bluuebunny/crossref_metadata_2025_split huggingface dataset:
Update of a GITIL Cohort Study: Frontline High Dose Sequential Chemotherapy with Rituximab and Autologous Stem Cell Transplantation Induces a High Rate of Long-Term Remissions in Patients with Mantle Cell Lymphoma
Authors: Cortelazzo Sergio , Magni Michele , Tarella Corrado , Mian Michael , Billio Atto , Rossi Andrea , Marchesi Maddalena , Gallamini Andrea , Corradini Paolo , Ciceri Fabio , Parvis Guido , Majolino Ignazio , Patti Caterina , Mirto Salvo , Benedetti Fabio , Pizzolo Giovanni , Gianni Alessandro M. , Rambaldi Alessandro 
Published: October 2019

Abstract
We updated a cohort study with the aim of evaluating if an up-front Rituximab supplemented high-dose sequential chemotherapy (R-HDS), supported by autologous bone marrow transplantation (ASCT) can induce log-term remissions in Mantle Cell Lymphoma (MCL), with an acceptable toxic profile. From 1997 to 2005, 77 consecutive MCL patients, <61 year old, considered suitable for ASCT in 11 Italian cancer centres were enrolled in this study (Group 1). Their clinical outcome was compared with that of 79 age-matched historic controls treated between 1978 and 1999 with standard-dose anthracyclin or fludarabine containing regimens (group 2). The majority of both groups had an advanced stage, bone marrow infiltration and >1 IPI risk factors, while >1 extranodal sites prevailed in Group 1 and a poor ECOG-PS in Group 2. After 2–3 cycles of either doxorubicin- or cisplatin-containing chemotherapy, Group 1 received R-HDS including: HD-cyclophosphamide (CTX) 7 gr/sqm and HD-Ara-C (2 g/sqm every 12 hours for 6 days), followed by HDS HD-melphalan (180 mg/sqm) and/or HD-mitoxantrone plus melphalan (60 and 180 mg/sqm) and ASCT. Rituximab (375 mg /sqm) was given for a total of 6 doses, twice after HD-CTX and HD-Ara-C, as in vivo purging before CD34+ cells harvest and twice after ASCT. Sixty-nine patients (90%) in Group 1 completed the planned program and a median number of 6.3 x 10^6 cells CD34+/kg were transplanted. In Group 2, 85% of patients received the planned chemotherapy. The CR rate was 86% in Group 1 and 35% in Group 2 and the treatment-related mortality was 1.3% and 0.8%, respectively. Moreover, in Group 1, 4 patient developed sMDS, and 4 died of solid tumors (n=3), or septic shock (n=1). After a median follow-up of 50 months (range 3–111) in Group 1 and 37 months (range 1–141) in Group 2, the rate of 1st CCR was 65% and 14%, respectively. The 5-year projected OS, EFS and DFS were 74%, 61% and 70%, in Group 1 and 31%, 14% and 25%, in Group 2, respectively. Cox multivariate analysis failed to identify within potential prognostic markers factors predictive for OS and EFS. In conclusion, R-HDS induces long-term remissions with a manageable toxicity in patients with newly diagnosed MCL. Studies comparing this program with other intensive regimens are needed for ascertaining the role of R-HDS in the treatment of this otherwise incurable disease.
Early Results of a Phase II Trial Testing Low Dose Total Body Irradiation (LTBI) after Chemoimmunotherapy in Elderly High Risk Patients with Diffuse Large B-Cell Lymphoma (DLBCL)
Authors: Safwat Akmal , Specht Lena , Hansen Flemming , Hansen Mads , Jurlander Jesper , Boesen Anne Marie , d’Amore Francesco 
Published: October 2019

