bluuebunny/crossref_metadata_2025_split huggingface dataset:
Protection Against Graft-Versus-Host Disease and Retention of Graft-Versus-Tumor Effect after Allogeneic BMT in Mice Conditioned with TLI and Anti-Thymocyte Serum.
Authors: Pillai Asha , Teo Pearline , Strober Samuel 
Published: April 2020

Abstract
In a completely MHC-mismatched model of bone marrow transplantation [C57BL/6 (H-2b) donors into BALB/c (H-2d) hosts], we have developed a technique of non-myeloablative host conditioning using fractionated total lymphoid irradiation (TLI) and and anti-thymocyte serum (ATS) that prevents lethal graft-versus-host disease (GVHD). We have previously reported that this GVHD prevention is dependent on the secretion of IL-4 and on host regulatory NKT cells. In the current study, we assessed the graft-versus-tumor (GVT) effect of BMT to determine whether the GVT effect remains intact in this non-myeloablative conditioning model. Male BALB/c mice were given fractionated TLI (17 doses of 240 cGy each), 3 doses of ATS, and subsequently received intravenous infusion of 50 x 106 bone marrow and 60x 106 splenocytes from C57BL/6 donors, with and without the BCL1 B-cell lymphoma. Animals were observed for minimum of 100 days, and underwent autopsy at death to assess for sub-clinical evidence of GVHD or tumor infiltration.
TLI/ATS-conditioned mice achieved a high percentage of donor chimerism, in the range of 50–100% in all lineages. TLI/ATS-conditioned hosts uniformly survived without signs of GVHD beyond day +100. By contrast, hosts conditioned with a single dose of 800cGy total body irradiation (TBI) died of acute GVHD (severe diarrhea, hunched back, weight loss) by day +21. When TBI/ATS or TBI-treated mice receive bone marrow, splenocytes, and BCL1 lymphoma, all hosts died with signs of acute GVHD by day +28. TLI/ATS-conditioned hosts receiving marrow, splenocytes and tumor cells showed no evidence of disease progression by day +100 and either cleared tumor idiotype completely or had persistence of low-intensity staining for tumor idiotype (tumor dormancy). TLI/ATS-conditioned hosts given BCL1 tumor cells without allogeneic BMT all succumbed to tumor. TLI/ATS hosts receiving bone marrow plus BCL1 without splenocytes all died by day +108 with high circulating BCL1 tumor burden and no clinical evidence of GVHD.
The data indicate that peripheral donor T cells are necessary to maintain a robust graft-versus-tumor effect after TLI/ATS conditioning, and that complete donor chimerism is not a requirement for tumor eradication. In conclusion, using the TLI/ATS non-myeloablative conditioning regimen, it is possible to maintain a clinically significant graft-versus-tumor effect without inducing GVHD despite a high dose of infused donor peripheral T cells.
Treatment for Acute Myelogenous Leukemia by Low Dose Irradiation Based Conditioning and Hematopoietic Cell Transplantation from Related and Unrelated Donors.
Authors: Niederwieser Dietger W. , Hegenbart Ute , Sandmaier Brenda M. , Maris Michael B. , Stuart Monic , Greinix Hildegard , Cordonnier Catherine , Rio Bernard , Gratwohl Alois , Lange Thoralf , Pönisch Wolfram , Grommisch Leante , Storer Barry , Maloney David , McSweeney Peter , Chauncey Thomas , Agura Ed , Blume Karl , Storb Rainer 
Published: April 2020

Abstract
Conventional allogeneic hematopoietic cell transplantation (HCT) is effective treatment for AML, but its use has been restricted to younger patients in good medical condition. However, AML is increasingly common with advancing age, and older patients have more adverse prognostic features than younger patients. The vast majority of older patients who reach a CR with chemotherapy relapse within two years from diagnosis and die within three years. The situation is similar in patients with secondary AML or with AML in CR2, more advanced remission status or in partial remission, where median duration of disease-free survival (DFS) is generally &lt;12 months. The use of low-dose irradiation-based preparative regimens has allowed extending allografting to, and exploring graft-versus-tumor effects in, older and medically infirm patients.
