bluuebunny/crossref_metadata_2025_split huggingface dataset:
Patients with aaIPI 2-3 Diffuse Large B-Cell Lymphoma Achieve 75% Long-Term Survival Following First-Line Rituximab-Supplemented High-Dose Sequential Chemotherapy and Autograft: Final Results of the Prospective Phase II GITIL (Gruppo Italiano Terapie Innovative nei Linfomi) Trial.
Authors: Tarella Corrado , Zanni Manuela , Di Nicola Massimo , Patti Caterina , Castellino Claudia , Crocchiolo Roberto , Zoli Valerio , Caracciolo Daniele , Magni Michele , Boccadoro Mario , Ciceri Fabio , Corradini Paolo , Gallamini Andrea , Majolino Ignazio , Mirto Salvo , Gianni Alessandro M. 
Published: April 2020

Abstract
Background The outcome of Diffuse Large B Cell Lymphoma (DLB-CL) has been definitely improved by the addition of the anti-CD20 rituximab to conventional chemotherapy. However, despite the advantages offered by rituximab, results are still disappointing in patients presenting with adverse prognostic factors. For these patients, rituximab-supplemented intensive programs with autograft might represent a suitable option. Thus, a prospective multicenter study has been performed using first-line the Rituximab-supplemented high-dose sequential chemotherapy program delivered with multiple autologous peripheral blood progenitor cell (PBPC) support (R-HDS-maps regimen), in DLB-CL patients with score 2 or 3 according to the age-adjusted International Prognostic Index (aaIPI). Preliminary results have been already reported (ASH 2005; Leukemia2007, 21: 1802). Updated results after a prolonged follow-up are here presented.
Methods. R-HDS-maps includes:
3 APO courses; sequential administration of hd-cyclophosphamide (CY), hd-Ara-C, both supplemented with Rituximab, hd-etoposide/Cisplatin, with PBPC harvests following hd-CY and hd-Ara-C; hd-Mitoxantrone/L-Pam + 2 further Rituximab doses; involved-field radiotherapy.
PBPC rescue was scheduled following Ara-C, etoposide/Cisplatin and Mitoxantrone/L-Pam. Six GITIL Centers participated in the multicenter study, with patients enrolled between November 1999 and September 2004.
Results. Overall, 112 consecutive patients (74 score 2, 38 score 3) entered the study protocol. There were 5 early toxic deaths (3 sepsis, 1 pneumonia, 1 JC-virus leucoencephalopathy) + one late toxic death due to pneumonia, at 10 mos.; two more patients died for secondary myelodysplastic syndrome at 3.4 and 3.6 yrs. As reported in Figures 1–2, at a median follow-up of 59 mos., 86 patients (77%) are alive; 79 (70%) are in continuous CR, with a 5-yr event-free survival (EFS) projections of 69%; no significant differences in OS and EFS between subgroups with Germinal-Center and Activated B-cell phenotype were observed.
Conclusions. R-HDS-maps regimen:
is feasible in a multicenter setting, with a toxicity similar to that of other dose-intense/high-dose regimens; offers prolonged survival to most patients with aaIPI 2–3 DLB-CL.
Its comparative efficacy versus R-CHOP-14 is being tested in an ongoing GITIL phase III study.
Figure 1 . Overall Survival of 112 aaIPI DLB-CL Figure 1. . Overall Survival of 112 aaIPI DLB-CL Figure 2. Event-free Survival according to GC and ABC phenotype Figure 2. Event-free Survival according to GC and ABC phenotype
Clinical Outcomes of Patients with Recurrent/Refractory Hodgkin Disease Receiving Cyclosporine, Interferon-γ, and Interleukin-2 Immunotherapy To Induce Autoreactivity after Autologous Stem Cell Transplantation with BEAM: A COG Study.
Authors: Chen Allen R. , Hutchison Robert , Hess Allan , Gardner Sharon , Trippett Tanya , de Alarcon Pedro , Hogan Shirley , Mitchell Joy , Massey Vickie , Constine Louis S. , Chen Lu , Schwartz Cindy L. 
