bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interobserver Agreement of Centrally Adjudicated Venous Ultrasound Video Documents in Asymptomatic Patients after Hip and Knee Replacement.
Authors: Schmidt Benjamin A. , Guenther Matthias , Halbritter Kai , Beyer Jan , Schellong Sebastian M. 
Published: October 2019

Abstract
Feasibility of venous ultrasound as an endpoint measure in multicenter trials critically depends on the type and quality of documents which can be assessed by central adjudication. We evaluated the offline assessability of standardized video documents of complete compression ultrasound (CCUS) in asymptomatic patients 7 days after hip or knee replacement. The study was performed at a single study center. Consecutive asymptomatic patients one week after hip or knee replacement were screened for deep vein thrombosis by complete compression ultrasound of proximal and distal veins including muscle veins by one trained sonographer. Examinations were recorded on video tape in a standardized format. Video sequences with an approximate duration of 60 seconds demonstrated femoral veins, popliteal veins, peroneal veins and tibial posterior veins, respectively. The video documents were digitized and electronically stored in a central adjudication unit. All videos were read by two independent readers, and veins were scored as normal, thrombotic or nonevaluable. All thrombotic findings were re-assessed by two senior readers according to the same protocol. Analysis of inter-observer agreement was performed by Cohen’s Kappa coefficient. Video documents of 300 legs were recorded in 150 patients. Documents of 10 patients (6.7%) or 13 legs (4.3%) were scored as non-evaluable by at least one reader. Reading A revealed 5.5% proximal DVT and 18.7% distal DVT including muscle vein thrombosis. Reading B revealed 4.1% and 23.6%, respectively. Kappa values for different types of DVT are given in the table.
Conclusion: In a single center setting, interobserver agreement of centrally adjudicated standardized CCUS documents in the diagnosis of asymptomatic postoperative DVT is strong for all categories of DVT. It remains to be established how these figures will be affected by a multicenter setting.
Interobserver Agreement Vein segment Kappa (95% CI) 1) Interobserver agreement according to number of legs (n=300) All vein segments 0.92 (0.84–0.99) Proximal deep vein segments 0.87 (0.70–1.00) Distal deep vein segments 0.84 (0.73–0.94) Femoral veins - Popliteal and confluent veins 0.87 (0.70–1.00) Peroneal veins 0.79 (0.60–0.99) Posterior tibial veins 0.83 (0.60–1.00) Calf muscle veins 0.77 (0.64–0.91) 2) Interobserver agreement according to number of patients (n=150) All vein segments 0.90 (0.81–0.99) Proximal deep vein segments 0.85 (0.65–1.00) Distal deep vein segments 0.81 (0.65–0.97)
Immune Tolerance Resulting in a Dramatic Clinical Improvement in a High-Responding Inhibitor Hemophilia A Patient Using Immunosuppression with Mycofenolate Mofetil and a Factor VIII Concentrate Containing Von Willebrand Factor.