The present study included 122 patients with AML ineligible for conventional transplants. Their disease stages ranged from CR1 to resistant disease, and their median age was 57.5 (range 17–74) years. The patients were given 2 Gy total body irradiation (TBI) on day 0 with and without preceding fludarabine (30 mg/m2/d from days -4 to -2). After HCT, cyclosporine, 6.25 mg/kg, was given twice daily from day -3, and mycophenolate mofetil, 15 mg/kg, twice daily from day 0. HLA-matched related donors were used in 58, and HLA-matched/partially matched unrelated donors in 64 patients. Among 121 (one died to early after transplant) evaluable patients, 116 (95.8%) had durable engraftment. Cumulative incidences of acute GvHD grade II-IV were 33 % after related and 42% after unrelated HCT. With a median observation time of 17 (range 4–57) months, 58 patients were alive, 53 of whom were in complete remissions. Cumulative non-relapse mortalities (NRM) were 12% and 27%, and the cumulative relapse mortalities were 47% and 34% at 2 years for related and unrelated recipients, respectively. Two-year overall survival (OS) was 41%, and DFS was 35%, with stages of the disease and cytogenetic risks being major determinants for outcomes. Patients transplanted in CR1 had a 2-year OS of 40% after related and 57% after unrelated HCT. We concluded that HCT from related and unrelated donors after low-dose TBI is promising therapy for elderly patients and medically infirm younger patients with AML not eligible for conventional HCT. Due to the lower relapse rates, results in patients with unrelated donors were better than results in patients with related donors. Results have encouraged studies of the role of low-dose irradiation-based conditioning and allogeneic HCT in the primary treatment of patients with AML ≥60 years.
Acquired Hemophilia Caused by Non-Hemophilic Factor VIII Gene Variants.
Authors: Tiede Andreas , Eisert Roswith , Czwalinna Andreas , Miesbach Wolfgang , Scharrer Inge , Ganser Arnold , von Depka Mario 
Published: April 2020

Abstract
The development of inhibitory antibodies against coagulation factor VIII (FVIII) in patients without congenital hemophilia A is a rare disorder known as acquired hemophilia. The etiology of the disease remains obscure. In approximately half of the patients, acquired hemophilia is associated with autoimmune disease, malignancy, multiple transfusions or the postpartum period. The remaining patients present without concomitant disorders. We hypothesized that anti-FVIII inhibitor formation might result from allo-immunization against antigenetically different FVIII variants in some patients with acquired hemophilia. The FVIII gene sequence was analyzed in 18 patients with acquired hemophilia and in two kindred of female patients with postpartal inhibitors. A hemizygous missense mutation (E2004K) was found in a male patient who developed an inhibitor after receiving multiple blood transfusions. This mutation has not been reported in the HAMSTeRS database and was not found in 50 male and 50 female healthy blood donors. It does not cause inherited hemophilia A as demonstrated by the patient’s unremarkable bleeding history before the onset of acquired hemophilia and a FVIII activity of &gt;100 % after eradication of the inhibitor. Peptides containing E2004 or K2004 scored among the top 1 % of A3 domain-derived peptides presented on the patient’s major histocompatibility complex (MHC) class II allele, HLA-DRB1*0101. A further single amino acid substitution (D1241E) was found in four male patients and three female patients. This substitution resides in the FVIII B domain and represents a previously unknown polymorphism as it was also found in eight out of 50 male and in 17 out of 50 female controls. Comparing the allelic frequency of FVIII gene variants in patients and controls, these were equally frequent in female patients (3/18 or 17 %) and controls (18/100 or 18 %, P=0.74), but significantly more frequent in male patients (5/9 or 56 %) compared to male controls (8/50 or 16 %, P&lt;0.01). Peptides containing D1241 or E1241 scored among the top 2 % of B domain-derived peptides presented on some MHC class II alleles (HLA-DRB1*0701 and *1501), but were unlikely to be presented on other alleles (*0101, *0301, *0401, *1101). In summary, we report allo-immunization against antigenetically relevant FVIII variants presented in a suitable MHC class II background as a novel potential mechanism of inhibitor development. Thus, exposure to ‘foreign’ FVIII variants during pregnancy or transfusion may elicit an immune response that eventually cross-reacts with ‘self’ FVIII in some patients resulting in acquired hemophilia. Similar inhibitory immune reactions may also cause loss of efficacy in patients receiving other therapeutic proteins, e.g. erythropoietin, or multiple transfusions.
Pathology of Bone Marrow in Human Herpes Virus 8 (HHV8) - Associated Multicentric Castleman’s Disease.
