bluuebunny/crossref_metadata_2025 huggingface dataset:
Post-Transplant Lymphoproliferative Disorders in Transplant Recipients: 14-Yr Experience at the Hospital Israelita Albert Einstein - Brazil
Authors: Blumenschein Danielle Isadora , da Rocha Juliana Dall Agnol , Perini Guilherme Fleury , Esteves Iracema , Bezerra Alanna Marra P. S. , Pasqualin Denise da Cunha , Ribeiro Andreza Alice Feitosa , Santos Fabio Pires de Souza , Hamerschlak Nelson , Helman Ricardo
Published: October 2019

Introduction: The number of patients who have undergone organ and bone marrow transplantation continues to increase, as does long-term survival. Post-transplant lymphoproliferative disorders (PTLD) are potentially life-threatening complications after solid organ transplantation. Epstein-Barr virus (EBV) infection that leads to uncontrolled B cell proliferation and tumor formation. PTLD is relatively common malignancy after transplantation and is seen up to 10% of all solid organ transplant recipients, and varies considerably among the different types of organs transplanted. We sought to determine incidence and mortality risk of PTLD in recipients of Hospital Israelita Albert Einstein, Sao Paulo, Brazil.

Patient and Methods: We conducted a retrospective observational study of 3006 recipients of lung, kidney, liver, pancreas, heart and bone marrow between 2002 and 2015. A total of 26 cases (0.8%) of PTLD were identified in 3006 transplants. Kaplan-Meier analysis was performed for PTLD patient survival after PTLD.

Results: Median interval from transplantation to diagnosis was 49 (4-150) months. Median age was 49 years (12-73) and 73% were men. Histological subgroups included: Monomorphic PTLD (50%), Hodgkin Lymphoma (11,5%), Burkitt (15,3%), Anaplastyc large cell (7,6%) and Plasmacytic Hyperplasia (15,3%). Sixteen patients (61,5%) were EBV (+) and eleven (42,3%) were IPI III-IV only two had bone marrow infiltration. Treatment of PTLD varied according to stage and clinical circumstances: six patients (23%) were treated with Rituximab only and seventeen (65,3%) treated with R-chemotherapy. Nine (34,6%) patients died. Changing immunosuppression (IS) from calcineurin inhibitor to sirolimus at the time of diagnosis may have improved survival, since 5 patients remain alive. The median overall survival was 1260 days, and 2-years overall survival was 65,4%.

Conclusion: PTLD after solid organs transplantation remains a challenge as a result of its frequency, complexity and disappointing outcome. We found a paucity of early onset PTLD in our cohort with only one case in the first posttransplant year. Potential contributing factors included a high prevalence of previous EBV virus exposure. The rate of PTLD malignancies in our group is comparable to that reported in other centers in Europe and North American, since it is the largest series reported by a single institution in South America. Consistent with the known antiproliferative effect of sirolimus, switching IS from calcineurin inhibitor to sirolimus may improve survival.

Disclosures

No relevant conflicts of interest to declare.
NKG2D Gene Polymorphism Is Associated with Disease Control of Chronic Myeloid Leukemia By Dasatinib
Authors: Hara Ryujiro , Onizuka Makoto , Matsusita Erika , Kikkawa Eri , Nakamura Yoshihiko , Ogiya Daisuke , Murayama Hiromichi , Omachi Ken , Shirasugi Yukari , Ogawa Yoshiaki , Kawada Hiroshi , Ando Kiyoshi
Published: October 2019

Dasatinib (DA) is a tyrosine kinase inhibitor (TKI), and is approved for the treatment of naïve and relapsed/refractory Philadelphia chromosome positive leukemia. DA is a potent and multi-target TKI, and a part of patients treated with DA are reported to exhibit lymphocytosis and that is caused by a proliferation of NK cells or CD8 T cells. Nowadays, a lot of reports about the stop TKI trials suggested that treatment free remission of the CML after TKI discontinuation was significantly associated with NK cell proliferation in peripheral blood of the patients. So far, little is known about the individual differences in NK cell response among patients treated with Dasatinib.