Authors: Lambert Thierry , Goujard Cécile , Rafowicz Anne , Guillet Benoît , Taoufik Yacine , Dreyfus Marie 
Published: October 2019

Abstract
A 40 year-old Caucasian patient with severe familial hemophilia A (FVIII <1%) related to an intron 22 inversion developed at the age of 2 a high-responding inhibitor. His elder brother also suffers from hemophilia A with high-responding inhibitor. Until 2000, the patient had been treated either using activated prothrombin complex concentrates (Autoplex® and Feiba®) or factor VIII (FVIII) concentrates of human (1983) and porcine origin (1992), resulting respectively in an inhibitor level rise at 360 Bethesda Units (BU) and 1800 BU. Between 2000 and 2003, the patient received exclusively recombinant activated Factor VII (NovoSeven®), and his inhibitor levels stabilized at a plateau of 15–20 BU. Between 2000 and 2003, several life or function threatening bleeding episodes occurred, such as hematomas of the iliopsoas muscles, spinal cord hematoma with transient paraplegia. Furthermore, due to hemarthroses the patient was confined to a wheelchair. Given the major impact of the inhibitor on the patient’s functional prognosis, life expectancy and quality of life, immune tolerance (IT) treatment was initiated, despite the high risk of failure (initiation 36 years after inhibitor onset, historical peak titer at 1800 BU, persistence of a plateau of 15–20 BU despite the absence of any stimulation with FVIII within the 3 last years). It started with an immunosuppressive drug, mycofenolate mofetil (Cellcept®) first given in may 2003 (no effect alone on inhibitor titer) and then in November 2003, infusions of a FVIII concentrate rich in von Willebrand factor, Factane® (LFB, Les Ulis, France) using 12,000 IU/day (150 IU/kg) of FVIII. The inhibitor peaked at 520 BU on D19 and was 0.5 BU by May 2004. Thus, the FVIII dosage was progressively reduced to 7000 IU/day. In July 2005, 24 hours after a 7000 IU FVIII infusion, inhibitor level was 0.7 BU, the residual FVIII level was 0.04IU/ml with a recovery of FVIIIc of 1.37%/IU/kg infused and a half-life of 4.9 hours. No significant change in the immunophenotype of peripheral blood lymphocytes was observed during this course. The patient’s quality of life was dramatically improved, with no hospitalization required and no bleeding episode observed within the 16 last months. The patient can now stand and has returned to his previous social activities.
These preliminary results show that this IT treatment, performed despite a high theoretical risk of failure, resulted in this patient in a dramatic clinical improvement, even though biological criteria of success have not yet been achieved. The respective roles of the type of FVIII concentrate, and of immunosuppression remain to be assessed, as well as the cost/benefit analysis on a longer follow-up period.
Intratumoral Treg Cells Completely Inhibit the Induction and Function of Tumor-Infiltrating CD8+ T-Cells in B-Cell NHL.
Authors: Yang Zhi-Zhang , Novak Anne J. , Stenson Mary J. , Witzig Thomas E. , Ansell Stephen M. 
Published: October 2019

Abstract
Background: Numerous studies have shown that lymphoma B-cells are resistant to CTL-mediated death, however the underlying mechanism for this resistance is not clear. In previous work, we have identified a subset of CD4+CD25+ T-cells overrepresented in the tumor sites of B-cell NHL that display a phenotype compatible with regulatory T cells (Treg cells). These cells express high levels of Foxp3 and CTLA-4, and are capable of suppressing the proliferation and cytokine production of autologous infiltrating CD4+CD25- T cells in B-cell NHL.
Goal: To explore whether Treg cells exert a suppressive effect on the induction and function of autologous tumor-infiltrating CD8+ T-cells in B-cell NHL.
Results: Using fresh specimens obtained from patients with B-cell lymphoma, we found that intratumoral Treg cells had a significantly suppressive effect on autologous tumor-infiltrating CD8+ T-cells in B-cell NHL. When activated CD8+ T-cells were cocultured with infiltrating CD4+CD25- T-cells, they displayed less proliferation than CD8+ T-cells cultured alone. However, we found that with a 1:4 ratio of stimulating cells (Treg cells) to responding cells (CD8+ T-cells), intratumoral Treg cells completely inhibited the proliferation of autologous tumor-infiltrating CD8+ T-cells activated with PHA. Furthermore, we have observed that 20% of infiltrating CD8+ T-cells in fresh isolated samples from B-cell NHL coexpress perforin and granzyme B. When intratumoral Treg cells were cocultured with CD8+ T-cells, the Treg cells inhibited the activation-induced production of perforin and granzyme B of autologous tumor-infiltrating CD8+ T-cells in a dose-dependent fashion. We also found that cytokine treatment (IL-2 and IL-12) or PHA activation induced the capability of tumor-infiltrating CD8+ T-cells to kill lymphoma B-cells, which was accompanied by upregulation of expression of CD107a on the surface of cytotoxic CD8+ T-cells. Intratumoral Treg cells significantly inhibit cytotoxicity of activated infiltrating CD8+ T-cells to lymphoma B-cells. Finally, we found that there was an inverse correlation of cell frequencies between intratumoral Treg cells and tumor-infiltrating CD8+ T cells in patients with B-cell NHL, suggesting that Treg cells may inhibit the migration of cytotoxic T-cells to the sites of B-cell lymphoma.
