bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long-Term Safety Experience with Arsenic Trioxide in Patients with Acute Promyelocytic Leukemia
Authors: Tallman Martin S. , Lo-Coco Francesco , Pathak Ashutosh 
Published: October 2019

Abstract
Introduction: Therapeutic agents approved by the FDA are required to undergo postmarketing safety surveillance to meet regulatory and contractual requirements. Arsenic trioxide (Trisenox®) is approved for the treatment of patients with acute promyelocytic leukemia (APL) in the second-line setting, but is also commonly used in first-line regimens in combination with all-trans retinoic acid. Here, we summarize the accumulated safety data from global postmarketing surveillance of arsenic trioxide since its initial approval in 2000 to better understand its long-term safety in patients with APL.
Methods: Cumulative data were collected from patients with APL since initial approval in 2000 from spontaneous reports submitted by healthcare professionals and consumers. The data collected were housed in the Teva Pharmaceuticals safety database. Adverse events (AEs) were coded according to MedDRA terms and classified by seriousness and expectedness (unexpected AEs are those not included in the product label at the time of the report or those that occurred at a higher incidence than previously reported).
Results: As of July 7, 2016, a total of 2197 AE reports were received in association with arsenic trioxide use in patients with APL. There were 1735 reports classified as serious and 462 classified as nonserious. The most frequently reported (≥ 30 reports) serious AEs and serious AEs of interest are summarized in the table. Serious QT prolongation was the most commonly reported event, but the majority of events were expected, including four cases of torsades de pointes that may be associated with prolonged QT. Serious hematologic toxicities, including neutropenia and leukocytosis, were also common and expected, as was liver toxicity. The most common serious and unexpected events reported included white blood cell decrease, pancytopenia, increased gamma-glutamyltransferase level, and cardiac disorders (primarily ventricular tachycardia, ventricular extrasystoles) that may be associated with prolonged QT in some patients.
Conclusions: The overall safety profile of arsenic trioxide is consistent with known toxicities; the majority of serious AEs are associated with QT prolongation. The clinical significance of the reported QT events is unclear, and reporting rates may change in the future because of evolving criteria for QT assessments (Roboz GJ, et al. J Clin Oncol 2014;32(33):3723). This overview was limited by voluntary reporting. However, the long-term, real-world experience with arsenic trioxide administration as a single agent or in combination provides a broader understanding of its safety profile.
Sponsor: Teva Branded Pharmaceutical Products R&D

Disclosures
Lo-Coco: Teva, Novartis, Baxalta, Pfizer: Consultancy; Teva, Lundbeck: Honoraria, Speakers Bureau. Pathak:Teva Pharmaceuticals: Employment, Equity Ownership.
PD-L1 Is up-Regulated By EBV-Driven LMP1 through NF-κb Pathway and Correlates with Poor Prognosis in Natural Killer/T-Cell Lymphoma
Authors: Bi Xi-Wen , Wang Hua , Zhang Wen-Wen , Xia Zhongjun , Zhang Yu-jing , Wang Liang 
Published: October 2019

Abstract
Background:
Natural killer/T-cell lymphoma (NKTCL) is an EBV-associated, highly aggressive lymphoma. Treatment outcome remains sub-optimal, especially for advanced-stage or relapsed diseases. Programmed cell death receptor 1 (PD-1) and PD ligand 1 (PD-L1) have become promising therapeutic targets for various malignancies, but their role in the pathogenesis and their interactions with Epstein-Barr virus (EBV) in NKTCL remains to be investigated.
Materials and methods:
Expression of PD-L1 was measured in NK-92 (EBV-negative) and SNK-6 (EBV-positive) cells by western blot, quantitative real-time PCR, and enzyme-linked immunosorbent assay, respectively. Latent membrane protein 1 (LMP1)-harboring lentiviral vectors were transfected into NK-92 cells to examine the correlation between LMP1 and PD-L1 expression. Proteins in the downstream pathways of LMP1 signaling were measured in NK-92 cells transfected with LMP1-harboring or negative control vectors, respectively. PD-L1 expression on tumor specimens and serum concentration of soluble PD-L1 were collected in a retrospective cohort of patients with Ann Arbor stage I~II NKTCL and their prognostic significance were analyzed.
Results:
Expression of PD-L1 was significantly higher in SNK-6 cells than in NK-92 cells, at both protein and mRNA levels. Expression of PD-L1was remarkably up-regulated in NK-92 cells transfected with LMP1-harboring lentiviral vectors compared with those transfected with negative control vectors. Proteins in the MAPK/NF-κB pathway were up-regulated in LMP1-expressing NK-92 cells compared with the negative control. Selective inhibitors of those proteins induced significant down-regulation of PD-L1 expression in LMP1-expressing NK-92 cells. Patients with a high concentration of serum soluble PD-L1 (≥ 3.4 ng/ml) or with a high percentage of PD-L1 expression in tumor specimens (≥ 38%) exhibited significantly lower response rate to treatment and remarkably worse survival, compared with their counterparts. A high concentration of serum soluble PD-L1 and a high percentage of PD-L1 expression in tumor specimens were independent adverse prognostic factors among patients with stage I~II NKTCL.
Conclusions:
PD-L1 expression positively correlated LMP1 expression in NKTCL, which was probably mediated by the MAPK/NF-κB pathway. PD-L1 expression in serum and tumor tissues have significant prognostic value for early-stage NKTCL.