Abstract
Background: The addition of rituximab (R) to bi-weekly CHOP (CHOP-14) in the RICOVER-60 trial resulted in improved time to treatment failure in 828 elderly (61–80 years) DLBCL patients (Blood106:9a, 2005). We investigated the addition of LTBI in a dose of 1,6 Gy given as adjuvant therapy in high-risk elderly patients with DLBCL treated according to the best performing arm of the RICOVER-60 trial (R-CHOP-14 x 6 + 2xR).
Methods: A phase II trial including pts >60 yrs with stage II-IV, CD20-positive DLBCL was performed between 2003 and 2007. Pts received 6x R-CHOP-14 and 2 x R alone followed by LTBI given as 2 courses of 4 daily fractions of 0,2 Gy separated by 2 weeks of rest.
Results: We report the results of the first 36 patients. The median age was 69 years; 56% had ≥ 1 extranodal lesion; 67% had stage III or IV; 48% had B symptoms and 37% had Bulky (> 7.5 cm) disease; 54% had ECOG score ≥ 1; 75% had elevated LDH and 63% had IPI of >2, while 73% stained positive for BCL2 in pre-therapeutic histological samples. One patient got off study because of the discovery of breast cancer and one patient refused to get LTBI. Twenty one pts achieved a CR or CRu at the end of chemotherapy (58%), 10 (27%) were in PR while only one patient progressed under chemotherapy. All 10 PR pts achieved CR in the first follow up after LTBI. Four pts relapsed within 12 months after achieving CR. All treatment failures occurred in patients with IPI 3&4. Of the administered R-CHOP-14, Rituximab and LTBI cycles, 95%, 100% and 96%, respectively, were given in full dose and on time. CTC Gr 3–4 neutropenia occurred following 50 of 250 R-CHOP-14 cycles (20%). There were 3 toxic deaths (7.8%) due to sepsis occurring during chemotherapy. CTC Gr. 3–4 thrombocytopenia was seen in 8 pts following the last LTBI cycle (22%) and could be prolonged. The 2-Y Overall survival (OS) was found to be 79% (SE ± 8%) while the 2-Y disease free survival (DFS) was 74% (SE ± 10%).
Conclusion: In a selected DLBCL group of elderly patients with high-risk prognostic profile, R-CHOP-14 followed by LTBI, although sometimes associated with severe infections and thrombocytopenia, seems to achieve high response rates and provide correspondingly high OS and DFS values.
Evidence for QTLs Influencing the Endogenous Thrombin Potential (ETP) and Protein C Concentrations in a Dutch Family with Unexplained Thrombophilia.
Authors: Tanck Michael W.T. , Wichers Iris M. , Meijers Joost C.M. , Büller Harry R. , Reitsma Pieter H. , Middeldorp Saskia 
Published: October 2019

Abstract
Introduction: In Dutch families with unexplained thrombophilia (GENES study), plasma levels of the endogenous thrombin potential (ETP) discriminated affected from non-affected family members. A high variance, i.e. >60%, attributable to genetic factors was found for the ETP in one extended family. Increases in ETP levels could not be readily explained by known determinants of ETP from the coagulation cascade or anticoagulant pathways. In the present study, a genome-wide scan was performed in this family to identify quantitative trait loci (QTL) influencing ETP and several other coagulation factors.
Methods: Phenotypic data, plasma, and DNA were available for 135 of the 185 individuals in the pedigree. Patients using anticoagulation medication were excluded from the analyses. If necessary, data were transformed prior to the analyses. Multipoint Identity by Descent (IBD)-estimation and variance component multipoint (bivariate) linkage analysis including covariates were performed using SOLAR. LOD scores were empirically adjusted.
Results: For ETP levels, suggestive evidence for linkage was found at 36 cM (one-lod support interval: 1 – 61 cM) on chromosome 20 (LOD = 2.57). Interestingly, significant evidence for linkage with protein C levels (LOD=6.6) was found in the same region at 48 cM (41 – 59 cM). A bivariate LOD score of 5.8 (p<2x10−6) was obtained for this region of chromosome 20, but the correlation between the two traits due to QTL effects was low (0.10 ± 0.28, p=0.734). This finding, together with the fact that the test for complete pleiotropy had to be rejected (p<0.0001), indicates that ETP and protein C levels are most likely influenced by two different QTLs (i.e. coincident linkage) on chromosome 20.
Conclusion: In this Dutch family, ETP and protein C levels were influenced by two putative major genes, both localized in the same region of chromosome 20. This region is known to harbor several liver-enriched transcription factors, e.g. hepatocyte nuclear factor (HNF) 3b (20p11) and HNF4a (20q12-q13.1). Since most of the plasma proteins that determine the level of ETP are synthesized in the liver, these candidate genes are now further explored within this family with unexplained thrombophilia and inherited high ETP levels.
In Vivo Permanent Marking of Cells with RAG1 Activation History Demonstrates That Lymphoid and Myeloid Derived Dendritic Cells Operate an Identical Developmental Program after Their Lineage Commitment.
Authors: Chong Yong , Iino Tadafumi , Mizuno Shin-ichi , Shigematsu Hirokazu , Arinobu Yojiro , Iwasaki Hiromi , Akashi Koichi 
Published: October 2019

