bluuebunny/crossref_metadata_2025 huggingface dataset:
Single Cell RNA-Seq Reveals Clonal Consistency and Differential Malignancy in Extramedullary Plasmacytoma of Multiple Myeloma
Authors: Geng Shuang , Wang Jing , Chen Mingyi , Wang Wenming , Pang Yuhong , Liu Yuanyuan , Huang Yanyi , Jing Hongmei
Published: October 2019

Extramedullary Plasmacytoma (EMP) is a minor yet devastating metastatic form of Multiple Myeloma (MM), shortening patients' survival from 10 years to 6 months on average. Genetic cause of EMP in MM is yet to be defined. Transcriptome difference between EMP+ patients and EMP- patients is studied here on single cell level by RNA Sequencing (RNA-Seq). We sorted CD38+CD138+ malignant plasma cells from bone marrow and peripheral blood samples by flow cytometry, then picked up single malignant plasma cell and performed single cell RNA-Seq with SmartSeq2 protocol followed by Tn5-based library preparation from bone marrow, peripheral blood and extramedullary tissue of EMP patients. From the single cell RNA-Seq results, in bone marrow we found differential gene expression between EMP+ and EMP- samples, such as CTAG2, STMN1 and RRM2. By comparing circulating malignant plasma cells in PBMC and malignant plasma cell from the sample EMP+ patient, we observed metastatic clone in blood with the same VDJ immunoglobulin heavy chain as in bone marrow. Several genes' expression of these metastatic cells are down-regulated than in bone marrow, such as PAGE2, GTSF1, DICER1. These genes may correlate with egress capability of MM cells into peripheral to become circulating plasma cells (cPCs), and EMP eventually.

Disclosures

No relevant conflicts of interest to declare.
5-Azacitidine Remolds the Methylation Status and Inhibits Growth in Multiple Myeloma
Authors: Wang Wenming , Wang Jing , Chen Mingyi , Liang Yaoxian , Li Zhengqian , Zhang Zhe , Jing Hongmei
Published: October 2019

Multiple myeloma (MM) is a malignant disorder characterized by the proliferation of a single clone of plasma cells derived from B cells. Previous studies have demonstrated that both gene-specific hypermethylation and global hypomethylation characterizes the multiple myeloma epigenome. 5-azacytidine as a DNA methylation inhibitor has therapeutic efficacy in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Nevertheless,the effects of 5-azacytidine on MM remains unclear. We used RT-PCR to detect the expression of PTPL1 and used MS-PCR to determine the methylation status of PTPL1 in MM cell lines and after 5-azacytidine treatment. ELISA-like reaction was used to detect global DNA methylation level. The cytotoxic activity of 5-azacytidine was tested using cell viability and apoptosis assays. Flow cytometry was used to detect cell cycle after 5-azacytidine treatment. Our experiments discovered that the PTPL1 gene was hypermethylated in the U266 and H929 cell lines, and the expression of PTPL1 mRNA could be re-inducible by 5-azacytidine. 5-azacytidine also inhibited the proliferation of multiple myeloma cell lines U266 and H929 in a time- and dose-dependent manner, induced G2/M cell cycle arrest and caspase-dependent apoptosis. But in our study 5-azacytidine increased the methylation level for both cell lines. Our study showed that PTPL1 was epigenetically regulated in MM which can be reversed by 5-azacytidine, and highlights 5-azacytidine is a potential therapeutic candidate for MM, but additional studies are needed to determine the effects of genome-wide methylation changes in MM.

Disclosures

No relevant conflicts of interest to declare.
MDR1 polymorphisms Have an Impact on the Prognosis of Chinese Diffuse Large B Cell Lymphoma Patients
Authors: Kourong Miao , Zhengrui Xiao , Ying Ni , Guangli Yin , Li Jianyong
Published: October 2019

MDR1 (multidrug resistance 1) encodes an adenosine triphosphate (ATP) dependent efflux transporter that plays a fundamental role of transport harmful compounds outside cells to maintain optimal health. The present study aimed to investigate whether the MDR1 gene single nucleotide polymorphisms (SNPs) were associated with the prognosis of diffuse large B-cell lymphoma (DLBCL). Three common SNPs, including C1236T, G2677T/A and C3435T were focused on and a total of 150 DLBCL patients from Jiangsu Han population were successively genotyped by polymerase chain reaction-allele specific primers (PCR-ASP) method or DNA direct sequencing. At locus C1236T, patients carrying T allele (genotype CT and TT) had a prolonged overall survival (OS) when compared with patients with CC genotype (2-year OS 82.6% vs. 60.0%, respectively; HR=0.1, 95% CI 0.01-0.6, p =0.016). At locus C3435T, complete remission/ complete remission unconfirmed (CR/CRu) rate in C allele group was significantly higher than T allele group (66.7% vs. 51.9%, respectively; p=0.009). The progression-free survival (PFS) curves of with T (genotype CT and TT) and without T (genotype CC) were significantly different (2-year PFS 46.4% in with T group vs.73.7% in without T group, respectively; HR=1.9, 95% CI 1.0-3.6, p=0.045). At locus G2677T/A, the age for genotypes AG and AT groups were significantly younger than the other genotypes (51.1±12.6 years vs. 57.7±13.4 years, respectively; p=0.033). In the haplotype analysis of loci 1236-3435, compared with T-C group, the C-T group displayed an inferior PFS rate (2-year PFS 23.0% vs. 50.6%, respectively; HR=7.8, 95% CI 1.9-32.6, p=0.005), while C-C and T-T groups showed an intermediate PFS rate. Our findings demonstrate that genotype CT+TT at locus C1236T, allele C and genotype CC at locus C3435T might contribute to a relatively superior prognosis in DLBCL, as well as haplotype of T-C in loci 1236-3435. Besides, genotypes at locus G2677T/A might affect age at diagnosis, which has important prognostic value for DLBCL. These results could provide evidence that the MDR1 SNPs may influence the biologic feature and prognosis of DLBCL and shade new lights in disease association studies.

