allowed the identification of the immunodominace of T cell epitopes presented upon RNA transfection. The HLA-2 directed responses were more pronounced as compared to the HLA-A1, -A11, -A24 or -B35 allels. In contrast, in 7 out of 7 HLA-A2 and HLA-B7 positive donors B7-peptides elicited a stronger T cell response than the A2-peptide, indicating the immunodominance of HLA-B7 epitopes. Interestingly, transfection of DC with pp65 RNA resulted in the induction of CD4+ antigen specific T cells that produced IFN-g and proliferated upon stimulation with transfected DC. In the next set of experiments we analyzed the possible induction of CMV specific T cells that recognize epitopes deduced from different antigens. Co-transfection of DC with a mixture of RNAs coding for the CMV pp65 and IE1 antigens elicited polyclonal T lymphocytes specific for peptides derived from both antigens. More importantly, polyclonal cytotoxic T cells could be elicited in peripheral blood of 2 out of 3 CMV negative donors demonstrating the efficiency of this approach. Our results demonstrate that DC transfected with RNA can elicit polyclonal T cell responses and have implications for the development of immunotherapeutic strategies to target viral or tumor associated antigens.
Molecular Characterization of AML1 (RUNX1) Amplification: A Poor Risk Chromosomal Marker in Acute Lymphoblastic Leukaemia (ALL).
Authors: Strefford Jon C. , van Delft Frederic , Raghavan Manoj , Robinson Hazel M. , Moorman Anthony V. , Young Bryan D. , Saha Vaskar , Harrison Christine J. 
Published: April 2020

Abstract
We have recently defined a new recurrent chromosomal abnormality in patients with acute lymphoblastic leukemia (ALL) involving the duplication of chromosomal band 21q22 and amplification of the AML1 (RUNX1) gene. Currently, fluorescence in situ hybridization (FISH) with probes directed to the AML1 gene is the only reliable detection method. AML1 signals are seen as clusters in interphase cells and in tandem duplication on the long arm of chromosome 21 in metaphase. To date, we have identified 46 patients with this abnormality: 26 males and 20 females. The median age of the 44 children was 9 years (range 4–16 years): two adults were 20 and 30 years old. Their median white cell count was 3.7x109/L (range 1−80x109/L) and all had a common/pre-B immunophenotype. The 3 year event free survival for the 24 children treated on MRC ALL97 was 51% (95% confidence interval 27%–71%). Hence, this abnormality has been associated with older children with a low white cell count and, most significantly, a poor prognosis. The NCRI UK Childhood Leukaemia Working Party has categorized these children into a high-risk group and recommended that they be treated on a more intensive protocol, making their accurate detection vital. To achieve this goal, we have attempted to define the amplified region on chromosome 21 and to identify the genes involved, employing a range of molecular techniques. Microarray analysis (genomic and expression) in conjunction with FISH and quantitative PCR were used to investigate DNA and/or RNA samples from 11 patients. Comparative genomic hybridization (Spectral Genomics 1Mb) (aCGH) showed variable regions of amplification (common minimal region ~10Mb DNA).
Complementary FISH, using a range of specific probes corresponding to the aCGH clones, confirmed the extent of the amplified region on chromosome 21, while indicating the precise copy number changes for each clone. FISH also revealed unexpected chromosomal rearrangements of the amplified chromosome, including loss of the 21q telomeric region. These observations confirm the chromosomal instability associated with this abnormality, as previously indicated from the variable chromosome morphology seen by cytogenetic analysis. Expression profiling (Affymetrix HG-U133) detected 60 over-expressed genes in these patients, of which six were located within the chromosome 21 amplicon. This study has defined the extent of the chromosome 21 amplified region surrounding AML1, and highlighted the over-expression of specific genes within the amplicon. This combined molecular approach will help to identify the most appropriate test for the detection of this high-risk abnormality.
Mechanisms of IL-21 Enhancement of Rituximab Efficacy in a Lymphoma Xenograft Model.
Authors: Hughes Steve D. , Bannink Ken , Krejsa Cecile , Heipel Mark , Johnson Becky , Holly Rick , Sivakumar P.V. , Henderson Katherine , Clegg Chris , Sievers Eric , Kindsvogel Wayne , Foster Don 
Published: April 2020