Abstract
Dendritic cells (DCs) have been shown to arise from both myeloid and lymphoid pathways, by evaluating the in vivo reconstituting potential of myeloid- and lymphoid-committed progenitor populations. However, evaluation of DC development after conventional adoptive transfer experiments may not correctly represent normal DC development including lineage contribution toward the formation of the DC pool. By crossing RAG1-Cre knockin with yellow fluorescence protein (YFP)-floxed reporter lines, we developed a mouse line in which cells with a history of RAG activation should be permanently marked with YFP as a result of lymphoid commitment. Lymphoid-derived DCs were successfully marked as YFP+ in vivo. We found that only ∼10% of conventional DCs (cDCs) and ∼20% of plasmacytoid DCs (pDCs) were YFP+, even in the thymus. This is a formal evidence that the majority of DCs in steady-state hematopoiesis originate from stages that have committed to the myeloid lineage. The lineage origin of DCs did not affect their functional abilities, including antigen-presentation and cytokine production. We then profiled the gene expression of the YFP+ and YFP- DCs at a genome wide level by DNA microarray analysis. Unexpectedly, the gene expression profiles of lymphoid and myeloid-derived DCs were virtually identical, irrespective of their organs. In contrast, the genetic programs were apparently different between splenic and thymic DCs, regardless of their lineage origin. Moreover, thymic DCs contained a number of more activated genes, such as MHC class II-related ones, as compared to splenic DCs. These results suggest that lymphoid and myeloid DCs might use a common developmental program that can be activated even after lymphoid or myeloid commitment. Thus, DCs are a unique cell population independent of other conventional lineage cells. Lineage-restricted DCs might be merged into an identical pool, distributed to various tissues, and finally fated by the microenvironment of their sites.
Marrow-Derived Mesenchymal Stromal Cells Can Block an Antigen-Driven Humoral Response by Suppressing Plasma Cell Activity Via Production of CCL2.
Authors: Rafei Moutih , Hsieh Jeremy , Li MengYang , Galipeau Jacques 
Published: October 2019

Abstract
Marrow-derived Mesenchymal Stromal Cells (MSCs) have been demonstrated to possess powerful immunomodulatory suppressive properties. In vitro studies by many groups have shown that MSCs can suppress th1 immune responses as exemplified by in vitro blockade of a 2-way mixed lymphocyte reaction (MLR) by an assortment of mechanisms including production of soluble factors such as: nitric oxide, transforming growth factor-β, IGF-1 and hepatocyte growth factor. Lately, interesting studies have also demonstrated the potency of MSCs in modulating humoral immunity by inhibiting B-cell migration, proliferation as well as immunoglobulin secretion in vitro. We here sought to further define the ability of autologous MSCs in modulating an ovalbumin (OVA) antigen-specific humoral response in normal immune competent C57BL/6 mice. Immunologically naïve mice were vaccinated with 50 ug of recombinant chicken ovalbumin protein followed by a boost dose 2 weeks later. All mice developed a robust IgM and IgG anti-OVA antibody response as measured in serial plasma samples over time. Following establishment of anti-OVA humoral immunity, test mice (n=10) were administered 1.5 million autologous MSCs in the peritoneal cavity twice at one month interval. Compared with same-treated controls (n=10), we found that MSC treated mice significantly suppressed anti-OVA IgG titer. This inhibitory effect requires metabolically active MSCs since live MSCs inhibited anti-OVA IgG secretion in ELISPOT assays, whereas paraformaldehyde fixed MSCs had no effect. Interestingly, the addition of MSC conditioned media directly on spleen-derived plasma cells derived form OVA immunized mice inhibited OVA-specific IgG secretion in vitro. A cytokine array screen on MSC secretome identified CCL2 as a possible effector molecule in suppressing plasma cell activity, and we found that anti-CCL2 neutralizing antibodies abolished the suppressive effect of MSCs on plasma cells. In conclusion, we have found that MSCs can suppress a pre-established humoral response to a defined antigen in vivo. This effect is contact independent, and requires metabolically active MSCs. MSC-derived CCL2 appears to be a key suppressor of antigen-specific immunoglobulin in this system.
Treatment of Indolent Non-Hodgkin’s Lymphoma in Germany - Results of a Representative Population-Based Survey.
Authors: Dreyling Martin , Fetscher Sebastian , Kornek P. , Nusch Arnd , Kornacker Martin , Angermund Ralf , Pliskat Harold , Kellermann Lenka , Kegel Thomas 
Published: October 2019