Disclosures

No relevant conflicts of interest to declare.
Dental Problems in Adult Patients with Sickle Cell Disease
Authors: Master Samip , Walton Jacqueline , Mansour Richard Preston
Published: October 2019

Introduction

Previous studies of children with SCD have shown developmental problems occurring in the enamel and dentin. Mucosal pallor, delayed eruption, dental hypoplasia, and radiographic changes are also common oral finding in patients with SCD. Preventive dental therapy is the ideal approach for management of patients with SCD. We surveyed a sample of our adult patients with SCD to determine the prevalence of patient reported dental problems, including existing "bad tooth", and tooth. We also investigated the prevalence of dental insurance that pays for regular dental exams.

Methods:

We have surveyed 74% of the IRB approved 100 patient sample and gathered the above mentioned information. We collected data on dental insurance, last dental exam, number of adult teeth removed, and patient self-assessment of bad teeth, tooth abscess and number of past episodes of either.

Results

Mean age was 33 years. There were 34 males and 40 females. Seventy percent (52/74) did not have dental insurance. Forty-two percent (31/74) have not had a dental exam within the last 12 months. Twenty-two percent (30/74) of patient had two or more adult teeth removed. 46 % reported that they currently have bad tooth and 31 %( 23/74) have now or have had a tooth abscess. 11 patients reported one episode, 9 patients reported 2 episodes and 4 patients reported three or more episodes of tooth abscess.

Conclusion

In our surveyed population of adult patients with SCD, we find a high number of self-reported advanced dental disease and failure to obtain regular dental care. 70 percent of these patients do not have dental insurance for preventive or advanced dental care. We conclude that adequate preventive dental care is an unmet need for the majority of this special population.

Disclosures

No relevant conflicts of interest to declare.
Clinical Profile of Langerhand Cell Histiocytosis- Single Center Experience
Authors: Al Jassmi Abdulrahman M.
Published: October 2019

Background/Objectives:

Dubai hospital is one of the three main centers which carters for the management of children presenting with benign and malignant blood disorders in the United Arab Emirates. This study is to demonstrate the varied clinical profile of children with Langerhans cell histiocytosis (LCH) who presented to Dubai hospital since 2012.

Methods/Design:

A Prospective analysis of children with LCH treated at our center was done. Complete history, physical examination, relevant laboratory and radiological investigations were studied for all children suspicious to have LCH. Diagnosis was confirmed by obtaining tissue from biopsy of involved areas. Once histopathology confirmed the diagnosis, extent of disease was evaluated and chemotherapy started based on the LCH-IV protocol.

Results:

A total of 10 children presented to Dubai hospital with LCH from 2012 to 2016. The age at diagnosis ranged from 5 months to 5 years. Diagnosis was confirmed by positive CD1a and S100 immuno-markers of involved tissue (100%). These children had varied presentations like respiratory distress, recurrent chest infections, chronic diarrhea, abdominal pain, back pain, inability to walk, lymphadenopathy and buccal mucosa swelling. Median time of diagnosis once the children reached to our center was between 15 days to 1 month. Five children (50%) had multisystem LCH with risk organ involvement. Four children (40 %) had single system involvement and one child had single system multifocal involvement. Osteolytic lesions were present in six children (60%) leading to an early diagnosis.

Good response to Induction I therapy (Prednisolone, Vinblastinefor 6 weeks) of Stratum I, LCH-IV protocol was seen in sevenchildren (70%). Two children were upgraded to Stratum II chemotherapy, LCH-IV protocol at the end of Induction II of stratum I chemotherapy (total 12 weeks of prednisone and Vinblastine) because of either poor response or progressive disease. One child was started on salvage chemotherapy, (Cladiribine, Cytarabine) during Induction therapy because of no response. There has been no mortality in our cohort.

Conclusion:

There should be high index of suspicion for LCH. One needs to be well acquainted to varied presentations of LCH for quickerdiagnosis. Induction therapy with Prednisolone and Vinblastine is a good prognostic marker for children with LCH in our study. It should still be considered the first line therapy for all children with LCH requiring chemotherapy because of lower toxicity profile and good response in the majority. Poor response to Initial Induction of 6 weeks with Vinblastine and Prednisolonewas salvageable with second line therapy in our cohort.

Disclosures

No relevant conflicts of interest to declare.
Venous and Arterial Thromboembolism Related Hospitalizations Among Patients with Gastrointestinal Malignancy in United States - Data from Nationwide Sample
Authors: Puligondla Chaitanya , Kumar Rachit , Parasa Sravanthi
Published: October 2019

Introduction:

Patients with underlying malignancies are at high risk for developing venous thromboembolism (VTE). We sought to characterize the risk and risk factors for developing VTE (both deep vein thrombosis (DVT) and Pulmonary embolism (PE)) and arterial thromboembolism among patients with underlying Gastrointestinal(GI) malignancies.