NKG2D is an activating receptor expressed on NK cells. Recently, functional SNP were identified between LNK1 and HNK1 haplotypes of the NKG2D gene. We analyzed the association between patient's NKG2D polymorphism and achievement of the deep molecular response by Dasatinib. We retrospectively investigated thirty-one patients who were treated with Dasatinib for the first-line treatment of CML at Tokai university school of medicine between 2011 and 2015. Patients with HNK1 haplotype tended to achieve MR4.5 more frequently (not significant), and these patients accomplished MR4.5significantly faster than others.

Next, we harvested NK cells from healthy volunteers, and investigated NK cell responses by Dasatinib in vitro. There were differences in the degree of NK cell proliferation capacity among subjects after DA treatment in vitro. We found that NK cells with NKG2D LNK1/LNK1 haplotype exhibited significantly lower proliferation capacity than others in the population. NK cells of higher proliferation capacity exhibited Vav-1 Tyr174 phosphorylation, but they didn't show any differences in cytotoxicity capacity.

In this study, our data suggest that DA may stimulate NK cells with NKG2D HNK1 haplotype more strongly than LNK1 haplotype, and therefore patients with HNK1 haplotype can achieve deep molecular response faster than others. So, personalized medicine according to their NKG2D haplotype may be useful to the treatment of CML, especially when they are considered to discontinue DA in stop TKI trials.

Disclosures

No relevant conflicts of interest to declare.
A Potent Small Molecule Compound Might Overcome High Level Drug Resistant Mutations of Bcr-Abl1
Authors: Wang Feng-Juan , Niu Ting
Published: October 2019

Objective: The third-generation tyrosine kinase inhibitor (TKI) ponatinib can overcome many kinds of single mutations including T315I of Bcr-Abl1. Unfortunately, recent clinical studies have identified some new point mutations resistant to ponatinib and the other marketed TKIs. These mutations include compound mutations or T315M single mutation, which we called high level drug resistant mutations in this study. Therefore, it is an urgent task to find a potent small molecule inhibitors, which can overcome these high level drug resistant mutations.

Methods: To screen for compounds that can overcome the high level drug resistant mutations of Bcr-Abl1, we firstly established genetic engineering cell models using the Ba/F3 cell line, including: (1) Ba/F3-Bcr-Abl1T315M; (2) Ba/F3-Bcr-Abl1T315I/E255V; (3) Ba/F3-Bcr-Abl1E255V/Y253H. The established cell lines were also carefully verified .Then we used these established cell models and others we have already obtained, including Ba/F3-Bcr-Abl1WT, Ba/F3-Bcr-Abl1T315I, and Ba/F3-Bcr- Abl1E255V, to screen an in-house chemical library. The most potent compound SKLB-518 was finally chosen to perform further studies both in vitro (cell and protein level) and in vivo (allograft subcutaneous cancer mice model).

Results: In vitro assays, three marketed TKIs, namely imatinib, dasatinib, and ponatinib, were chosen as the references. The IC50 value of SKLB-518 to inhibit Ba/F3-Bcr-Abl1E255V/Y254H cells was 0.033 μM, which was more active by >100 times and 6.14 times than that of imatinib (IC50: >10 μM) and ponatinib (IC50:0.201μM), respectively, and comparable with dasatinib (IC50:0.028 μM). The IC50 of SKLB-518 to inhibit Ba/F3- Bcr-Abl1T315I/E255V cells was 0.094 μM, which was more potent by >100 times, 30~100 times, and 8.69 times than that of imatinib (IC50: >10 μM), dasatinib (IC50: 3~10 μM), and ponatinib (IC50: 0.817 μM), respectively. In vivo, thedata indicated that SKLB-518 could significantly inhibit tumor proliferation at the doses of 30 mg/kg/d and 45 mg/kg/d (%T/C was 62.1 and 72.5, respectively; both groups p<0.001), while ponatinib couldn't inhibit tumor growth at the 30 mg/kg/day dose (%T/C was 87.8, p=0.157). Immunohistochemical staining assays indicated that SKLB-518 at the doses of 45 mg/kg/d could potently inhibit Bcr-Abl1 downstream targets (Crkl and Stat5). Meanwhile, we didn't find severe toxicity of SKLB-518 in the effective doses both in cells and in mice.