Conclusion: Intratumoral Treg cells dramatically suppress the proliferation and activation-induced production of granules in infiltrating CD8+ T-cells in B-cell NHL. These Treg cells also inhibit the ability of activated tumor-infiltrating CD8+ T-cells to kill lymphoma B-cells in vitro, and may prevent the migration of CD8+ cells to the sites of lymphoma. Taken together, these data indicate an important role for intratumoral Treg cells in CTL-mediated anti-tumor immunity in B-cell NHL.
Incidence and Risk Factors for Central Nervous System Manifestation in Elderly Patients with Aggressive Non-Hodgkin’s Lymphoma.
Authors: Ösby E. , Hagberg H. , Kvalöy S. , Teerenhovi L. , Anderson H. , Cavallin-Ståhl E. , Holte H. , Myhre J. , Öst Å. , Pertovaara H. , Björkholm M. 
Published: October 2019

Abstract
Introduction: Manifestation of central nervous system (CNS) disease in patients with aggressive non-Hodgkin’s lymphoma (NHL) during or after first line treatment is often a devastating condition, which is associated with a poor prognosis. There is today no general consensus regarding prophylactic treatment in this patient category, particularly in the elderly. The aim of this study was to define the incidence and risk factors for CNS manifestation in a large cohort of elderly (>60 years) patients with aggressive NHL and no CNS disease at diagnosis.
Patients and methods: This Nordic study included a total of 455 previously untreated patients with advanced (stage II–IV) aggressive NHL without CNS involvement at diagnosis (Blood2003;101:3840). The vast majority had diffuse large B cell lymphoma. Patients (median age, 71 years; range, 60–86 years) were randomised to receive CHOP (doxorubicin 50 mg/m2) or CNOP (mitoxantrone 10 mg/m2) with or without G-CSF (5 microg/kg from day 2 until day 10–14 of each cycle every 3 weeks; 8 cycles). Intrathecal methotrexate was given as prophylaxis to patients with lymphoma bone marrow involvement and in patients with testicular, orbital, sinus and epidural sites of presentation.
Results: At this time point information is available for 441/455 patients. After a median observation time of 113 months in surviving patients 30/441 (6.8%) developed CNS disease. Advanced stage (p=0.004) and a high age-adjusted International Prognostic Index (IPI; p=0.034) were associated with an increased risk of CNS disease. Age, sex, performance status, bone marrow involvement/extranodal disease, serum lactate dehydrogenase level, or treatment received were not related to the risk of CNS manifestation. All patients with CNS disease were dead at follow-up.
Conclusion: A significant proportion of elderly patients with advanced aggressive NHL and no CNS manifestation at diagnosis develop CNS disease despite prophylactic measures in clinically defined high-risk patients. CNS occurrence is related to clinical stage and age-adjusted IPI. The prognosis of elderly aggressive NHL patients with CNS manifestation is poor.
Selective Induction of the p53-Pathway as Treatment for Multiple Myeloma.
Authors: Stühmer Thorsten , Zöllinger Angela , Chatterjee Manik , Bommert Kurt , Bargou Ralf C. 