Methods:

We used the Nationwide Inpatient Sample (NIS) database to perform a cross-sectional study. The study group was defined as all hospitalized patients with GI malignancies above 18 years included in the NIS 2011 database with a primary discharge diagnosis of thromboembolism (Venous or arterial), as per the International Classification of Diseases - Clinical Modification, 9th revision (ICD-9-CM) codes. This VTE and arterial embolism population's demographics and outcomes were compared to the remainder of inpatient GI cancer patients without the diagnosis. All analyses were performed using STATA MP 12.VTE and Arterial embolism, identified by the ICD-9-CM codes, were studied comprehensively for their association with GI cancers and the risk factors were using multivariate logistic regression analysis. Odds ratios were calculated adjusting for relevant patient comorbidities.

Results:

Based on the location of GI cancer, there were a total of 37,872 patients hospitalized with underlying diagnosis of esophageal cancer, 97020 patients with pancreatic cancer, 45669 patients with gastric cancer and 267756 patients with colorectal cancer. The rates of VTE were highest among patients with pancreatic cancer (3.3%) followed by esophageal cancer 2.2%; gastric cancer 1.9%; colorectum (1.4%).

In multivariate analysis, risk of VTE diagnosis was highest among pancreatic cancer patients, adjusted Odds ratio (aOR) - 2.8; 95% CI (2.53 - 3.09) after adjusting for active chemotherapy status, race, age, gender and comorbidities as determined by Deyo - Charlson comorbidity index. aOR for risk of VTE among Esophageal cancer patients was 1.73 , 95% CI (1.49-2.01) ; Colorectal cancer 1.18; 95% CI (1.09-1.27) and gastric cancer 1.52, 95% CI(1.30-1,78). The risk of PE was higher than DVT among patients with VTE. Underlying GI cancer was not associated with increased risk of arterial embolization, acute cerebro vascular events or acute myocardial infarction. The number of death associated with a principal discharge diagnosis code of VTE were not significantly high.

Conclusion:

Patients with pancreatic cancer have the highest risk of hospitalization for VTE among patients with underlying GI malignancies. Underlying GI malignancy is not associated with increased risk of arterial embolization, acute cerebro vascular events or acute myocardial infarction.

Disclosures

No relevant conflicts of interest to declare.
An Active Intervention Has Reduced RBC Transfusion Number: A Single Center Expierience
Authors: Kirgner Ilya , Hareuveni Mara , Sagy Yael , Weiss-Meilik Ahuva , Oster Howard S , Avivi Irit , Barabash Gabriel , Mittelman Moshe
Published: October 2019

Background: "Choosing wisely" strategies have been applied in Tel Aviv Sourasky Medical Center (TASMC). Limiting red blood cell (RBC) transfusions according to the 1999/2005 guidelines, without compromising patient care, has been selected as a major goal. Our preliminary single center experience is described.

Methods : We initiated a program including physician education, inspection and feedback. We retrospectively reviewed the inpatient charts and the hospital RBC transfusion data from 2011-2015.

Results: Approximately 80,000 non-surgical patients are admitted yearly to TASMC, primarily to the Department of Medicine (350 beds). The percentage of transfused patients declined from 4.6% in 2011 to 4.2% in 2013. Most transfused patients were older than 80 years with cardiovascular disease or other co-morbidities. The % of patients requiring RBC transfusions who had pre-transfusion Hb ≥ 9 g/dL was reduced from 23.8% (2011) to 21.9% (2012) and 14.4% (2013). Those with pre-transfusion Hb ≥ 8g/dL declined from 62.9% (2011) to 59.6% (2012) and 51.8% (2013). The total number of RBC units transfused declined from 2982 in 2012 to 2404 in 2015, a 19.4% reduction.

Summary : An active policy including education, awareness, and feedback from blood bank to physician, using a lower Hb threshold, resulted in a dramatic reduction of RBC transfusions.

Disclosures

Kirgner: Tel Aviv Sourasky Medical Center: Consultancy. Avivi:Tel Aviv Sourasky Medical center: Consultancy, Other: consultancy to :BMS Roche.
Impact on Acute Myeloid Leukemia Relapse in Granulocyte Colony Stimulating Factor Application: A Meta-Analysis
Authors: Feng Xiaoqin , Li Chunfu
Published: October 2019

Objective: This meta-analysis evaluated the impact of granulocyte colony-stimulating factor (G-CSF) added to chemotherapy on treatment outcomes including survival and disease recurrence in patients with acute myeloid leukemia (AML).

Methods: Medline, Cochrane, EMBASE,Google Scholar databases were searched until December 7, 2015 using the following search terms. Randomized control trials (RCTs), two-arm, and prospective studies that investigated patients with AML who underwent stem-cell transplantation were included.

Results: The overall analysis revealed significant improvement in overall survival (OS) (pooled HR= 0.90; 95%CI, 0.83 to 0.98; P = 0.017) and disease free survival (DFS) (pooled HR = 0.85; 95% CI, 0.77 to 0.94; P = 0.002) for patients receiving G-CSF with chemotherapy. Among patients without prior AML treatment, there was significant improvement in DFS (pooled HR = 0.87; 95% CI, 0.77 to 0.98; P = 0.021) and reduction in incidence of relapse (pooled HR = 0.81; 95% CI, 0.68 to 0.96; P = 0.015) for those who received G-CSF. However, subgroup analyses found no significant difference between G-CSF (+) and G-CSF (-) treatments in rates of OS (P = 0.135) and complete remission (CR) (P = 0.357) for patients without prior AML treatment. Among patients with relapsed/refractory AML, there was no significant difference found between G-CSF(+) and G-CSF(-)groups for OS (P = 0.225), DFS (P = 0.209) and CR (P = 0.208).[EG1]

Discussion and Co nclusion: Treatment with chemotherapy plus G-CSF appears to provide better survival and treatment responses compared with chemotherapy alone, particularly for patients with previously untreated AML.