Authors: Bacon Chris M. , Miller Robert F. , Noursadeghi Mahdad , McNamara Christopher , Du Ming-Qing , Dogan Ahmet 
Published: April 2020

Abstract
Human Herpes virus 8 (HHV8) associated multicentric Castleman’s disease (MCD) is an unusual multifocal lymphoid hyperplasia induced by HHV8 infected B cells and associated with a characteristic systemic syndrome attributed to raised levels of IL-6. Most cases develop on a background of immunosuppression, often as a result of human immunodeficiency virus (HIV) infection. Despite the haematological problems at presentation and the difficulties in initial diagnosis, the bone marrow appearances of MCD have not been so far described. In this study we examined the pathology of bone marrow in 13 patients with MCD, 11 of whom had HIV infection, with a view to identifying features that may be helpful in early diagnosis. Patients typically presented with fever, lymphadenopathy, hepatosplenomegaly and cytopaenias. Bone marrow aspirates showed mild to moderate trilineage dysplasia, a mild plasmacytosis, and a mild eosinophilia similar to that seen in HIV infected patients without MCD. Bone marrow biopsies showed hypercellularity, architectural disorganisation, variably prominent dysplasia especially in megakaryocytes, mild eosinophilia, and a polytypic plasmacytosis representing 5–20% of all cells. Interestingly, two cases showed marked megakaryocytic and granulocytic hyperplasia with reticulin fibrosis, similar to the effects of IL-6 on the marrow in experimental systems. Importantly, in 3 cases there were small lymphoid follicles typical of MCD in diagnostic nodal specimens. Depleted germinal centres were surrounded by mantle zones containing scattered large plasmablasts which expressed HHV8 latent nuclear antigen (LNA) and showed lambda immunoglobulin light chain restriction. Furthermore, varying numbers of dispersed interstitial HHV8-LNA positive plasmablasts were present in 11/13 cases. Double immunohistochemical staining confirmed the B cell phenotype of these plasmablasts. The presence of these cells was highly specific for MCD as rare single HHV8 positive cells were identified in only 4 of 66 control bone marrow biopsies from HIV positive patients. Each of these 4 patients had Kaposi’s sarcoma and 1 also had a primary effusion lymphoma. HHV8 positive cells were not identified in bone marrow biopsies from 23 other HIV positive patients with lymphoma. These results suggest that the presence of HHV8 positive plasmablasts in bone marrow biopsies, within characteristic lymphoid follicles and/or the interstitium, is highly specific and sensitive for MCD. As the examination of bone marrow is the first diagnostic test performed in virtually all MCD patients, the features described in this study should greatly enhance the chances of early diagnosis by either providing the tissue diagnosis or prompting a lymph node biopsy and further investigations. Furthermore, the HHV8 positive cells within the bone marrow may play an important pathogenetic role in the haematological disturbances typically seen in MCD.
Prognostic Factors in Localized Hodgkin’s Lymphoma: How To Define Intermediate/Unfavourable Disease?.
Authors: Gisselbrecht Christian , Mounier Nicolas , Casanovas Olivier , Reman O. , Sebban Catherine , Divine Marine , Brice Pauline , Briere Josette , Hennequin Christophe , Feugier Pierre , Ferme Christophe 
Published: April 2020

Abstract
Actually, the prognosis of localized Hodgkin’s lymphoma (HL) patients may be assessed by different scoring systems. Although many similar characteristics have been identified, these scoring systems are not easy to relate to advanced stage HL. The aim of the present study was to refine the assessment of risk using the published scoring systems and to construct a statistical model for predicting risk of death. We report here the results of the EORTC, GHSG and Canadian-ECOG scoring systems obtained in 1156 patients for whom hematological data were available among the 1390 patients with localized HL prospectively treated within GELA centres in H8 (518 pts) and H9 (638 pts) trials. The International prognostic score (IPS) was available only for the H9 subset. All patients have been treated with radio-chemotherapy of different intensity or duration according to their prognostic factors. Median age was 30 yr [14–69] and age≥45yr.: 18%, female 50%; stage 1: 25%; stage 2: 75%; B symptoms with elevated ESR: 40%; number of nodal sites 1–2: 52%; ≥3: 48%; extra nodal involvement: 8%, bulky mediastinum&gt; 0.35, 28%; elevated