Published: October 2019

Abstract
The p53 pathway is central to cellular defences against neoplastic transformation, and mutations that impair p53 function are prominent oncogenic events. However, certain malignancies, such as multiple myeloma (MM), rarely present with p53 defects except in late stages. MM might therefore be vulnerable to p53 induction therapy, but it is unknown if the p53 pathway remains actually functional in this disease, and if it can be sufficiently well triggered to induce tumor cell death. We have used nutlin-3, a newly developed small-molecule antagonist against the p53 suppressor murine double minute 2 (MDM2), to analyze the effect on myeloma cell lines and a large panel of patient tumor samples. Nutlin-3 specifically and exclusively induced p53 downstream targets in myeloma cells with wild-type p53, and a large majority of primary medullary myeloma samples was susceptible to nutlin-3-mediated apoptosis. Comparison with the clinically relevant genotoxic drugs melphalan and etoposide showed that nutlin-3 was as effective or better at inducing apoptosis of primary tumor cells, and that combinations of nutlin-3 with genotoxic cytostatics at low doses produced better than additive anti-tumor effects. Importantly, broad anti-tumor activity of nutlin-3 persisted even when primary tumor cells were kept in coculture with bone marrow stromal cells (BMSCs). However, primary tumor isolates often contain a fraction of cells apparently unaffected by drug treatment, and some primary samples were conspicuously less sensitive to nutlin exposure when the cells were kept in coculture with BMSCs, as compared to culture in medium supplemented with interleukin-6. We have begun to analyze to what extent heterogeneity for p53 induction within the tumor cell population may underlie these differences, and if the capacity to activate intracellular growth and survival pathways has an influence on the result of p53 pathway activation. Nutlin-3, as a non-genotoxic agent to specifically induce or strengthen p53-mediated apoptotic responses may be a promising agent to complement standard genotoxic regimens for the treatment of MM.
Hsp90 Is Critical for the Regulation of Human T Lymphocytes and NK Cell Phenotype and Function.
Authors: Bae Jooeun , Mitsiades Constantine , Prabhala Rao Prabhala , Yu-Tzu Tai , Martinson Jeff , Hartson Steven , Hideshima Teru , Catley Lawrence , Li Xianfeng , Batchu Ramesh Babu , Bertheau Robert , Masood Shammas , Samala Sushima , Miller Jeff , Anderson Kenneth , Munshi Nikhil 
Published: October 2019

Abstract
Hsp90 inhibitor has shown promising anti-tumor activity through the destabilization and eventual degradation of Hsp90 client proteins critical for cell survival. In this study, we examined the in vitro effects of Hsp90 inhibitor on the phenotype and function of human T lymphocytes and NK cells. We observed no significant effects of Hsp90 inhibitor treatment on cell survivals. However, Hsp90 inhibitor treatment for 24 hours led to irreversible down-regulation of expression of critical T-cell surface antigens including CD3, CD4, CD8, CD28, CD154 (CD40L) and TCRab. Among the antigens evaluated, expression of CD4 antigen was most significantly downregulated (untrt vs. trt = 326 vs. 88 in Mean Fluorescence Intensity) following Hsp90 inhibitor treatment. Decreased CD3+ T lymphocytes proliferation (untrt vs. trt = 222839 cpm vs. 111102 cpm, 3[H]-thymidine incorporation) and reduced IFN-g secretion (untrt vs. trt = 77 vs. 48 pg/ml) was observed upon stimulation with allogeneic dendritic cells following 24 hrs treatments of T cells with Hsp90 inhibitor. Furthermore, CD3+ T-cell proliferation in response to mitogen stimulation, as measured by flow cytometry using CFSE was decreased following Hsp90 inhibitor treatment (untrt vs. trt = 41% vs. 3%, CFSE). Specifically, the CD4+CD28+ (untrt vs. trt = 32% vs. 1%) and CD8+CD28+ (untrt vs. trt = 27% vs. 17%) activated T-cell subpopulations displayed a significant decrease in proliferation in response to mitogen. Similarly, NK cells displayed decreased activation receptor expression including CD2, CD11a, CD94, NKp30, NKp44, NKp46, and KARp50.3 and reduced cytotoxic activity against multiple myeloma cells (untrt vs. trt = 49% vs. 11% against MM1S cells, 65% vs. 8% against ARP cells) following Hsp90 inhibitor treatment. These studies demonstrate that Hsp90 inhibitor treatment significantly affects phenotype and function of human T-lymphocytes as well as NK cells, and suggest the need to monitor immune functions in patients being treated with Hsp90 inhibitor in our future studies.