Abstract
Interleukin 21 (IL-21) is an IL-2 family cytokine produced by activated CD4+ T cells. Potent effects of IL-21 have been observed on the growth, survival, and functional activation of T cells, B cells, and natural killer (NK) cells. A Phase I clinical trial of IL-21 in metastatic melanoma and renal cell carcinoma is currently in progress. We recently reported that IL-21 significantly enhanced rituximab mediated clearance of CD20+ lymphoma cell lines both in vitro and in vivo, and that these effects were potentially mediated through IL-21 enhancement of NK cell capacity to effect antibody dependent cellular cytotoxicity (ADCC). Specifically, NK cells treated with IL-21 showed increased cytotoxicity, granzyme B and IFNg production. Current studies aim to further evaluate the mechanisms by which IL-21 enhances ADCC. A number of observations suggest a multi-factorial basis for IL-21 synergy with rituximab. In a xenograft tumor model, SCID mice were injected IV with HS Sultan cells on day 0. Treatment with recombinant murine IL-21 (mIL-21; starting day 1) combined with rituximab (starting day 3) resulted in significantly increased survival (70% vs. 20% on day 100), compared to rituximab alone. In separate studies, the spleens of mice treated with mIL-21 showed increased numbers of activated macrophages and granulocytes. As macrophages and granulocytes can participate in ADCC, IL-21 synergy with rituximab in vivo may be partly dependent on its activation of these cell types. We have also evaluated whether direct effects of IL-21 on lymphoma cells contribute to enhancement of rituximab efficacy. The xenogeneic B lymphoma models in which IL-21 plus rituximab exhibited enhanced survival are highly aggressive and these models were not shown to respond to treatment with mIL-21 alone. In vitro studies were performed to determine if IL-21 could potentiate the growth inhibitory and pro-apoptotic effects of rituximab. In the absence of effector cells synergistic interaction was not observed. In addition, we tested the ability of IL-21 to enhance cytotoxicity when combined with antibodies targeting non-hematopoietic tumor cells (e.g. trastuzumab). Human NK cells treated with IL-21 displayed significantly increased cytotoxicity in ADCC assays using trastuzumab to target breast cancer cells expressing varying levels of HER-2 antigen. In summary, the current evidence suggests that IL-21 can enhance antibody-mediated tumor cell lysis through activation of multiple effectors of ADCC. Thus IL-21 may prove to be broadly applicable to monoclonal antibody therapy of cancer.
First-Line Treatment with Rituximab Improves Survival of Patients with Post-Transplant Lymphoproliferative Disease (PTLD).
Authors: Gonzalez-Barca E. , Domingo-Domenech E. , Gomez-Codina J. , Capote F. , Flores E. , Briones J. , Salar A. , Panizo C. , Montalban C. , Ribera J. M. , Caballero D. , Muñoz A. , Gallur L. , Canales M.A. , Fernandez P. , Encuentra M. , de Sevilla A. Fernandez 
Published: April 2020

Abstract
Purpose: to compare the response rate and survival between patients diagnosed of PTLD and treated with front-line rituximab and those not treated with rituximab.
Patients and Methods: 108 patients with PTLD have been studied from January 1996 to January 2004. Survival curves were expressed as Kaplan-Meier plots and were compared by the Log-rank test. A multivariate Cox regression analysis was performed to asses the effect of prognostic factors on survival.
Results: median age was 55 years (limits: 18–73). 70% were males. The transplanted organ was: kidney 46%, liver 28%, heart 16%. Median time between transplant and PTLD was 59 months, 25% were diagnosed during the first year after the transplant. The most frequent histological subtypes were: large B-cell lymphoma 53% and polymorphic SLPT 13%. 70% were EBV +. Clinical characteristics at diagnosis were: disseminated disease: 52%, extra-nodal disease: 81%, ECOG 3 2: 43%, LDH &gt;N: 60%, IPI 3 3: 40%. Treatments used were: reduction of immunosuppression 91%, chemotherapy 59%, rituximab 33%, antiviral 13%. Response to treatment was: CR 46%, PR 13% failure 11%, not evaluable (early deceased): 29%. With a median follow-up of 15,2 months, survival was: OS 21% and EFS 15%. Forty-six (43%) patients died. The causes of death were: lymphoma progression 15 (33%), infection 15 (33%), toxicity 16 (34%). Survival of patients treated with rituximab was significantly better than the general group: OS 76% (p=0.007) and EFS 70% (p=0.02). Among patients treated with rituximab, 8 (23%) patients died. The significant bad prognostic factors for EFS in the multivariate analysis were: disseminated disease (RR: 2, 95% IC:1,02–3,8; p=0,04), ECOG 3 2 (RR: 5, 95% IC:2,6–9,8; p=0,0001), not been treated with rituximab (RR: 3,8, 95% IC: 1,7–10; p=0,001). IPI did not have prognostic impact.
Conclusions: survival of patients with PTLD is low with conventional therapy, and the main causes of death are toxicity and infections. Treatment with Rituximab significantly improves their survival. Patients with disseminated disease and bad performance status have worse prognosis. IPI is not a useful index of prognosis in patients with PTLD.