ESR&gt; 50:33%; Hb&lt; 10.5 g/dl: 7%; Lymphocytes &lt; 600/μl: 6%; WBC &gt; 15000/μl:11 %; albumin&lt; 40g/l: 37%. With the EORTC scoring system 36% of patients had favourable HL, with GHSG 35% and with Canadian-ECOG 38%. The IPS was 0 in 19% and 1 in 45%. With a median follow up of 42 months, 54 patients died. Survival curves according to the different scoring systems significantly discriminated favourable and unfavourable patients outcomes (5 yrs OS 95% vs 92%, p=0.01). By multivariate Cox analysis, age &gt; 45yr (RR=2.0), sex male (RR=2.5), haemoglobin &lt;10.5g/dl (RR=2.3), lymphocytes &lt; 600/μL (RR=3.6), B symptoms with elevated ESR (RR=3.6), extra nodal sites (RR=1.2) retained a significant prognostic value. The 5 yrs OS was 99%, 98%, 92%, 82%, 73% for patients with 0,1, 2, 3, 4–5 factors respectively (p&lt; 0.0001, see figure). 10% of the patients had 3–5 factors. The covariates selection was validated by the bootstrap method. The introduction of albumin&lt; 40g/l in the H9 subset population did not bring more significant information. In conclusion, these factors are similar with those described in the IPS when stages 3–4 are replaced by extra nodal (E) localization. They should be validated in other prospective trials because such a scoring system could unify the assessment of the prognosis for HL patients and facilitate the treatment choice.
Figure Figure
African Americans and Caucasians with Myeloma Have Similar Outcomes in the Current Era: A Tumor Registry Study.
Authors: McClune Brian , Kumar Birendra , Buadi Francis , Womeodu Robin , Wright Kathy , Baskin Reed , Minhas Sohail , Ratliff Thomas W. , Spiers Kathleen , Yunus Furhan , Przepiorka Donna 
Published: April 2020

Abstract
Multiple myeloma is essentially an incurable disease, and SEER data suggests striking differences in survival between caucasians and African Americans. Recent advances in stem cell transplantation, however, can improve survival. To determine whether survivals continue to differ between caucasians and African Americans in the era of stem cell transplantation, we performed a retrospective analysis of 474 patients identified from a hospital tumor registry with a diagnosis of myeloma made consecutively from 1981 to 2000. The study cohort was comprised of 238 African Americans and 236 caucasians. Seven patients were lost in follow-up while still alive, and the remainder have either died or have follow-up to within one year of the analysis. There were 239 females and 235 males, and the distribution by gender did not differ by race (p=0.93). Median age of the cohort was 70 years (range 30–95 years); 6.5% were &lt;50 years old, 67.9% 51–75 years old, and 25.5% &gt;75 years old. The distribution by age differed significantly by race. A higher proportion of African Americans were diagnosed when &lt;50 years old or when &gt;75 years old in comparison to caucasians (p=0.006). Median survival for the entire cohort was 2.07 years, 1.92 years for African Americans and 2.31 years for caucasians (p=0.475). The difference in survival was essentially limited to patients diagnosed prior to 1996 (1.84 years vs 2.33 years, p=0.02). For patients diagnosed 1996–2000, the median survivals were similar (2.27 years vs 2.03 years, p=0.89). In a multivariate analysis, increasing age group was significantly predictive of poorer survival, but race, gender and quartile of year of diagnosis were not independent risk factors. We conclude that race is no longer associated with poorer survival for patients with myeloma.
Severe Gemcitabine-Associated Lung Injury in Hodgkins Disease & Other Cancers: Reporting Quality and Clinical Characteristics of Cases Reported in the Medical Literature and to the FDA.
Authors: Belknap Steven M. , Slimack Nicolas , Kuzel Timothy , Carson Kenneth R. , Yarnold Paul R. , Raisch Dennis W. , Trifilio Steven M. , Bennett Charles L. 
Published: April 2020

Abstract
Background: In view of concern about substantially increased risk of gemcitabine-associated lung injury (ALI), vigilant post-marketing surveillance is necessary to further characterize the frequency, severity, and clinical features of gemcitabine-associated pulmonary injury.
Methods: From 2001–2003, investigators with the Research on Adverse Drug reactions And Reports (RADAR) program compared the clinical characteristics and adverse event reporting quality of gemcitabine-associated lung injury contained in published case reports and adverse event reports submitted in the setting of clinical trials or the non-clinical trial setting.