Low Dose Radiation Induces a Highly Effective p53 Response and Rapid Tumor Regression in Follicular Lymphoma.
Authors: Knoops Laurent , Haas Rick L. , de Kemp Sanne , Broeks Annegien , van ‘t Veer Laura J. , de Jong Daphne 
Published: October 2019

Abstract
Involved field radiation therapy with 30 to 40 Gy is a valuable local treatment for follicular lymphoma (FL) that is routinely used in clinical practice. We previously showed that very low dose radiation (2x2 Gy, days 1 and 3) is also effective, with rapid and often long lasting remissions in up to 90% of FL patients (Haas et al, JCO, 2003). However, the biological mechanism of this extremely effective response is not known. To study the molecular response to low dose radiation therapy in FL, gene-expression profiling using 35K spotted 60-mer oligo-arrays was performed from lymph node biopsy samples taken before treatment and 24 hours after the second dose of 2 Gy irradiation, in 15 patients. The clinical response was excellent (10 CR, 5 PR). In all patients, a major and consistent induction of p53 and p53 target genes was seen, reflecting both proliferation arrest (e.g., P21, repression of cell-cycle regulated genes) and apoptosis induction (NOXA, PUMA, BAX, TRAIL/DR5 and FAS). P53 upregulation, p53-mediated proliferation arrest and apoptosis were substantiated using immunohistochemistry with dramatic increase of p53 protein levels in B-cells, T-cells and accessory cells. There was also a significant increase in the numbers of cleaved-caspase 8 positive cells (death receptor pathway apoptosis) with a minor increase of cleaved-caspase 3 positive cells and morphological features of apoptosis, suggesting a relatively early stage in the apoptotic process.
The other induced genes revealed an ‘immune signature’, with a whole set of biologically meaningful genes related to macrophages (e.g., CD68, TLR4), TH1 immune response (e.g., IL18, CXCL9, 10, 11), clearance of apoptotic cells (e.g., C1Q, lysosomal enzymes), tolerance (ILT-3, IL-4, IDO) and death receptor ligands (FASL, TRAIL). Immunohistochemical analysis did not show an increase in T-cell subsets and macrophages density, rather suggesting an activation or differentiation of resident macrophages by radiation and/or apoptotic cells than recruitment of novel cell populations.
This is the first global analysis of the direct molecular effect of radiotherapy and p53 related apoptosis in vivo in human lymphoma. Moreover, the ‘immune signature’ suggests that radiation-induced apoptosis in FL is not an immunologically silent process, but rather an early event that could contribute to the death and clearance of tumor cells. These insights may have important implications for modulation of the cancer-related immune response and for immunotherapeutical approaches in FL.
Altered Hepcidin Regulation in Hereditary Hemochromatosis and Dysmetabolic Hyperferritinemia.