Abstract
In advanced stage indolent lymphoma, therapeutic approaches may vary from watch and wait, antibody monotherapy, conventional chemotherapy or dose-intensified consolidation up to allogeneic strategies. In this nation-wide survey, representative hematological/oncological centers monitored current treatment strategies under routine conditions. 495 centers involved in the treatment of indolent lymphoma including university hospitals (UH), community hospitals (CH), and office-based hematologists (OBH) were contacted. 13% of identified centers provided information on 741 patients corresponding to 10% of the expected national prevalence. Detailed data on 576 unselected patients (median age 67 years, range 17 to 95) with treatment decision in the second and third quarter of 2006 (start, change or end of therapy) of 46 representative centers (2 UH, 25 CH, and 19 OBH) were included in this analysis. Data were verified by monitoring anonymized patients source data. Median age was 67 with hypertension (28%), coronary heart disease (14%), diabetes (11%), heart failure (8%), cardiac arrhythmia (7%) and renal impairment (7%) being the most frequent concomitant diseases at time of diagnosis. Histology included 39% follicular lymphoma, 26% chronic lymphocytic leukemia (CLL), 10% marginal zone, 9% mantle cell lymphoma, and 16% other histologies. Aim of initial therapy was curative in 35%, aiming at improved survival in 62% and palliation in 54% of patients. Radiation (10%), antibody monotherapy (4%), chemotherapy (33%) and combined immuno-chemotherapy (31%) were the most frequent approaches. Applied chemotherapies included CHOP (46%), fludarabine combinations (F/FC/FCM: 15%), chlorambucil (14%), CVP/COP (9%), Bendamustin (4%), with maintenance (12%) and autologous/allogeneic stem cell consolidation both in 3% of patients. In first relapse, complex regimen including immuno-chemotherapy (49%), maintenance therapy (16%), and autologous/allogeneic transplantation (14%/4%) were more frequently planned. As expected, significant differences were observed between follicular, mantle cell lymphoma and CLL. Interestingly, supportive measures including antibiotics (34%), erythrocyte transfusions (32%), G-CSF (22%), immunoglobulins (19%), antifungal drugs (13%), and erythropoietin (10%) were frequently applied already in first line therapy. Overall response was 83% (FL: 97%, MCL: 95%, CLL: 74%) with a 39% CR rate. Only 10% of first line patients were treated within studies (UH: 19%, CH: 5%, OBH: 13%). In this population-based survey, patient characteristics differed significantly from published study cohorts as did clinical strategies and therapeutic approaches. Thus, clinical studies more relevant to the treatment of medically compromised patients are urgently warranted.
Primary Central Nervous System Lymphoma (PCNSL): Intent-to-Treat Analysis of Monocenter Long-Term Experience.
Authors: Korfel Agnieszka , Kiewe Philipp , Fischer Lars , Mertus Peter , Thiel Eckhard 
Published: October 2019

Abstract
Background This is a retrospective, long-term single-center analysis of immunocompetent patients with PCNSL treated at our institution.
Methods All 72 consecutive patients diagnosed with PCNSL between January 1994 and February 2005 were scheduled to receive high-dose methotrexate (HDMTX; 1.5–4 g/m2) based chemotherapy.
Results The median age of the patients was 62 years, the median Karnofsky performance status (KPS) was 70%. Twelve patients did not receive HDMTX based chemotherapy due to poor physical condition or renal insufficiency. Of 60 patients treated with HDMTX based chemotherapy, 9 were followed by whole brain irradiation (WBI). Of 54 patients evaluable for response 35 (65%) responded (52% CR and 13% PR), and 19 (35%) did not. At a median follow-up of 58.7 months, median progression-free survival (PFS) was 9 months, and median overall survival (OAS) was 41.4 months. Eight patients have survived 60 months or longer (median age 48, range 19–76; median KPS 80, range 40–100), 5 of whom relapsed after primary therapy at a median of 5 months (range, 3–39.7) after initial diagnosis. According to the Memorial Sloan-Kettering Cancer Center (MSKCC) prognosis score, patients could be divided into three groups with significantly different OAS: 52.9 months for patients younger than 50 years, 42.4 months for patients ≥50 years and with KPS ≥70, and 5.2 months for patients ≥50 years and KPS <70 (p=0.009; log-rank test). Eleven of 17 patients alive without cerebral lymphoma after 27–84 months tested exhibited clinical deficits attributable to late neurotoxicity.
Conclusions This study providing long-term data shows that a relatively moderate HDMTX-based chemotherapy can result in prolonged survival and probably cure even in older and early relapsing patients. However, the probability of late neurotoxicity with prolonged survival is considerable. The comparison of our results to other retrospective studies underscore the importance of treating PCNSL patients preferably at experienced institutions. The MSKCC score proved useful to predict survival.
Preclinical Results of the Camptothecin-Polymer Conjugate IT-101 in Multiple Human Lymphoma Xenografts.
Authors: Numbenjapon Tontanai , Wang Jianyi , Colcher David , Schluep Thomas , Davis Mark E. , Duringer Julienne , Forman Stephen J. , Raubitschek Andrew 
Published: October 2019