Disclosures
No relevant conflicts of interest to declare.
Prognostic Value of Interim Positron Emission Tomography Among Children with Advanced Hodgkin Lymphoma in Developing Countries: Children Cancer Hospital Egypt Experience
Authors: Khedr Reham , Hamouda Asmaa , Naguib Sawsan , Khalaf Mohamed , Fikry Sally , Elsayed Amr , Taha Hala , Zaghloul Mohamed , Attia Iman 
Published: October 2019

Abstract
Rationale and aim of the study: This is a retrospective, single center study was done to assess the prognostic role of 'interim' positron emission tomography (PET) performed during treatment of advanced stages HL with doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) in pediatric patients.
Patients and methods: Three hundred and eighty one patients with newly diagnosed Hodgkin lymphoma were enrolled. One hundred sixty five patients with early unfavorable and 216 with advanced-stage disease were treated with ABVD ± involved-field radiotherapy (IFR). PET scan was performed at baseline and after two cycles of chemotherapy. Treatment was not changed according to the results of the interim scan. PET scans reports was used using the Deauville five-point scale, blinded to treatment outcome.
Results:Eighty-seven scans out of 336 were scored as positive (17.3%) and 249 (82.7%) as negative. The 5- years overall survival (OS) was 94% (95% Confidence Interval (CI) :91.5 Ð 96.6) for the whole study population, 86.2% (95% CI :78.3 - 94) for patients with interim positive scans and 97% (95% CI:94.2 - 99.3) for patients with interim negative scans (P&lt;0.0001) [Figure:1].
The 5-year Event-free survival (EFS) rate was 80% (95% CI :74.3 Ð 84.4) for the whole study population, 63.2% (95% CI :48.6 Ð 77.4) for patients with interim positive scans and 82.6% (95% CI :76.3 Ð 88.8) for patients with interim negative scans (P&lt;0.0001) [Figure:2].
In conclusion: The prognostic role and validity of using the interim PET scan response have been confirmed to be strongly related to treatment outcome by the present study. These results confirm that ABVD with or without IFR is an adequate treatment for more than 70% of pediatrics patients in advanced stages HL.
Figure 1 Figure 1. Figure 2 Figure 2.

Disclosures
No relevant conflicts of interest to declare.
Treating B Cell Lymphomas with Anti CD81 Antibodies
Authors: Vences-Catalan Felipe , Kuo Chiung-Chi , Rajapaksa Ranjani , Duault Caroline , Levy Ronald , Levy Shoshana 
Published: October 2019