Conclusion:Independently developed small molecule SKLB- 518 might overcome the high level drug resistant mutations of Bcr-Abl1.

Disclosures

No relevant conflicts of interest to declare.
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

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

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

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<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<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

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

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

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

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

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

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

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

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

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

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

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.
Brief Note: Observations on a Case of Probable Bone Marrow Anthracosis
Authors: MILLER DAVID
Published: October 2019

A case is described in which marrow aspiration demonstrated a foreign material which is presumed to be carbon on the basis of its appearance and resistance to the action of strong acid. The resemblance to a previous description of anthracosis involving the bone marrow is noted.
The Collection, Storage and Preparation of Viable Cadaver Marrow for Intravenous Use
Authors: FERREBEE JOSEPH W. , ATKINS LEONARD , LOCHTE HARRY L. , MCFARLAND ROBERT B. , JONES A. RICHARDSON , DAMMIN GUSTAVE J. , THOMAS E. DONNALL
Published: October 2019

A procedure for collecting and storing viable cadaver marrow in a form suitable for intravenous use is described. Vertebral bone marrow is removed under sterile conditions within a few hours after death. The marrow cells are screened and suspended after centrifugation in an equal volume of a liquid medium consisting of 30 per cent glycerol and 70 per cent human serum and frozen to -80 C. in plastic bags. Suggestions for thawing, deglycerolizing and administering the cells intravenously are given.
On the Erythropoietic Principle in the Blood of Rabbits Made Severely Anemic with Phenylhydrazine
Authors: LOWY PETER H. , KEIGHLEY GEOFFREY , BORSOOK HENRY , GRAYBIEL ASHTON
Published: October 2019

1. An assay for erythropoietic factor is described based on reticulocytosis in normal, adult mice. The advantages of the method are the short time required (4 days), the small amount of test material needed and the facility with which many tests may be run simultaneously.

2. For the measurement of uptake of Fe59 a procedure is described which allows counting of whole dried blood with an end-window Geiger-Müller tube.

3. A procedure is described for preparing highly active erythropoietic filtrates from the boiled plasma of rabbits made severely anemic with phenylhydrazine.

4. Evidence is presented that the ineffectiveness of whole plasma (anemic) on the one hand, and the effectiveness of the filtrate after the plasma is boiled on the other hand, is associated with respective presence and absence of antibody-provoking antigens.

5. A fractionation procedure is described whereby a fraction was obtained which, on the basis of amount of protein, is much more potent than unfractionated plasma filtrate, by tests based on reticulocytosis in mice, uptake of Fe59 in starved rats and polycythemia in normal rats. When this material was subjected to zone electrophoresis two-thirds of its protein and all the activity was found confined to one band. It is noteworthy that the material which gave the positive responses to the three tests has so far remained together in one fraction.

6. Some physical and chemical properties of erythropoietically active plasma fractions are described. So far erythropoietic activity has been inseparable from protein.