Disclosures

No relevant conflicts of interest to declare.
Predicting Early Mortality in Diffuse Large B-Cell Non-Hodgkin Lymphoma
Authors: Maddox Jamie M
Published: October 2019

It is difficult to find figures for the expected rate of early mortality in diffuse large B-cell non-Hodgkin lymphoma (DLBCL) as many of the patients who are destined to die early do not enter clinical trials. Our own rate of early mortality (death within 100 days of the diagnostic test being performed) was higher than we had anticipated (23%). We undertook a study to look at risk factors for early mortality, and to see if there were any factors which could be improved by altering our investigation and initial management.

Our haematology database has baseline demographic and prognostic information on all cases of haematological malignancy diagnosed in our centre. A two year period was chosen retrospectively from 1st January 2013 until 31st December 2014. This gave 97 registered patients with DLBCL.

Early mortality was significantly related to the patient age, Eastern Cooperative Oncology Group (ECOG) performance status, lactase dehydrogenase value, presence of 2 or more sites of extranodal disease and the presence of B-symptoms. We did not see a significant relationship to the presence of marrow disease or the presence of disease bulk. As the majority of the relevant factors are already part of validated prognostic scoring systems, we evaluated the (International Prognostic Index) IPI, the R-IPI (revised International Prognostic Index) and the NCCN-IPI (enhanced International Prognostic Index) to see which was the best predictor of early mortality. The IPI gave the chance of 100 day mortality as 4% for low or low-intermediate risk patients, 16% for high-intermediate risk patients and 53% for high risk patients. The R-IPI gave the chance of 100 day mortality as 0% for low risk patients, 5% for intermediate risk patients and 48% for high risk patients. The NCCN-IPI gave the chance of 100 day mortality as 0% for low or low-intermediate risk patients, 13% for high-intermediate risk patients and 57% for high risk patients (figure 1). By six months, the mortality rate in high risk NCCN-IPI patients had reached 71% while the low and low-intermediate groups remained at 0%. Some patients were included who were not considered for potentially curative chemotherapy. Even with these patients excluded, the risk of 100 day mortality was still 50% in the high risk NCCN-IPI group.

Some of the risk factors for mortality will likely worsen if the diagnosis or initial treatment are delayed. We therefore looked at the overall pathway from referral until first treatment. We found that those with early mortality tended to have a shorter time course until receiving their first treatment, likely reflecting the fact that they were more unwell when they first presented.

Disclosures

Maddox: Janssen: Other: Funding to attend ASH 2016 (travel, accommodation, registration); Boehringer-Ingelheim: Other: Funding to attend ASH 2014 (travel, accommodation, registration).
Azacitidine As Post-Allograft Maintenance Helps Reduce Relapse Risk in High-Risk MDS and AML
Authors: El Cheikh Jean , Massoud Radwan , Fares Elie , Kreidieh Nabila , Mahfouz Rami , Kharfan-Dabaja Mohamed A , Bazarbachi Ali
Published: October 2019

Purpose: Relapse after allogeneic hematopoietic SCT (allo-SCT) for AML or myelodysplastic syndrome (MDS) remains the main cause of treatment failure and is associated with a very poor prognosis and a short survival despite the type of the salvage therapy. Options include reductions of immunosuppressive therapy, chemotherapy with or without infusion of donor lymphocytes (DLI) or second allo-SCT, but results remain disappointing. Other studies (C Jabbour et al, and Craddock Charlie et al) demonstrated the efficacy and safety of 5-azacytidine (Vidaza) maintenance post Allo-SCT.

Patients and Methods: The aim of our observational study was to evaluate the anti-leukemic effect of 5-azacytidine (Vidaza) as post-transplantation prophylactic therapy to prevent relapse in patients with high risk AML or MDS in our center. We identified 16 patients, 13 AML and 3 MDS. Twelve patients (75%) received a risk-adapted intensity of busulfan at 130mg/m2/day for either 2, 3 or 4 days, with a fixed dose of fludarabine (30mg/m2/day for 5 days), and thymoglobulin (2.5mg/kg/day for 2 days). Our algorithm was based on age, co-morbidity (ies) and disease risk.

Twelve patients (75%) received peripheral blood stem cells (PBSC) from HLA identical siblings, 3 patients (19%) from haplo-identical donor and 1 patient from matched unrelated donor. Azacitidine was started after a median of 60 days post-transplant with a reduced dose of 32 mg/m2/day for 5 days monthly for 5 years. None of the patients experienced graft rejection. Patient and transplant characteristics are outlined in Table 1.

Results: Nine patients (56%) had either a monosomal karyotype or a complex karyotype. Patients received a median number of 8 cycles (1-37) of vidaza. None of our patients stopped definitively vidaza for toxicity reasons. Three patients (19%) discontinued their treatment: one for 3 months because of pneumonia, one for acute GvHD grade II then resumed Azacitidine therapy after 6 months, the third stopped for 2 weeks because of neutropenia. After a median follow-up of 10 months (1-56) from allo-SCT, 13 patients (81%) still alive and 3 patients died; one because of CMV infection, one from disease progression and one from cardiac infarct. At the last follow up 13 patients (81%) remain in complete remission.

Conclusions: Azacitidine prophylactic maintenance therapy appears to reduce the risk of relapse by helping consolidate post-allograft responses in high risk AML or MDS. The toxicity related to this dose of azacitidine was very low. Our findings require validation in a large prospective multicenter randomized study.