Published: April 2020

Abstract
The major risk for patients with recurrent or refractory Hodgkin Disease (HD) who receive standard treatment with high-dose chemotherapy and autologous hematopoietic stem cell rescue (ASCR) is relapse. However, in HD, the allogeneic graft-vs.-lymphoma effect is offset by high transplant-related mortality. The Children’s Oncology Group has completed a pilot study of immunotherapy using cyclosporine, interferon-γ, and interleukin-2 to induce autologous graft-vs.-host disease (auto GVHD) in an effort to reduce the relapse rate without excessive morbidity and mortality. From 11/2003 to 2/2005, 24 patients with biopsy-confirmed recurrent/refractory HD were enrolled at 13 COG stem cell transplant institutions. One patient was inevaluable because of errors in protocol administration. At initial diagnosis, 5 were stage IV, 8 stage III, 7 stage II, 1 stage 1, and 3 unknown; 16 had B symptoms, and 15 had bulky disease. All patients had failed intensive multi-agent chemotherapy, and most had received prior radiation therapy. High risk patterns of relapse included extranodal disease (8), B symptoms (3), and bulky disease (2). We have previously presented the tolerability of this regimen, with the expected reversible complications and 4% non-relapse mortality. Moreover, we detected circulating autoreactive lymphocytes in vitro from the majority of patients during immunotherapy. These autoreactive lymphocytes respond to the HLA class II invariant peptide (CLIP). We therefore isolated these cells from selected patients by flow cytometry after staining with CLIP-DR2 tetramers, and demonstrated high perforin expression in CD8+ effector cells early in the course of immunotherapy, and a subsequent rise of FOXP3 expression in CD4+ regulatory T cells later in the course of immunotherapy. Importantly, CLIP was strongly expressed on the surface of Hodgkin Reed-Sternberg cells, as demonstrated by monoclonal antibody LN2 immunostaining of tumor samples from 8/9 patients for whom adequate tissue was submitted. To date, only 6 relapses have been reported. Updated event-free and overall survival data will be presented. We conclude that this immunotherapy regimen is tolerable, induces autoreactivity in a majority of patients, targets a molecule expressed consistently on Hodgkin Reed-Sternberg cells, and has produced encouraging clinical outcomes. We will proceed to test the efficacy of this immunotherapy regimen by randomizing patients with chemosensitive recurrent/refractory HD to receive immunotherapy or not after BEAM and ASCR.
When May Patients Be Considered Cured after Autografting for Hodgkin Lymphoma?.
Authors: Dean Robert M. , Sweetenham John W. , Jin Tao , Brown Stacey , Pohlman Brad , Sobecks Ronald , Kalaycio Matt , Andresen Steve , Copelan Edward , Bolwell Brian J. 
Published: April 2020

Abstract
Patients who undergo high-dose chemotherapy with autologous stem cell transplantation (ASCT) for Hodgkin lymphoma routinely undergo surveillance for post-transplant recurrence. Follow-up schedules after ASCT are based largely upon expert opinion rather than data. To formally describe the evolution of recurrence risk over time for Hodgkin lymphoma after ASCT, we used a prospectively maintained database to retrospectively evaluate the outcomes of 245 patients who underwent ASCT for Hodgkin lymphoma at the Cleveland Clinic Foundation from 1985 through 2005. Patient characteristics: male gender in 64%; median age, 34 years (range, 18–70); median time from diagnosis to transplant, 22 months (4–327); Karnofsky score &gt; 80 in 89%; median 2 prior regimens (1–4); prior XRT in 52%; bulky disease &gt; 10 cm in 20%; stage III-IV in 62%; disease status of CR1/PR1 in 8%, CR2/PR2 in 69%, refractory in 11%, other in 12%; preparative regimen of BuCyVP in 65%, CBV in 26%, TBI/others in 9%. Median follow-up after ASCT for all pts was 35 months (0–223); for surviving pts, 74 months (3–223). At 5 years, estimated overall survival and relapse-free survival were 47% and 36%, respectively. Relapse occurred in 115 pts, with 5-year relapse rate estimated at 44% (Figure).
Figure Figure
Landmark analyses were conducted to estimate long-term outcomes for patients in remission at various times after ASCT, as shown in the Table:
Duration of Remission after ASCT Long-Term Likelihood of Continued Remission 1 year 63.8% 2 years 78,8% 3 years 83.0% 5 years 97.0%
These data illustrate the declining threat of relapse that faces patients who achieve remission following ASCT for Hodgkin lymphoma. Most patients who are destined to experience disease recurrence after ASCT do so within the first 2 years post-transplant. Patients who remain in remission 5 years after ASCT are at extremely low risk for subsequent relapse and can be reassured that they are likely cured. This analysis provides a factual basis to support gradually decreasing the frequency of surveillance visits and to discontinue routine monitoring for relapse at 5 years after ASCT.
High-Dose Cytoxan, Etoposide, and Cisplatin Followed by Autologous Hematopoietic Cell Transplantation for the Treatment of Hodgkin Lymphoma: A 20-Year Single-Institutional Experience.
Authors: Klumpp Thomas R. , Chasky Moshe C. , Emmons Robert V. , Martin Mary E. , Gajewski James L. , Mangan Kenneth F. 