Abstract
The tetraspanin CD81 associates with CD19 on B cells; this molecular complex functions as co-receptor to lower the threshold of BCR-initiated B cell activation.
Recently we have shown the importance of CD81 in tumor growth and metastasis of solid tumors (Vences-Catalan et al., 2015). However, the role of CD81 in lymphoid malignancies has not been explored. Previous studies demonstrated anti-proliferative effects of anti-CD81 antibodies on human B cell lymphomas using in vitro assays (Oren et al., 1990). Here we tested the therapeutic effect of an anti-human CD81 antibody in vivo against Raji and SUP-B8 B cell lymphomas using a xenograft model in SCID mice. Our studies demonstrated that our anti-human CD81 antibody (mouse IgG1) had therapeutic effect comparable to Rituximab (human IgG1) (Figure 1A). Yet, the two antibodies differ in their ability to mediate antibody-dependent cell cytotoxicity (ADCC), Rituximab is known to be highly effective, whereas the mouse IgG1 anti-CD81 antibody is not expected to mediate ADCC.
To enhance the anti-CD81-mediated ADCC, we class switched the hybridoma to mouse IgG2a; we also engineered a chimeric antibody containing human IgG1ADCC-HIGH Fc constant region. Indeed, mouse IgG2a and the chimeric human IgG1 anti-CD81 mAb showed a remarkable increase in NK cell-mediated ADCC as well as complement-dependent cytotoxicity (CDC) when compared to Rituximab in vitro (data not shown) and in vivo (Figure 1B). These results suggest that CD81 can be a potential therapeutic target on B cell lymphomas by virtue of both its direct cytotoxic effect and as a mediator of ADCC and CDC. The humanized IgG1 version is being developed as a therapeutic candidate.
Comparable efficacy of anti-CD81 to Rituximab. SCID mice were I.V.-injected with 1.5x106 Raji-GFP-Luc cells, tumors growth proceeded for 5 days before IP injection of 4 weekly doses of 100 ug of the indicated antibodies. (A) Survival of Raji-GFP-Luc bearing SCID mice given anti CD81 (n=30), Rituximab (n=20) or control MsIgG1 (n=30). (B) In vivo bioluminescence imaging of tumor growth in mice injected (left to right) with control mouse IgG1; anti-CD81 (MsIgG1); anti-CD81 MsIgG2a; chimeric anti-CD81 (HuIgG1) and Rituximab. Comparable efficacy of anti-CD81 to Rituximab. SCID mice were I.V.-injected with 1.5x106 Raji-GFP-Luc cells, tumors growth proceeded for 5 days before IP injection of 4 weekly doses of 100 ug of the indicated antibodies. (A) Survival of Raji-GFP-Luc bearing SCID mice given anti CD81 (n=30), Rituximab (n=20) or control MsIgG1 (n=30). / (B) In vivo bioluminescence imaging of tumor growth in mice injected (left to right) with control mouse IgG1; anti-CD81 (MsIgG1); anti-CD81 MsIgG2a; chimeric anti-CD81 (HuIgG1) and Rituximab.

Disclosures
Levy: Kite Pharma: Consultancy; Five Prime Therapeutics: Consultancy; Innate Pharma: Consultancy; Beigene: Consultancy; Corvus: Consultancy; Dynavax: Research Funding; Pharmacyclics: Research Funding.
Biomodulatory Metronomic Therapy Shows Remarkable Activity in Chemorefractory Multi-System Langerhans Cell Histiocytosis
Authors: Heudobler Daniel , Rehe Klaus , Foell Juergen , Corbacioglu Selim , Hildebrandt Gerhard , Herr Wolfgang , Reichle Albrecht , Vogelhuber Martin 
Published: October 2019

Abstract
Background:
Langerhans cell histiocytosis (LCH) is a disorder characterized by lesions that include CD207+ dendritic cells along with an inflammatory infiltrate, ranging from a single lesion to potentially fatal multi-system disease. Empirically derived chemotherapy with vinblastine and prednisone still represents the standard of care, curing fewer than 50% of patients. As a result of the discovery of activating mutations in the MAPK-pathway, BRAF inhibitors seem to be a novel therapeutic option. In LCH patients who were refractory to (or not eligible for) conventional chemotherapy we administered a multi-targeted therapeutic approach targeting the deregulation of homeostatic pathways in LCH, e.g. notch, thereby simultaneously modulating tumor-associated inflammation, angiogenesis and immune response. The present retrospective analysis reports a single-center experience with a biomodulatory therapy in a cohort of patients with refractory LCH.
Methods:
At the University Hospital Regensburg seven patients with multi-system LCH (2 female/5 male, including two pediatric patients), ranging from 11 months to 77 years old, were selected for compassionate use treatment with a biomodulatory therapy schedule (Br J Haematol. 2005;128:730-2). Six patients have been refractory to up to three different standard regimens. One patient was not eligible for conventional therapy due to severe comorbidities. The biomodulatory metronomic therapy consisted of low dose trofosfamide, pioglitazone, a PPAR alpha/gamma agonist, etoricoxib, a COX-2 inhibitor and low-dose dexamethasone. Each drug was administered daily until disease progression or in case of complete remission for additional 6 months. Treatment response was reported using the criteria established in the Histiocyte Society Evaluation and Treatment Guidelines.
Results:
All of the patients in our cohort showed response to treatment as determined clinically, by CT/MRI scans and re-biopsies. Two of them developed a complete remission, three regression of disease and two stable disease. To date, none of the patients developed progressive disease (representing a progression-free-survival of 10 to 55 months until now). In one patient a dose reduction had to be made due to leukopenia. No other significant adverse events have been observed.
Conclusion:
Biomodulatory metronomic therapy demonstrated high activity against multi-system LCH with minimal toxicity even in refractory patients following multiple systemic chemotherapies. Long-lasting disease control was achieved in all of the treated patients. Confirmation of efficacy should be evaluated in a prospective trial.