7. A number of hormones, vitamins and other growth-promoting materials were tested for erythropoietic activity and were found to be negative by the tests employed.
Effect of Myleran and 6-Mercaptopurine (6-MP) on the Serum Level of Vitamin B12 in Chronic Myelocytic Leukemia
Authors: DOCTOR V. M. , BERGSAGEL D. E. , SHULLENBERGER C. C.
Published: October 2019

Serum vitamin B12 determinations and the total leukocyte counts were made at regular intervals in chronic myelocytic leukemia patients before, during and after therapy with 6-MP or Myleran. The results indicate that a reduction in total leukocytes following therapy is followed by a gradual lowering of serum vitamin B12. The levels of serum vitamin B12 at the completion of therapy may be related to the duration of remission.
A Serum with an Albumin-Active, Autoagglutinating Property
Authors: MOORE B. P. L. , LININS I. , MCINTYRE J.
Published: October 2019

A case is reported which possesses an unusually serologic property. The serum agglutinates all cells, including the patient’s own, but only when these are suspended in either human or bovine albumin. It appears to be an acquired and impermanent characteristic, but its etiology is unknown.
The Basophilic Granulocyte
Authors: FREDRICKS ROBERT E. , MOLONEY WILLIAM C.
Published: October 2019

1. The history, morphology and technics of counting of basophils have been briefly reviewed.

2. A marked relative and absolute increase of basophils was always found in chronic myelogenous leukemia. Moderate relative and absolute increases of basophils usually occurred in myeloid metaplasias (including polycythemia vera with leukocytosis). In some cases of iron-deficiency, hemolytic and toxic anemias of long standing there may be moderate increases of blood basophils.

3. Marked relative and absolute decreases of basophils occurred in almost all cases of neutrophilic leukocytosis or leukemoid reaction, associated with infection, neoplasia, tissue necrosis or acute anemia. Patients with chronic lymphatic leukemia, monocytic leukemia or acute leukemia almost always have relative and absolute decreases of circulating basophils.

4. In our experience there is no evidence that basophils possess any peculiar radioresistant qualities. In general, the basophils fall proportionately with the decline of leukocyte counts during Myleran, P32 and x-ray therapy of chronic myelogenous leukemia and myeloid metaplasia. The suppressing action of these therapeutic agents seems to be on the proliferating blast cell.

5. The function of the basophils is not known, but it has been postulated that they might act as "heparinocytes," inhibiting clotting and stasis of blood and lymph in areas of inflammation.

6. There is suggestive evidence that the basophilopenia in cases of infection, neoplasia, tissue necrosis and acute anemia is analogous to the eosinophilopenia of the "stress reaction" mediated via the adrenal glands; however, it must be admitted that this has not been unequivocally established, and other mechanisms may play a role in controlling the levels of circulating basophils.
Inability of Haptoglobin to Bind Myoglobin
Authors: JAVID JAMSHID , FISCHER DAVID S. , SPAET THEODORE H.
Published: October 2019

1. The old and the current concepts of the renal handling of extracorpuscular plasma Hgb are briefly reviewed.

2. Studies are presented on the starch gel electrophoretic behavior of Mb alone and Mb in serum.

3. It is suggested that Mb is not bound by Hp, known to bind Hgb, and that this constitutes the reason for the "low renal threshold" of Mb as compared to that of Hgb.
Patterns of Hemopoietic Recovery in Irradiated Mice
Authors: SMITH WILLIE W. , MARSTON ROBERT Q. , CORNFIELD JEROME , Alderman Ilo M. , Gillespie Ruth E. , Ruth H. Jeanette
Published: October 2019

We have demonstrated three distinct patterns of altered hemopoietic recovery in irradiated mice:

1. That seen in mice given isologous hemopoietic cells, in which granulocytes, lymphocytes, hemoglobin and platelets all showed an early recovery The time required for granulocyte and lymphocyte recovery was relatively unaffected by the amount of radiation to which the host was exposed (LD1-99). The time between injection and recovery was also relatively constant.

2. That seen in mice given rat bone marrow, in which only granulocytes and hemoglobin showed an early increase in concentration, with lymphocytes and platelets recovering near the control times.