Published: April 2020

Abstract
Since 1988 we have treated 66 patients with relapsed, refractory, or high-risk Hodgkin lymphoma (HD) with high-dose CEP consisting of cyclophosphamide 1,500 mg/m2/day × 4 (total dose, 6,000 mg/m2), etoposide 400 mg/m2 twice daily × 6 doses (total dose, 2,400 mg/m2), and cisplatin 50 mg/m2/day × 3 by continuous i.v. infusion (total dose 150 mg/m2) followed by infusion of autologous peripheral blood stem cells (n=49), bone marrow (n=16), or both (n=1). The patient population included 41 males and 25 females. The median age at transplant was 33 years (range, 17–64 years). Twenty-three patients (35%) had never achieved complete remission prior to transplant, 36 (55%) had previously achieved a complete remission but subsequently relapsed, and 3 (5%) were in first complete remission. Information regarding the disease status at transplant was unavailable for 4 patients (6%). Twenty-seven patients (41%) remain alive and free of any post-transplant relapse or progression as of the most recent follow-up, and an additional 10 patients (15%) manifested active disease post-transplant but are currently in remission following additional post-transplant therapy, yielding a total of 37 patients (56%) currently in CR. In addition, 5 patients (8%) remain alive with active disease, 23 patients (35%) died of progressive disease, and only 2 patients (3%) died of treatment-related causes including diffuse alveolar hemorrhage (1 patient) and hepatic veno-occlussive disease (1 patient). With a median follow-up of 4.4 years among surviving patients, the Kaplan-Meier 5-year estimates for event-free survival and overall survival are 34% and 60%, respectively, and five-year survival was superior among patients who had achieved at least one CR prior to transplant versus patients who had never been in CR prior to transplant (71% versus 43%, p = 0.03). Detailed adverse events data is available regarding all patients transplanted since September 1996: Of these, only 3 (7%) suffered grade 3 or greater pulmonary toxicity, 12 (29%) exhibited grade 3 or higher mucositis, and 10 (24%) had grade 3 or higher nausea or vomiting. The median number of days from transplant to neutrophil recovery (500 cells/uL) was 10 days, whereas the median number of days to platelet recovery (20,000 cells/uL) was 12 days. We conclude that high- dose CEP followed by autologous transplant is an active and well-tolerated treatment program in patients with relapsed or refractory HD. The low incidence of pulmonary toxicity is noteworthy given that a high percentage of patients had been exposed to bleomycin and/or thoracic XRT prior to transplant, and appears to be superior to that reported with conventional CBV-conditioned transplants in patients with HD.
Phenotypic and Functional Characterization of Mesenchymal Stromal Cells Derived from CD271+- Bone Marrow Mononuclear Cells and Mesenchymal Stromal Cells Derived through Plastic Adherence.
Authors: Kuci Selim , Puetsch Kathrin , Kuci Zyrafete , Huenecke Sabine , Kreyenberg Hermann , Amara Chandra Sekhar , Piechaczek Christoph , Koehl Ulrike , Klingebiel Thomas , Bader Peter 
Published: April 2020

Abstract
Mesenchymal stromal cells (MSCs) are non- hematopoietic multipotent cells which can be derived from bone marrow mononuclear cells either by plastic adherence (PA-MSCs) or by a positive selection with antibodies against cell surface antigens expressed by MSC-progenitor cells (CD271, CD73, CD146, CD105, CD166, SSEA-4 and recently GD2). In this study, we compare the phenotype, proliferation potential, differentiation potential, the cytokine expression pattern and inhibitory potential of MSC- derived by plastic adherence and MSCs derived from positively selected CD271+ bone marrow mononuclear cells (BM-MNCs). According to CFU-F assay, the enriched CD271+ BM cells possess a significantly higher frequency (2952 per 1×106 BM cells) compared to PA-MSCs (21 per 1×106 BM cells). Phenotypically, both populations expressed high levels of common MSC antigens such as CD73, CD105, CD44, CD166, CD90, HLA-Class I and were negative for CD34, CD133, and CD14. Compared to PA-MSCs, CD271+ BM cells after the isolation express high levels of the hematopoietic antigen CD45 which is down- regulated within the first passage and HLA-DR, which remains constant through many passages. These cells have a 10- to 1000-fold higher proliferation capacity compared to PA- MSCs. However, both populations differentiated in vitro along adipogenic, chondrogenic and osteogenic lineage. In MLR, both populations significantly suppressed the proliferation of PHA- stimulated allogeneic T- lymphocytes at the ratio 10: 1 (MSCs:T-cells). However, CD271+ BM- derived MSCs were more efficient in secreting IFN-γ, IL-1β, IL-2, IL-4, GM-CSF and TNF-α, whereas PA- MSCs secreted significantly more IL-6 and IL-8 than CD271+ BM- derived MSCs. Ongoing in vivo studies with immunodeficient NOD/SCID mice will show the whole potential of both population in the improvement of engraftment of mobilized peripheral blood hemaatopoietic CD133+ cells. Based on their higher frequency and proliferation capacity we suggest that CD271+ BM- cells may represent a better source than PA- MSCs in order to generate bulk quantities of MSCs for clinical applications.