Legend: AML, Acute Myeloid Leukemia; MDS, Myelodysplastic Syndrome; CR, Complete Remission; FB2 Fludarabine 2 days Busulfan,;FB3 Fludarabine 3 days Busulfan; FB4 Fludarabine 4 days Busulfan; TBF Fludarabine Busulfan.

Disclosures

No relevant conflicts of interest to declare.
Two Cases Report of Haploid Hematopoietic Stem Cell Transplantation Treatment of Adrenal Leukodystrophy
Authors: Chen Libai , Wen Jianyun , He Yuelin , Feng Xiaoqin , Li Chunfu , Wu Xuedong
Published: October 2019

Background : Adrenal leukodystrophy is one of the beta oxidation peroxidase disease, an x-linked recessive heredity, can lead to very long chain fatty acids in tissue accumulation, result in adrenal and cerebral white matter of the progressive deterioration. Hematopoietic stem cell transplantation (HSCT) is a curative treatment for early childhood cerebral type of X-ALD. We report two cases of haploid hematopoietic stem cell transplantation for the treatment of adrenal leukodystrophy.

Methods: Two patients were male, 5 years old, 6 years old, respectively, by the gene diagnosis of adrenal leukodystrophy.Case 1 received father haploid bone marrow and peripheral blood stem cell(HLA7/10 match)combine with unrelated umbilical cord blood(HLA 9/10 match). Case 2 received sister haploid bone marrow and peripheral blood stem cell(HLA5/10 match)combine with unrelated umbilical cord blood(HLA 7/10 match).Case 1 conditioning regimen use cyclophosphamide, fludarabine and thiotepa.Case 2 conditioning regimen use cyclophosphamide , busulfan ,fludarabine , rabbit anti-human thymocyte immunoglobulin and thiotepa.Case 1 bone marrow infused total nucleated cell dose was 2×108/kg (CD34+:0.75%,CD3+:1.67%), peripheral blood stem cell infused total nucleated cell dose was 29×108/kg (CD34+:0.19%,CD3+:4.96%), unrelated umbilical cord blood infused total nucleated cell dose was 1.16×108/kg (CD34+:0.44%). Case 2 bone marrow infused total nucleated cell dose was 0.89×108/kg (CD34+:0.74%,CD3+:2.29%), peripheral blood stem cell infused total nucleated cell dose was 25.85×108/kg (CD34+:0.5%,CD3+:15.23%), unrelated umbilical cord blood infused total nucleated cell dose was 0.39×108/kg (CD34+:0.93 %). GVHD prophylaxis Case 1 used mycophenolate mofetil,sirolimus,while Case 2 used mycophenolate mofetil,tacrolimus and sirolimus.

Results: The absolute neutrophil count (ANC) greater than 0.5×109/L of two patients were 21 and 23 days , case 1 had a successful engraftment with father donor-derived as case 2 had a successful engraftment with umbilical cord blood donor-derived.Follow-up time of 35 months and 3 months respectively,Case 1 Check head MRI again show a smaller lesionswhile Case 2 progression-free.Two cases' C24:0, C26:0, C24:0 / C22:0, C26:0 / C22:0 of plasma decline than before transplantation.

Conclusion: In the absence of HLA-match donor, haploid bone marrow and peripheral blood stem cell combined unrelated umbilical cord transplantation is a effective method of treatment of adrenal leukodystrophy, but which will successful engraftment need more further studies.

Disclosures

No relevant conflicts of interest to declare.
Adult Lymphoma-Associated Hemophagocytic Syndrome Is a Life-Threatening Disease: Retrospective 10-Year Review of 89 Cases at a Single Center
Authors: Jin Zhili , Wang Yini
Published: October 2019

Lymphoma is classified into Hodgkin's and non-Hodgkin's lymphoma (B- cell or T-cell type). Lymphoma-associated hemophagocytic syndrome (LAHS) is a life-threatening disease with dismal prognosis. To assess the hemophagocytic lymphohistiocytosis (HLH)-related clinical features and prognosis in the immunophenotype of LAHS, we retrospectively evaluated 483 patients with HLH presented at our institution between December 2006 and March 2016. Eighty-nine adult patients were diagnosed with LAHS. Of those, 2 cases (2.2%) were Hodgkin's lymphoma with Epstein-Barr virus infection. Eighty-seven cases (97.8%) were non-Hodgkin's lymphoma consisting 25 cases (28.7%) of B-cell LAHS (B-LAHS) and 62 cases (71.3%) of T-cell LAHS (T-LAHS). There were 17 male and 8 female patients in B-LAHS with a median age of 57 years. There were 40 male and 22 female patients in T-LAHS with a median age of 39 years. T-LAHS patients were associated with younger age which was significantly different with that in B-LAHS patients (p=0.000). Clinical features were summarized according to HLH-2004 diagnosis criteria. For B-LAHS, fever and elevated serum ferritin exhibited in 100% of cases; elevated sCD25 was found in 94.7%; decreased NK cell activity was identified in 42.1%; pancytopenia was found in 80.0%; hemophagocytosis was found in 80.0%; splenomegaly presented in 92.0%; hypofibrinogenemia was found in 20.0%; hypertriglyceridemia presented in 26.1%. For T-LAHS, fever exhibited in 98.4%; elevated serum ferritin was found in 96.3%; elevated sCD25 presented in 87.8%; decreased NK cell activity was identified in 51.3%; pancytopenia exhibited in 80.6%; hemophagocytosis was found in 84.2%; splenomegaly presented in 85.4%; hypofibrinogenemia was found in 59.3%; hypertriglyceridemia presented in 50.0%. The 1-month, 3-month, and 6-month overall survival rate was 88.0%, 67.6%, and 53.1% in B-LAHS patients versus 54.5%, 28.2%, and 18.8% in T-LAHS patients. Ten T-LAHS patients underwent allogeneic hematopoietic stem cell transplantation (HSCT) with survival time of 1, 3, 4, 5, 5, 6, 7, 52, 84, 113 months, respectively. Nine patients with T-LAHS (14.5%) survived up to the end of follow-up, of which 6 patients (66.7%) received HSCT and 3 patients (33.3%) were without transplantation. Our results indicated the HLH-related clinical features present differently between T-LAHS and B-LAHS. Compared with B-LAHS, T-LAHS associate with earlier onset and inferior prognosis. In addition, allogenic HSCT might be an effective treatment approach for T-LAHS patients to achieve long-term survival.