Results: Completeness of reporting was excellent for published case reports and intermediate to poor for FDA adverse event reports from clinical trials or observational studies, including age (100%, 92%, 91%); time to onset of toxicity (100%, 63%, 58%); dose (97%, 63%, 79%); results of imaging studies (94%, 56%, 59%); presence/absence of hypoxia (97%, 6%, 4%); and cause of death (88%, 82%, 66%). Temporal analyses identified a bimodal pattern for the onset of pulmonary symptoms: 90% occurred before 150 days and 8% after 300 days. The highest rates of severe lung injury were in high dose patients co-administered bleomycin (28%) and in lung cancer patients (16%).
Conclusions: Reporting completeness for severe gemcitabine-ALI to the FDA from the clinical trial and the non-clinical trial setting is poor, limiting the ability of the RADAR group to comprehensively assess this toxicity. Nonetheless, this toxicity is severe and, as shown in published case reports, frequent in the presence of concomitant pulmonary insults such as bleomycin-containing combination chemotherapy regimens for Hodgkin’s disease and taxol-containig combination chemotherapy regimens for lung cancer.
Gemcitabine-associated Acute Lung Injury in Selected Clinical Trials
Author DX Other ChemoRx N ALI % Friedberg JW Hodgkin Doxorubicin, Bleomycin, Vinblastine 12 5 42 Bredenfeld H Hodgkin BA_COPP 27 6 22 Chen YM Non-SCLC Vinorelbine 20 5 25 Popa IE Non-SCLC Docetaxel 32 6 19 Herbst RS Non-SCLC Vinorelbine 36 5 14 Blackstock AW Non-SCLC 16 2 13 Bhatia S Non-SCLC Paclitaxel 34 4 12 Safran H Pancr. Ca Paclitaxel, Radiation 19 2 11 Lobo F Breast Ca Vinorelbine, Anthracyclines 21 2 10
Tracing the Pre-B to Immature B Cell Transition in Human Leukemia Cells Reveals a Coordinated Sequence of Primary and Secondary IGK Gene Rearrangement, IGK Deletion and IGL Gene Rearrangement.
Authors: Klein Florian , Feldhahn Niklas , Mooster Jana L. , Wernet Peter , Müschen Markus 
Published: April 2020

Abstract
The BCR-ABL1 kinase expressed in acute lymphoblastic leukemia (ALL) drives malignant transformation of pre-B cells in humans and prevents further development. We studied whether inhibition of BCR-ABL1 kinase activity using STI571 can relieve this differentiation block. STI571 treatment of leukemia patients induced expression of the Ig light chain-associated transcription factors IRF4 and SPIB. Upregulation of RAG1 and RAG2, Cκ and Cλ germline transcription and rearrangement of IGK and IGL genes were also observed in cell culture experiments. However, STI571-treated pre-B ALL cells expressed λ- but almost no κ-light chains. This could be explained by STI571-induced rearrangement of the κ-deleting element (KDE), which can delete productively rearranged Vκ-Jκ joints. Amplifying short-lived DNA intermediates from double-strand breaks at recombination signal sequences within the IGK, KDE and IGL loci revealed a coordinated sequence of rearrangement events induced by STI571: Recombination of IGK gene segments is already initiated within one hour after STI571-treatment, followed by KDE-mediated deletion of Vκ-Jκ-joints six hours later and, ultimately, IGL gene rearrangement after 12 hours. Consistently, upregulation of Cκ and Cλ germline transcripts, indicating opening of IGK and IGL loci, was detected after one and six hours for IGK and IGL, respectively. Continued activity of the recombination machinery induced secondary IGK gene rearrangements, which shifted preferential usage of upstream located Jκ- to downstream Jκ- gene segments. Thus, inhibition of BCR-ABL1 in pre-B ALL cells i.) recapitulates early B cell development, ii.) directly shows that IGK, KDE and IGL genes are rearranged in sequential order and iii.) provides a model for Ig light chain gene regulation in the human.
Figure Legend: BCR-ABL1 + BV173, NALM1 and SUP-B15 cells were were cultured in the presence or absence of 10 μmol/l STI571 for the times indicated. Genomic DNA was isolated from 5 x 106 cells. Broken-ended DNA strand breaks were ligated to linker molecules and subjected to two rounds of PCR-amplification using primers specific for breaks at Jκ-RSS, KDE-RSS and Jλ-RSS sites.