3. That seen in mice given endotoxin or colchicine prior to irradiation in which the lymphocyte recovery was variable while the granulocytes, hemoglobin and platelets compared favorably with mice given isologous bone marrow.
Relation of Mastocytoma to Mast Cell Leukemia, and of Heparin, Histamine and Serotonin to Mast Cells
Authors: ONO SABURO , ZOMPETTI LENA , HAGEN PAUL , FURTH JACOB
Published: October 2019

A highly functional, transplantable neoplasm of mast cells is described. It causes solitary slowly growing tumors localized at the site of graft in muscles and subcutaneous tissues.

Mast cell leukemia results when isolated cells are injected intravenously. The blood of mice with mast cell leukemia produces solid mastocytomas when injected intramuscularly.

These and other observations suggest the essential identity of blood and tissue mast cells and suggest that mast cells are an independent cell type with primary residence in tissues outside the hemopoietic organs.

In mastocytomas, heparin, histamine and serotonin are present in great quantities. Some histamine is released and partly excreted in the urine.

In the mast cell leukemias, histamine plasma levels are slightly raised and urine levels are highly elevated.

Plasma heparin values may be slightly raised in mice with mast cell tumors and are greatly increased in mast cell leukemias without a hemorrhagic state.

The liver histamine and heparin values appear to be related to the number of infiltrating mast cells.
The Relationship of Age, Strain and Species to the Reducing Activity of Leukocytes
Authors: YAKAITIS ALBINA ANN
Published: October 2019

A method is presented for studying the reducing activity of leukocytes of mice and rats using 2-(p-iodophenyl)-3-)p-nitrophenyl)-5-phenyltetrazolium chloride (INT).

Between 48.0 per cent and 83.8 per cent of the leukocytes of young adult mice and between 47.8 per cent and 68.0 per cent of the leukocytes of young rats showed formazan formation.

Infant mice of C3Hf and BALBf strains had appreciably fewer leukocytes with the ability to reduce tetrazolium than did young adults of their respective strains.

Healthy adult mice belonging to the leukemia susceptible AKR strain showed a relatively high degree of leukocytic reduction.

Old mice of the C3Hfstrain showed less formazan formation than young adult animals. This decrease was more marked for the male members of the species.
Distinctive Myeloma Globulins Associated with a New Plasma Cell Neoplasm of Strain C3H Mice
Authors: FAHEY JOHN L. , POTTER MICHAEL , GUTTER FREDERICK J. , DUNN THELMA B.
Published: October 2019

A transmissible plasma-cell neoplasm (5647) accompanied by marked serum protein changes has been described in the mouse. The principal characteristics of this neoplasm and the associated serum protein changes have remained unchanged during two years of observation.

The transplanted neoplasm usually remains confined to the site of implantation. Osteolytic lesions and abnormal cells in the peripheral blood were not seen.

Morphologically the neoplastic cells retain many characteristics of normal plasma-cells, with clumping of the nuclear chromatin, an eccentric nucleus and a clear zone in the basophilic cytoplasm.

Serum electrophoretic analyses revealed a markedly abnormal serum protein pattern. The total serum protein was increased by two to three grams per cent in mice bearing 5647 neoplasms weighing 6 grams or more. Increased amounts of proteins with beta globulin and fast gamma globulin electrophoretic mobility were the most striking electrophoretic findings. These components comprised as much as 35 per cent of the serum proteins in animals with large neoplasms.

Serum ultracentrifugal analyses also demonstrated a markedly abnormal distribution of the serum proteins. Normal mouse serum contains components with sedimentation coefficients (S20,W) of 4, 6.5 and 16 S. Serum of mice bearing neoplasm 5647 contained, in addition to the normal components, proteins with sedimentation coefficients of 9, 11 and 13 S. These serum components, accounting for as much as 20 per cent of the total protein, have been found only with neoplasm 5647.

The quantity of the abnormal serum components seen on electrophoretic and ultracentrifugal analyses was found to increase as the tumor weight increased.

Bence Jones protein was not found in the urine of mice bearing the 5647 neoplasm.