Disclosures
No relevant conflicts of interest to declare.
Polycythemia in Primary Carcinoma of the Liver
Authors: MCFADZEAN A. J. S. , TODD DAVID , TSANG K. C. 
Published: October 2019

Abstract
In a series of 176 consecutive patients with hepatocarcinoma an increase in red cell count and in hemoglobin significantly above normal levels were encountered in 17 (10 per cent).
An investigation of 28 patients with hepatocarcinoma developing in a cirrhotic liver is reported. In three of the patients (10 per cent), the red cell counts and hemoglobin levels were significantly above those encountered in healthy Chinese.
In these 28 patients it has been shown that the plasma volume is increased, and this increase does not differ significantly from that encountered in uncomplicated cirrhosis of the liver. The total red cell volume, on the other hand, is significantly greater than in uncomplicated cirrhosis of the liver. While the mean total red cell volume in hepatocarcinoma is not significantly different from that in healthy controls, consideration of this finding in individual patients shows that it was above normal in 17, normal in six, and in the remaining five it was below normal.
It is concluded that the polycythemia encountered is a true polycythemia secondary to the development of the hepatocarcinoma. The expanded plasma volume is considered probably attributable to the pre-existing cirrhosis of the liver. Unfortunately, in the course of this investigation we did not encounter a patient in whom the carcinoma had developed in a liver which was not cirrhotic.
Erythrocyte Osmotic Fragility of Rats Receiving the Thermostable Plasma Erythropoietic Factor
Authors: LINMAN JAMES W. , LONG MARTHA J. 
Published: October 2019

Abstract
The following error occurred on page 230 of Linman, J. W. and Long, M. J.: Erythrocyte osmotic fragility of rats receiving the thermostable plasma erythropoietic factor. Blood 13:226-238 (March), 1958:
Although the legends of figures 3 and 4 are correctly positioned, the figures themselves should have been transposed, figure 3 becoming figure 4 and vice versa.
The Ultrastructure of a "Fibrillar Formation" of Leukemic Human Blood
Authors: FREEMAN JAMES A. , SAMUELS MONROE S. 
Published: October 2019

Abstract
A previously unsuspected cytoplasmic organoid, fibrillar in nature, was discovered by Bessis and Breton-Gorius. This structure exhibits a very high degree of structural organization, and appears as a barrel-shaped fibrillar formation, opened at both ends and enclosing an associated granular component within. Comparable fibrillar formations are rarely found in normal cells, even in the simplest form of a few closely packed fibrils. In its highest degree of structural organization, the whorl, the fibrillar formation has been found only in the blast or promyelocytes stages. Although the overall dimensions of this structure are well within the resolving limits of the light microscope, it is not visible in fresh, Wright stained or Giemsa stained preparations.
Identification of the Vitamin B12-Binding Protein in the Serum of Normals and of Patients with Chronic Myelocytic Leukemia
Authors: MENDELSOHN ROBERT S. , WATKIN DONALD M. , HORBETT ANN P. , FAHEY JOHN L. 
Published: October 2019

Abstract
Vitamin B12-binding proteins in the serum of normal subjects and of patients with chronic myelocytic leukemia have been compared. The in-vivo-bound B12 was utilized to identify the binding protein. Column protein chromatography and block and paper electrophoresis were employed individually and in combination to characterize the B12-binding protein.
B12 was found to be bound primarily to an alpha-l globulin in both normal individuals and in patients with chronic myelocytic leukemia. No qualitative difference was found in these proteins.
The increased amounts of B12-binding protein in the serum of patients with chronic myelocytic leukemia would seem to be attributable to abnormal metabolism of the same protein that binds B12 in normal serum.
Irradiation of the Entire Body and Marrow Transplantation: Some Observations and Comments
Authors: THOMAS E. DONNALL , LOCHTE HARRY L. , FERREBEE JOSEPH W. 
Published: October 2019

Abstract
Case reports of 5 patients with acute leukemia receiving total-body irradiation and intravenous infusion of normal marrow are presented. An eight-month follow-up on a previously reported patient with chronic leukemia is included and a review of an individual receiving nitrogen mustard and marrow is presented for comment.
Of several patients reported in this and in a previous communication only two may be said to have obtained significant clinical benefit. Potential reasons for this incidence of improvement are advanced and the general subject of total-body irradiation and marrow replacement in man is discussed. Pitfalls and problems biologic and physical and the theory of their circumvention are analyzed.
Studies on the Survival of Incompatible Cells in Patients with Hypogammaglobulinemia
Authors: CHAPLIN HUGH 
Published: October 2019