Disclosures

No relevant conflicts of interest to declare.
Enhancers and Transcriptional Regulation
Authors: Wysocka Joanna
Published: October 2019

Interactions between the genome and its cellular and signaling environments, which ultimately occur at the level of chromatin, are the key to comprehending how cell-type-specific gene expression patterns arise and are maintained during development or are misregulated in disease. Central to the cell type-specific transcriptional regulation are distal cis-regulatory elements called enhancers, which function in a modular way to provide exquisite spatiotemporal control of gene expression during development. We are using a combination of genomic, genetic, biochemical, and single-cell approaches to investigate how enhancers are activated in response to developmental stimuli, how they communicate with target promoters over large genomic distances to regulate transcriptional outputs, what is the role of chromatin modification and remodeling in facilitating or restricting enhancer activity and how regulatory sequence change leads to the phenotypic divergence in humans. I will discuss our latest results on the mechanisms underlying enhancer function and gene regulation in development and disease.

Disclosures

No relevant conflicts of interest to declare.
Detection of Leukocyte Antibodies by Means of I131-Labelled, Purified Anti—Human-Globulin Antibody. Problems of Nonspecific Adsorption of Globulin by Leukocytes
Authors: ANDERSON ROBERT E. , WALFORD ROY L.
Published: October 2019

Initial studies of a quantitative method for detecting sensitization of white blood cells by antileukocyte antibodies are presented. The method entails isolating I131-labelled, anti—human-globulin antibody (prepared in rabbits) by adsorption and elution from insoluble antigen, globulinazobenzylcellulose. The degree of adsorption of the labelled antibody by presumably sensitized as opposed to nonsensitized leukocytes is measured by radioactive isotope counting technics. The vexing problem of nonspecific adsorption of human or rabbit globulin by leukocytes is considered, and procedures for partially circumventing this problem are set forth. Seligmann's solution with normal rabbit serum added to a final concentration of 10 per cent appeared to be the most effective washing fluid in most instances for removing nonspecifically adsorbed globulins from leukocytes. The use of purified anti—human-globulin antibody, as opposed to whole Coombs serum, also very favorably affected the ratio between immunologically specific adsorption and nonspecific adsorption. Results of the over-all I131 method as applied to selected positive and negative human sera are detailed.
The Clinical Significance of Fever in Acute Leukemia
Authors: RAAB SPENCER O. , HOEPRICH PAUL D. , WINTROBE MAXWELL M. , CARTWRIGHT GEORGE E.
Published: October 2019

1. The total course of acute leukemia in 55 patients managed in one clinic disclosed 149 febrile episodes.

2. Fever occurred virtually only when the leukemia was in relapse.

3. Infection was the cause of fever in 102 of the 149 episodes of fever.

4. With survival after the onset of symptoms of acute leukemia beyond the mean duration of life characteristic of that kind of acute leukemia, infection appeared to be more often the cause of fever than when survival was less than the mean for that kind of leukemia.

5. Fever due to infection could not be reliably differentiated from fever not due to infection by either the height or character of the fever curve, or by counting the absolute number of mature polymorphonuclear leukocytes in the blood.

6. Infection causing febrile episodes was most successfully detected by means of history, physical examination, chest roentgenogram, blood culture and other cultures as indicated by the preceding maneuvers.

7. Consideration of the fever of acute leukemia from the point of view of present day studies of the pathogenesis of fever did not clearly implicate known mechanisms of pyrogenesis.

8. The interplay of state of leukemia, nature of infecting microorganism and anti-infectious and antileukemic therapies is related to outcome in febrile episodes due to infections. The management of febrile episodes is discussed.

9. Increased survival time in children with acute lymphoblastic leukemia has not been accompanied by increased morbidity.
A Comparative Study of Some Staining Properties of Crystals in a Lympho-plasmocytoid Cell, of Russell Bodies in Plasmocytes, and of Amyloids-With Special Emphasis on Their Isoelectric Points
Authors: GOLDBERG ARTHUR F. , DEANE HELEN WENDLER
Published: October 2019

A staining procedure for determining the approximate isoelectric points of substances has been applied to tissue sections containing (a) intracytoplasmic crystals in a lympho-plasmocytoid cell, (b) Russell bodies of plasmocytes, and (c) secondary and primary amyloids. The same method was also applied to sections of human gamma globulin.

The results indicate the similarity of Russell bodies, the crystals, and gamma globulin, all of which showed an isoelectric range between pH 6 and 7.5. Other staining methods employed tended to confirm this identity.

The discrepancies reported in the literature on the staining properties of Russell bodies are discussed.