Abstract
Camptothecin (CPT), a natural alkaloid isolated from Camptotheca acuminata, has potent broad spectrum antitumor activity by inhibiting type I DNA topoisomerase. It has not been used clinically because it is water-insoluble and highly toxic. As a result, irinotecan (CPT-11), a water-soluble analogue of CPT, has been developed and used as salvage chemotherapy in patients with refractory/relapsed lymphoma, but with only modest activity. For intravenous administration, we have developed IT-101, a ca. 40 nm diameter nanoparticle that is an assembly of cyclodextrin-based polymer conjugates of 20-(S)-CPT. The purpose of this study is to compare the preclinical efficacy of IT-101 with CPT-11 both in vitro and in vivo. Fluorescence microscopy studies demonstrated that incubation of a human lymphoma cell line with IT-101 resulted in the uptake and intracellular accumulation of CPT. Based on the demonstration of in vitro cytotoxity of IT-101 against multiple human lymphoma cell lines, we initiated experiments in xenograft models of lymphoma. In subcutaneous human xenograft models, a single cycle of three weekly doses of intravenous IT-101 at 10 mg/kg (CPT equivalents) showed significantly potent antitumor activity against Daudi, Karpas 299, and L540 cell lines compared to three weekly doses of intraperitoneal CPT-11 at its maximum tolerated dose in mouse of 100 mg/kg (P < 0.0001, P = 0.0072, and P < 0.0001, respectively). In the same animal models, IT-101 led to pathologically complete remissions in 78%, 44%, and 78% of animals inoculated with Daudi, Karpas 299, and L540 cell lines, respectively. In disseminated human xenograft models, IT-101, administered using the same dosing schedule, significantly prolonged the survival of animals intravenously injected with either Daudi or Karpas 299 cell lines when compared to CPT-11 (P < 0.0001 and P = 0.0049, respectively). The promising present results in a variety of lymphomas provide the basis for a phase I/II clinical trial in patients with refractory/relapsed lymphoma.
Targeted Therapy with Arsenic Trioxide and Interferon alpha Eradicates Leukemic Cells in SCID Mice Model of Adult T-Cell Leukemia/Lymphoma.
Authors: Hajj Hiba El , Hasegawa Hideki , El-Sabban Marwan , Zaatari Ghazi , Saab Shehrazad , Mahfouz Rami , Nasr Rihab , Kfoury Youmna , Hermine Olivier , de Thé Hugues , Hall William , Bazarbachi Ali 
Published: October 2019

Abstract
HTLV-I associated adult T-cell leukemia (ATL) is a severe, chemotherapy-resistant malignancy associated with poor prognosis. Recently, HTLV-I Tax transgenic mice, accurately reproducing human ATL disease were generated. To develop a more consistent and rapid model of disease development, direct transfer of Tax transgenic cells into SCID mice was assessed and showed that they die within 28 days, having developed both an extremely aggressive leukemia with characteristic flower cells, and extensive lymphomatous infiltration of the spleen, lymph nodes, bone marrow, liver, kidney and lung by malignant T lymphocytes highly expressing CD25. Furthermore, and as in ATL patients, we observed marked hypercalcemia and high level of LDH. We have previously identified in vitro several potential targeted therapies for ATL. To define the optimal schedule and drug combination to be evaluated in clinical trials, we tested the following drugs using the in vivo ATL SCID model: zidovudine, interferon alpha (IFN), arsenic trioxide, the proteasome inhibitor bortezomib, and the combinations of zidovudine and IFN, or of arsenic and IFN. The combination of zidovudine and IFN had no effect on the survival of ATL SCID mice confirming the hypothesis that this combination targets the viral replication since these animals have Tax-transgenic leukemic cells but no entire HTLV-I retrovirus, contrary to ATL patients. Inhibition of NF-kappaB using bortezomib or arsenic alone almost doubled the mice survival but was not sufficient to eradicate ATL malignant cells. Strikingly, the most relevant effect on the mice survival was obtained when we used the combination of arsenic trioxide and interferon alpha, which targets both the HTLV-I Tax oncoprotein and the constitutive activation of the NF-kappaB pathway. Indeed, after 6 months of follow up, this combination totally cured 40% of the treated mice, and tripled the survival of the remaining 60%. These impressive results suggest that double targeting of Tax and NF-kappaB by the combination of arsenic trioxide and interferon alpha may suffice to cure ATL. This combination is now tested in newly diagnosed ATL patients.