Neoplasm 5647 was found to differ significantly in biologic behavior and in the associated serum protein changes from two other transmissible plasma-cell neoplasms of the mouse (5563 and 70429) which have been under observation in these laboratories.

The mouse plasma-cell neoplasm 5647 resembles in several characteristics the malignant plasmacytomas in man having associated myeloma proteins of beta globulin electrophoretic mobility.
Iron Enzymes in Iron Deficiency. V. Succinic Dehydrogenase in Rat Liver, Kidney and Heart
Authors: BEUTLER ERNEST , BLAISDELL RICHARD K.
Published: October 2019

Manometric determinations of the enzyme succinic dehydrogenase have been carried out on liver, heart and kidneys of iron-deficient and control rats. Even after prolonged, moderately severe iron deficiency, no decrease in enzyme activity of liver homogenates could be demonstrated. However, enzyme depletion could be demonstrated to have occurred in the hearts and kidneys of iron-deficient animals.
Kinetics of Intracellular Iron in Rabbit Reticulocytes
Authors: ALLEN DAVID W. , JANDL JAMES H.
Published: October 2019

The kinetics of the intracellular iron were studied in an invitro system using reticulocyte-rich rabbit red cells incubated with Fe59-labeled plasma. The incubation was stopped at intervals of a few seconds to 70 minutes, and the cells were fractionated by differential centrifugation and by chemical means. In being selectively taken up by reticulocytes, Fe59 is first associated with particulate fractions and then gradually released to the soluble cytoplasm, when the iron is incorporated into hemoglobin and into a transient nonhemoglobin protein phase. The entire process from the initial binding of iron by cell surfaces receptors until the incorporation of iron into hemoglobin requires only 6 to 8 minutes at 37 C. It is probable that in suitable concentrations, lead allows Fe59 to accumulate in stroma but blocks its entry into the nonhemoglobin protein iron phase and into hemoglobin.
The Appearance of Labeled Cells in the Thoracic Duct Lymph of the Guinea Pig after the Administration of Tritiated Thymidine
Authors: EVERETT N. B. , REINHARDT W. O. , YOFFEY J. M.
Published: October 2019

Tritium-labeled thymidine was given by either intraperitoneal or intravenous injection to 13 male guinea pigs of approximately 400 Gm. weight.

At times varying from 1 hour to 30 days after the administration of thymidine, thoracic duct lymph was obtained and examined for the presence of labeled cells.

After a single dose of thymidine, a steady stream of labeled lymphocytes, ranging from 2 to 7 per cent of the total cells, enters the blood over the period studied. The intensity of the labeling appears to diminish gradually.

Labeled large and medium lymphocytes were found in the lymph during the first hour. Labeled small lymphocytes began to appear in the fourth hour, in small numbers, and thereafter increased, whereas the proportion of labeled large and medium lymphocytes steadily diminished.

This sequential appearance of large, medium and small lymphocytes is interpreted as indicating the pattern of development of the cell series. The labeled small lymphocytes appearing in the lymph are considered to be newly formed from precursor cells located in the various lymphatic tissues.
A Plasma Coagulation Defect in Systemic Lupus Erythematosus Arising from Hypoprothrombinemia Combined with Antiprothrombinase Activity
Authors: RAPAPORT SAMUEL I. , AMES SARA BETH , DUVALL BARBARA J.
Published: October 2019

A patient has been described with systemic lupus erythematosus and severe bleeding. Her bleeding was associated with a complex plasma coagulation disturbance consisting of profound hypoprothrombinemia plus an anticoagulant active against formed blood and tissue prothrombinase. The problem of the recognition of hypoprothrombinemia in the presence of this type of anticoagulant has been discussed in detail.

An analysis of previously reported cases reveals that our patient’s findings are not unique. It appears that the plasma coagulation disturbances of systemic lupus erythematosus characteristically result from a mixture of anticoagulant activity and true hypoprothrombinemia. In an individual patient one or the other may predominate.