All of the amyloids tested had an apparent isoelectric point near pH 5. Various suggestions in the literature about the nature and origin of amyloid are summarized.
A STATISTICAL STUDY OF MORTALITY FROM LEUKEMIA
Authors: SACKS MILTON S. , SEEMAN ISADORE
Published: October 2019

The recorded death rate from leukemia in the United States has risen continuously since 1900, with an accelerated rate of increase since 1930. The rise from a rate of 1.9 per 100,000 population in 1920 to 3.7 in 1940 represents an increase of 94.7 per cent in this twenty-year period. This increase cannot be accounted for by changes in the age distribution of the population, for the age specific death rates have increased in each age group. The factor of increasing recognition of the disease resulting from improved diagnostic technics and greater use of hospitals with their laboratory facilities must be given adequate consideration in an effort to determine the causes for the rising death rate.

White persons are affected at a rate more than twice as great as nonwhites. Some of the difference must be attributed to variations in the availability of diagnostic services. Males experience a rate approximately one-third greater than females.

Leukemia affects persons in the older ages, particularly over 55 years, with the greatest frequency, and the population under 5 years of age experiences a mortality rate higher than any other age under 45 years. In the intermediate ages the death rate falls to the lowest point. In 1940 the death rate from leukemia for all ages was 3.7 per 100,000 population. The highest rate, 15.7 per 100,000 occurred in the age group 75-84 years. Under 1 year the rate was 4.9 per 100,000. The lowest rate, 1.5 per 100,000, occurred in the ages from 15 to 2.4 years.

Figures for the city of Baltimore for the five-year period 1939-1943 indicate an almost equal incidence of lymphoid and myeloid leukemia. Nearly two-thirds of the deaths studied in Baltimore were reported as acute leukemia. Acute myeloid leukemia appears to be more common than acute lymphoid. After age 45 chronic leukemia is more frequently observed; younger persons experience acute leukemia most commonly.

Undoubtedly many deaths result from leukemia in which this disease was neither diagnosed nor recorded on a death certificate. Clinical evidence indicates that the causes in which this failure would occur most commonly are cancer, anemia, and diseases of the spleen. Statistical evidence reveals that these conditions are certified jointly with leukemia in a significant number and proportion of cases.

Comparison of the experience of several countries indicates that the general trends of mortality from leukemia in the United States are common to the other communities. The death rates per 100,000 population in 1931 adjusted for differences in age and sex composition of the population were: United States, 3.5; England and Wales, 3.0; Paris 2.5; and Canada 2.3.

Each year since 1940 more than 5,000 persons in the United States have died from leukemia.
THE IMPROVED DEMONSTRATION OF CIRCULATING ANTIBODIES IN HEMOLYTIC ANEMIA BY THE USE OF A BOVINE ALBUMIN MEDIUM
Authors: NEBER JACOB , DAMESHEK WILLIAM
Published: October 2019

1. Bovine albumin solution as a testing and diluting medium was used for the detection of abnormal iso-antibodies in the serum of various cases of hemolytic anemia.

2. Five patients with idiopathic acquired hemolytic anemia all showed a warm agglutinin, although in 4 of these patients antibody could not be detected by use of the standard saline technic. Higher titres than in salt sDlution were always obtained in the albumin medium. Three patients with congenital spherocytic anemia not in crisis, 2 patients with severe Mediterranean anemia, and 2 with sickle cell anemia failed to show antibody. In the crisis of 1 case of congenital spherocytic anemia an autohemolysin was temporarily found with the use of bovine albumin. Other cases of acquired hemolytic anemia (chemical, symptomatic, hypersplenic) failed to show antibody. Detection of antibody was of distinct value in the diagnosis of acquired hemolytic anemia of the "idiopathic" type. Its continued presence in such a case after splenectomy rendered the prognosis doubtful.

3. In the further differentiation of various types of familial and acquired cases, use was made of the red cell survival time. Parallel determinations of the survival time and of iso-antibodies showed a distinct correlation. Use of the anti-human globulin rabbit serum test to detect iso-antibody adsorbed to the red cell is cited as of further diagnostic aid.
THE ACTION OF PTEROYL GLUTAMIC ACID AND NATURAL SOURCES OF FOLIC ACID ON BLOOD DYSCRASIAS INDUCED BY SULFONAMIDE DRUGS
Authors: PETERING H. G. , DELOR R. A. , MURRAY H. C.
Published: October 2019

Sulfanilamide, sulfathiazole, and sulfadiazine have been fed at 1 per cent levels in highly purified diets and their effect on growth, mortality, and blood dyscrasias compared with that of sulfasuxidine.

The soluble drugs produce conditions which are similar to those produced by sulfasuxidine. The growth depression is alleviated in large measure in the case of sulfanilamide and to a lesser extent for sulfathiazole and sulfadiazine by folic acid. liver extract powder, and dried yeast extract as well as by para-aminobenzoic acid,

The blood dyscrasias due to sulfanilamide, sulfathiazole, and sulfadiazine are severe leukopenia, granulocytopenia, and mild-to-severe anemia. These are uniformly prevented or the severity greatly curtailed by feeding folic acid, liver extract powder, or dried yeast extract. PABA has a lesser effect in the amounts fed.

Liver extract powder seems to have a beneficial effect on growth and mortality which is not shown by the other supplements. Both free and conjugated folic acid (as yeast extract and in liver extract powder 1:20) are active in combating the dyscrasias.

Evidence from in vitro experiments with Str. haemolyticus (B Lancefield) indicates that neither folic acid, liver extract powder, nor dried yeast extract in ratios to sulfonamide which are effective in preventing the blood dyscrasias will inhibit or block the bacteriostatic action of the sulfonamide drugs in vitro.