Abstract
1. Four adult patients are described whose sera showed a complete lack of gamma globulin by paper electrophoresis.
2. All four patients might have been considered "universal recipients" because of the absence of isohemagglutinins on routine laboratory tests.
3. Weak isohemagglutinins were detectable in the sera from three of the four subjects when the sensitivity of the in vitro test was increased.
4. Following intravenous administration of 4 ml. of ABO-incompatible cells, red cell survival was shortened in all of the patients, with a wide range of half-survival times from <10 minutes to as long as 9 days.
5. Although in vitro tests for antibody activity revealed no qualitative differences among the sera from the three patients with detectable isohemagglutinins, two different mechanisms of red cell removal were observed, one which entailed nearly equal activity by both liver and spleen, the other being primarily a function of the spleen.
6. The survival of incompatible cells under conditions of antibody "excess" and antibody "insufficiency" was compared in one of the patients. The findings emphasize the sensitivity of in vivo survival studies employing small volumes of incompatible cells to detect minute quantities of circulating antibody.
7. A fall in anti-A titer following the administration of group B cells to one hypogammaglobulinemic subject is interpreted as a possible in vivo example of the absorption of "cross-reacting" antibody in the ABO system.
8. In the light of the in vivo and in vitro findings, none of the 4 hypogammaglobulinemic patients in the present series could be categorized as "universal recipients."
Efficacy of Water-Soluble Derivatives of Vitamin K1 in Counteracting Drug-Induced Hypoprothrombinemia
Authors: MUSHETT CHARLES W. , KELLEY KANE L. , HIRSCHMANN RALPH 
Published: October 2019

Abstract
The relative efficacies of vitamin K1 emulsion and several water-soluble derivatives of vitamin K1 were determined in dogs rendered hypoprothrombinemic by Dicumarol and Dipaxin.
In short term experiments equimolar intravenous doses of the disodium salt of 2-methyl-3-phytyl-1,4-naphthohydroquinone-1,4-diphosphate and of vitamin K1 emulsion exhibited like activity in reversing Dicumarol- and Dipaxin-induced hypoprothrombinemia. By this route, the 4-monophosphate derivative showed comparable activity to the 1,4-diphosphate, but the 1-propionate-4-phosphate derivative was less potent.
At equimolar dosage levels, the water-soluble diphosphate derivative was found to possess oral activity equivalent to that of vitamin K1 emulsion. It was appreciably more effective than the emulsion, however, by the intramuscular route.
With both K1 emulsion and the water-soluble diphosphate derivative, the most rapid effect followed intravenous administration. Oral treatment was less rapid and intramuscular the slowest.
Data obtained in prophylactic and therapeutic studies indicate that water-soluble vitamin K1 has a shorter duration of action than vitamin K1 emulsion. Because of this property, it should be possible to control treatment more precisely with water-soluble vitamin K1 and also to effect a rapid reversal of excessive hypoprothrombinemia with less liability of including refractoriness to reinstitution of anticoagulant therapy.
Anomalous Panleukocytic Granulation
Authors: SARAIVA LUIZ GONZAGA , AZEVEDO MIECIO , CORREA JOSÉ MAURICIO , CARVALHO GERSON , PROSPERO JOSÉ DONATO 
Published: October 2019

Abstract
Anomalous panleukocytic granulation is described in the peripheral blood, bone marrow and spleen of a 3 year old girl. Myeloid leukocytes showed giant peroxidase and Sudan Black B-positive granules. Lymphocyte corpuscles were positive in the periodic acid-Schiff test. Deviations in the structure and segmentation of the neutrophil nuclei were observed. Increase of gamma globulins and decrease of lipoproteins were found in the blood serum.
Hepatosplenomegaly, psychomotor underdevelopment, respiratory tract infections, roentgenologic changes of bones, lungs and heart were also found. The parents were first cousins, and anomalous corpuscles were seen in the father’s lymphocytes.
At necropsy diffuse or focal infiltration of the organs by lymphoid, plasma and reticular cells suggested a systemic condition.
Permanent Granulocytosis in Mice Due to Cortisone
Authors: WEIR DAVID R. , BRENNER VIVIAN 
Published: October 2019

Abstract
1. Intermittent cortisone therapy given over a period of 59 weeks caused permanent granulocytosis in mice from a nonleukemic Albino strain. The granulocytosis persisted for the lifetime of the animals, the longest survival being 97 weeks. Two of 40 animals developed histologic findings entirely comparable to human myeloid leukemia.
2. It is assumed that such cortisone therapy produces a permanent change in the basic mechanisms which control the production of granulocytes or their release from the bone marrow. Possibly the metabolic change may be related to inhibition of vitamin B6 activity.