Inhibition of Rhabdomyosarcoma’s Bone Marrow Metastasis through Blocking of MET Receptor Signaling.
Authors: Lesko Ewa , Miekus Katarzyna , Kijowski Jacek , Drabik Grazyna , Wilusz Miroslawa , Majka Marcin 
Published: April 2020

Abstract
Rhabdomyosarcoma (RMS) is a pediatric soft tissue sarcoma belonging to family of small blue cell tumors and it represents the largest subset of soft tissue sarcomas in this age group. RMS can be divided into two major subtypes based on chromosomal analysis - embryonal (ERMS) without translocations and alveolar (ARMS) with translocations. They differ in clinical outcome with ERMS having more favorable prognosis. However, nevertheless of subtype, if RMS is diagnosed at late stage (IV) or with metastatic disease the outcome is usually poor with only 21% of 5 years overall survival. RMS gives distant metastasis to various organs but predominantly to lung and bone marrow. Recently, MET receptor, which is highly expressed on RMS cells, has been shown to mediate RMS cells motility. Since HGF, a ligand for MET receptor, is abundantly expressed by bone marrow cells, it was also postulated that MET could be involved in bone marrow metastasis of RMS (Jankowski et al. Cancer Research 2003). In this study we have shown that blocking of MET receptor expression by RNA interference (RNAi) has strong influence on metastatic behavior of RMS cells both in vitro and in vivo. Using RNAi we created both ERMS and ARMS cell lines that lack MET receptor expression as was assessed by qRT-PCR and Western blotting. We showed in vitro that these cells possessed a reduced potential to migrate toward HGF (as study by chemotaxis, invasion and “would healing’ assays) and to secrete extracellular matrix degrading enzymes after stimulation with HGF. However, we did not see any influence of MET downregulation on mitogenic potential of RMS cells. We also found that inhibition of HGF-MET signaling blocks adhesion of RMS to stromal and endothelial cells. Most importantly, inactivation of HGF-MET axis strongly suppressed the ability of RMS cells to engraft and populate bone marrow cavities both in short and long term in vivo assays. In 24 hour seeding assay all mice injected i.v. with wild type RMS had detectable tumor cells in their bone marrow as measured by qRT-PCR and flow cytometry. At the same time mice injected with MET negative cells had bone marrow cavities free of tumor. In long term assay mice were injected s.c. with 5×106 RMS and after 30 days presence of tumor cells in bone marrow was investigated. qRT-PCR analysis revealed that 100% of mice injected with wild type cells and only 50% of mice injected with RMS negative cells had metastatic tumor in their bone marrow. In summary, we conclude that MET receptor plays a very important role in facilitating metastasis of RMS into bone marrow and that blocking of HGF-MET axis could be used in the future as a therapeutic option to inhibit spreading of RMS into this organ.
Significance of Suboptimal Response to Imatinib, as Defined by the European LeukemiaNet, in Long-Term Outcome for Patients (Pts) with Chronic Phase (CP) Chronic Myeloid Leukemia (CML).