It is suggested that the action of folic acid, liver powder, and yeast extract is not wholly explained by alleviating a folic acid deficiency caused by intestinal bacteriostasis due to the drugs, but by an increased demand of the animals for folic acid in the presence of certain sulfonamides.
PERNICIOUS ANEMIA, NUTRITIONAL MACROCYTIC ANEMIA, AND TROPICAL SPRUE
Authors: WILLS LUCY
Published: October 2019

The following tentative conclusions as to the relationship of pernicious anemia, nutritional macrocytic anemia and tropical sprue to one another and their pathogenesis are drawn from a study of the literature and from unpublished work:

1. That these three clinical conditions are three distinct entities possessing a common characteristic in the presence of a panhemopoietic dystrophy characterized by a megaloblastic erythropoiesis and corresponding changes in the myeloid cells and platelets.

2. That this panhemopoietic dystrophy possibly results from the breakdown of an intracellular enzyme system but that the deficiencies causing the breakdown differ; in pernicious anemia the liver principle is apparently at fault, in endemic nutritional macrocytic anemia another unidentified factor is missing, in sprue either or both may be at fault.

3. Folic acid is active therapeutically in all three diseases, but in all it generally fails to restore completely normal blood levels.

4. Pernicious anemia is probably due to a genetic defect which produces an atrophy of the gastric mucosa. As a consequence of this interference with gastric function there is a failure in the formation or absorption of the liver factor and possibly of another neurotrophic factor, which failure results in the development of a macrocytic megaloblastic anemia and the characteristic changes in the nervous system. Indefinite replacement therapy is necessary as the changes in the gastric mucosa are irreversible. The cause of the increased hemolysis is unknown.

5. Endemic nutritional macrocytic anemia is an unconditioned food deficiency, the deficiency being in a factor other than the liver principle, possibly a co-enzyme present in or associated with good biologic protein and the vitamin B2 complex. There are no characteristic pathologic changes except those of the hemopoietic organs which are not specific to the disease. A hemolytic type of the disease occurs in areas of high malarial incidence. After successful treatment the disease does not relapse if the diet is satisfactory. Pregnant women are particularly liable to develop the disease.

6. Tropical sprue is due to a functional disorder of the intestine, possibly primarily a failure in phosphorylation of fatty acids, glycerol and glucose. Diarrhea with characteristic stools and a macrocytic anemia are characteristic findings. The macrocytic anemia may be due to a failure in absorption of one or more essential hemopoietic factors or to a lack of Castle’s intrinsic factor. The cause of the functional breakdown is unknown. Treatment is with a high protein diet and liver extracts. Relapses are common.

My thanks are due to my colleagues for carrying on my work while I wrote this paper.
NORMAL BLOOD COUNTS IN DIFFERENT SEASONS
Authors: ENGELBRETH-HOLM J. , VIDEBAEK AA.
Published: October 2019

Report is given of examinations carried out on 40 healthy males and 29 healthy females in the months of January, March, June and October, with determination of the hemoglobin, the number of erythrocytes and reticulocytes, the sedimentation rate, the white cell and differential counts. The hemoglobin value appears to be lowest in October, the number of reticulocytes highest in June, the sedimentation rate lowest in June. The remaining figures present no exact seasonal variations. Some individuals have a high leukocyte level, others a low one. Normal values are illustrated.
THE USE OF FOLIC ACID ANTAGONISTS IN THE TREATMENT OF ACUTE AND SUBACUTE LEUKEMIA
Authors: DAMESHEK WILLIAM
Published: October 2019

In summary, the folic acid antagonists have, in varying degrees, the capacity to induce remissions in about one third of the cases of acute and subacute leukemia, in adults as well as in children, and in both leukemic and leukopenic forms.

Clinical, hematologic and (to lesser extent) marrow remissions, are obtained most commonly in the lymphoblastic types, least often in the monocytic types.

It is possible that folic acid is required by the primitive white cell as a growth factor. The folic acid antagonists, which resemble folic acid so strikingly in chemical structure, may result in cell death by modifying various enzyme systems within the primitive cells.

Both clinical and hematologic observations indicate that the proliferative process is by no means cured with aminopterin treatment. Acute leukemia may be likened to "wildfire" which, although damped by aminopterin, continues to "smolder." This smoldering may suddenly light up again into an active leukemic picture, unless continued maintenance therapy is given. Despite maintenance therapy, there finally comes a point in the leukemic process at which both the leukemia and increasing toxicity to drug make further progress impossible, and the patient dies.

Other growth factors or enzymes are probably of at least as great an importance as PGA in the metabolism of the primitive white cells and when these are discovered and their antagonists synthesized, the therapeutic results in acute leukemia may be of more consistent and durable nature. It should be realized further that chemotherapeutic methods against leukemia and the leukocytic proliferations in general (and, in fact, against all proliferative disease) are at least in their very infancy. The results thus far obtained in acute leukemia, although to large extent disappointing, indicate that well-defined remissions can be secured in about a third of the cases. For a disease such as acute leukemia, in which remissions previously were highly unusual and of sporadic nature, this indicates a well-defined therapeutic advance and a need for continued investigation along the same general lines.

Differences in results obtained by various groups of workers are difficult to explain. Several points may nevertheless be considered: some of the workers have given inadequate dosage of drug or have failed to use maintenance therapy; some have given folic acid in conjunction with anti-folic acid therapy; in some cases, a crude folic acid antagonist was used; and it is possible that some cases were not observed as minutely as seems necessary. An important factor, which can be determined only by the study of a large group of cases, is the natural variability of acute leukemia from case to case. We have the impression that our best results are obtained in the relatively subacute cases. The fulminating cases, with rapid onset of bleeding and a quick downhill course, are only slightly affected.