Authors: Nemeth Elizabeta , Loreal Olivier , Le Lan Caroline , Ropert Martine , Troadec Marie-Bérengère , Detivaud Lénaïck , Jard Christine , Pouchard Michele , Le Treut André , Deugnier Yves , Ganz Tomas , Brissot Pierre 
Published: October 2019

Abstract
Hepcidin, the key iron-regulatory hormone synthesized by the liver, blocks iron absorption in duodenum and iron recycling from macrophages. Hepcidin dysregulation is implicated in the pathogenesis of several iron disorders. Hepcidin deficiency was observed in most types of hereditary hemochromatosis, including the HFE-related hemochromatosis, where decreased levels of hepcidin mRNA were found in patients with HFE mutations and in mice lacking HFE. However, levels of the bioactive hepcidin peptide in this disease have not been evaluated. We analyzed urinary hepcidin concentrations in a large cohort of patients with hepatic diseases associated with iron dysregulation, including untreated and treated HFE hemochromatosis (HH), dysmetabolic hyperferritinemia (DYSH) and alcoholic cirrhosis (AC). In untreated HH patients (n=33), hepcidin levels were marginally increased in comparison to controls (n=71). However, the hepcidin/ferritin ratio, an index of appropriateness of hepcidin response to iron load, was decreased in untreated HH group compared to controls, suggesting that hepcidin levels were inappropriately low for the degree of iron loading.
In treated HH patients (n=41), hepcidin levels were decreased when compared to either controls or untreated HH group, but the hepcidin/ferritin ratio was not statistically different from the control group ratio. Since hemoglobin levels in the iron-depleted HH group remained unchanged, hepcidin decrease is likely not related to hypoxia, but rather demonstrates partial responsiveness to changes in iron stores.
In alcoholic cirrhosis (n=43), hepcidin levels were decreased when compared to controls which may be due to decreased hemoglobin levels observed in these patients and to the replacement of hepcidin-producing hepatocytes by scar tissue. Patients with DYSH (n=40) had increased hepcidin levels in comparison to the controls. Although the underlying cause is yet unclear, the increased hepcidin levels in DYSH could be a contributing factor for the characteristic iron accumulation in both macrophages and parenchymal cells, similar to anemia of chronic diseases.
Our study suggests that dysregulation of hepcidin is a likely cause of iron metabolism abnormalities in HH and in DYSH.
Inherited Bone Marrow Failure Syndromes in Children: 32 Years Experience in a Single Institution.
Authors: Drelichman Guillermo I. , Basack Nora F. , Maro Alejandra , Schwalb Graciela , Freigeiro Daniel H. , Pennesi Sandra , Moran Lorena , Awdejczuk Ana , Aversa Luis 
Published: October 2019

Abstract
Inherited bone marrow failure syndromes (IBMFS) present chronic bone marrow failures, a familial incidence and high risk of malignancy.
Objective: we describe our experience with patients with IBMFS. Since 02/73 to 02/05, 60 patients (pts) with IBMSF were diagnosed.
Fanconi’s Anemia Blackfand-Diamond TAR-Shwachman-Diamond-Dyskeratosis Congenita Amegakaryocytic Thrombocytopenia.- Kostmann’s S. Familial AA-Pearson’s S N Pts 26 17 6 – 2 – 2 2 – 2 2 – 1 Median age at diagnosis 7.1 y 3 m 3m – 4 m – 6.4 y 2 m – 1.8 m 4 y – 3 y First hematologic sign Pancytopenia Anemia Thrombocytop. – Neutrop. – Pancytop. Thrombocytop. – Neutrop. Pancytop. – Anemia Bone Marrow Aplastic Erythroid Aplasia Megakar. Aplasia – Myeloid arrest– Aplastic Megakar. Aplasia– Myeloid arrest Aplastic – Vacuolated myeloid Physical Abnorm.(%) 88 47 100 – 50– 100 50 – 0 0 – 0 Aplastic Anemia (%) 100 0 0 – 0 – 100 50 – 0 100 – 100 Leukemia / MDS (%) 11.5 0 0 – 0 – 0 0 – 0 0 – 0 Mortality(%) 62 0 17 – 50 – 0 50 – 50 50 – 0
Conclusion: 68 % pts. presented with associated physical abnormalities, 53 % began the symptoms with bone marrow aplasia. With a median follow up: 16. 3 years (r: 1y – 32 y), 39 (65%) pts are alive (9 pts. post bone marrow transplantation) and 3 pts with Fanconi’s Anemia developed refractory Acute Myeloblastic Leukemia.