Authors: Alvarado Yesid , Kantarjian Hagop , Faderl Stefan , Burger Jan , Borthakur Gautam , O’Brien Susan , Wierda William , Garcia-Manero Guillermo , Cortes Jorge 
Published: April 2020

Abstract
The European LeukemiaNet recently published recommendations for evaluating response to imatinib among pts with CML. Criteria for failure and suboptimal responses were proposed. The significance of failure is accepted and constitutes grounds for change in treatment. The prognostic implications of having a suboptimal response are less clear making treatment decisions less clear in this setting. We analyzed the outcome of 281 pts treated with imatinib as frontline therapy for CML in CP: 73 at initial dose of 400mg daily and 208 at 800mg daily. Their median age was 48 yrs (range, 15 to 84 yrs) and their median follow-up 48 months (mo) (2–79 mo). After 3 mo of therapy none of the 273 evaluable pts met definition of suboptimal response according to the European LeukemiaNet, while 3 of 273 (1%) met definition for failure. At 6 mo 10/259 (4%) evaluable had suboptimal response and 9 (3%) failure. At 12 mo 19/246 (8%) had suboptimal and 14 (6%) failure, and at 18 mo 91/224 (41%) had suboptimal and 21 (9%) had failure. The probability of having a suboptimal response at 6 and 12 mo was significantly higher for pts treated with a starting dose of 400mg than those treated at 800mg: at 6 mo [12% suboptimal at 400mg vs 1% at 800mg (p=0.002)] and at 12 mo [17% and 4%, respectively (p&lt;0.001)]. The outcome at 24 months* by the response at specific times was as follows:
Time Response % CCyR % MMR % Transf % Event CCyR=Complete cytogenetic remission, MMR=Major molecular remission, Transf=Transformation to accelerated or blast phase, Event=loss of complete hematologic response, loss of major cytogenetic response, transformation, or death 6 mo Optimal 91 60 2 6 Suboptimal 0 0 30 50 Failure 0 0 22 67 P .001 .001 .001 .001 12 mo Optimal 94 63 2 4 Suboptimal 56 25 0 16 Failure 0 0 21 57 P .001 .001 .001 .001 18 mo Optimal 98 85 0 1 Suboptimal 93 39 2 5 Failure 15 0 19 43 P .001 .001 .001 .001
Bone Marrow Reaction in Patients with Chronic GvHD - An Immunohistochemical Analysis of Microvessels and Lymphocytes.
Authors: Hill Wolfgang , Huss Ralf , Ullmann Johanna , Ledderose Georg , Tischer Johanna , Hausmann Andreas , Kolb Hans-Jochem 
Published: April 2020

Abstract
Chronic GvHD (cGvHD) is associated with endothelial injury mediated by cytotoxic T lymphocytes and loss of microvessels in skin biopsies as well as increase of von Willebrand factor in plasma (BC Biedermann, Lancet 2002). Moreover an increased quantity of CD45RO positive lymphocytes has been observed in bone marrow biopsies (bmb) in CML pts with acute GvHD (aGvHD) grade III and lV, who were transplanted from unrelated donors (J Thiele, Bone marrow transplantation 2001). We analysed factors of T-cell activation and microvessels in bmb of pts with cGvHD to evaluate the function of the bone marrow in cGvHD.
Methods: In an associated protocol of a prospective phase II study in 35 pts for the therapy of bone loss following HSCT with a bisphosphonate one bmb was taken prior of entry into the study and embedded in paraffin after decalcification. The interval between HSCT and time of biopsy was median 477 +/−998 days. For conventional semiquantitative evaluation of marrow and spongiosa a Giemsa staining was used. For immunological quantitative evaluation the following monoclonal antibodies were used with the APAAP method: CD34 and von Willebrand factor (VWF) for endothels of microvessels and CD45RO and CD8 for T-lymphocytes subsets. The pts were divided in 5 groups:
neither aGvHD nor cGvHD; no cGvHD but aGvHD before entry; cGvHD limited; cGvHD extensive inactive; cGvHD extensive active, needing immunosuppression.
Results: Conventionally analysed no pt had evidence of vasculitis. 1 pt of group 4 had one small immunoreactive aggregate of lymphocytes another pt of group 5 had a diffuse infiltration with lymphocytes. 32 pts had no or very small reduction of spongiosa and 3 had severe reduction of spongiosa &lt; 15%. The significant immunological results were:
Number/mm2 1. no GVHD (n=6) 2. aGvHD before (n=4) 3. cGvHD limited (n=5) 4. cGvHD ext. inactive (n=8) 5. cGvHD ext. active (n=12) p (group No) CD34+ vessels 12,6 10,4 8,5 20,7 27,9 &lt; 0,001 (1,2,3 vs 4,5) V. Willebrand 6,5 13,2 18,6 17,6 18,9 0,005 (1,2 vs 3,4,5) CD8+ 5,8 4,0 6,8 10,2 25,3 0,034 (1,2,3 vs 4,5)
The number of CD34 as well as the number of vWF positive microvessels increased with the grade of involvement and activity of cGvHD (11,1 vs 25,3 respectively 8,7 vs 18,1). Additionally the content of CD8 positive lymphocytes increased with the grade and activity of disease. In contrast to reported skin biopsies, bone marrow capillaries were not destroyed by cytotoxic lymphocytes with increased activity. The bone marrow seems to show a different immunological reaction in contrast to pts with cGvHD of whom the target organs are skin, liver or gut. This was not observed on conventional biopsies. Further studies will be directed to the pattern of microvessels with regard to hematopoietic function and relapse.