bluuebunny/crossref_metadata_2025_split huggingface dataset:
Patterns and Outcomes Of First-Line Management Strategies In Older Adults With Low-Grade Follicular Lymphoma (FL)
Authors: Rai Ashish , Nastoupil Loretta J. , Lipscomb Joseph , Ward Kevin , Howard David H. , Flowers Christopher R. 
Published: October 2019

Abstract

Background
Therapeutic decision making for patients with low-grade (grade 1 and 2) FL involves deciding whether to treat, when to treat, and which among the numerous treatment modalities to administer. The lack of trials comparing outcomes of these treatment modalities makes it a complex process. This study seeks to examine the evolving treatment paradigm and evaluate the outcomes of first-line management strategies for low-grade FL in adults aged ≥ 66.

Methods
We used the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database to identify 4,233 low grade FL patients (pts) aged 66 years and older diagnosed between 1995 and 2009. We ascertained first-line management strategies from Medicare claims made within 90 days of diagnosis. We used Kaplan-Meier estimators stratified by stage to evaluate survival functions for first-line management strategies. We used multivariate Cox proportional hazards models—stratified by stage and adjusted for patient demographics, comorbidity index, and year of diagnosis—to compare the impact of first-line management strategies on overall survival (OS).

Results
Of the 4,233 pts, 57% were female, 3% were African American, 93% were White, 51% resided in big metropolitan areas, 70% were diagnosed after 2000, 44% had stage III/IV disease, and 38% had extranodal involvement. The median age at diagnosis was 74 years (interquartile range 70-80). Common first-line management strategies were: observation (obs), 47%; chemotherapy (chemo) plus rituximab (R), 20%; chemo alone, 12%; R alone, 9%; and radiotherapy (XRT) alone, 9%. Among pts receiving chemo plus R (R-chemo), the most commonly used regimens were: R-CHOP (R, cyclophosphamide, doxorubicin, vincristine, and prednisone; 36%), R-CVP (R, cyclophosphamide, vincristine, and prednisone; 47%), R-Fludarabine based (9%), and R-other (7%).
The table displays median survival and hazard ratios (HRs) for first-line management strategies. Among stage I/II cases, most favorable outcomes were observed in cases receiving XRT alone, whereas among stage III/IV cases most favorable outcomes were observed in the group that received R-chemo. In the subset of stage III/IV pts that received R-chemo, R-CHOP was associated with the most favorable outcomes. HRs decreased steadily with increasing years of diagnosis.

Conclusion
First-line R-chemo is commonly used in older adults with low-grade FL in the United States and is associated with most favorable survival outcomes. XRT is associated with very favorable outcomes in stage I/II pts. Outcomes have improved steadily in the past 10 years.
CVP–cyclophosphamide, vincristine, prednisone; CHOP- cyclophosphamide, doxorubicin, vincristine, prednisone

Disclosures:
No relevant conflicts of interest to declare.
Limited Superiority Of Recombinant Thrombomodulin For Disseminated Intravascular Coagulation; A Comparative Analysis In 41 Children
Authors: Nishikawa Eri , Yagasaki Hiroshi , Shimozawa Katsuyoshi , Okuma Hirotsugu , Hirai Maiko , Kato Maiko , Shichino Hiroyuki , Chin Motoaki , Takahashi Shouri , Mugishima Hideo 
Published: October 2019

Abstract

Background and Objectives
Recombinant thrombomodulin (rTM), a new type of natural anticoagulant, has been available in Japan since 2008 for the treatment of disseminated intravascular coagulation (DIC). Since limited information is available on its efficacy in children, we compared the efficacy of rTM to that of conventional treatment.

Patients and Methods
Of 41 children with DIC, 21 were treated with rTM as a first-line therapy (rTM group) and 20 weere treated with conventional treatment (control group). The day on which anti-DIC treatment was first given was defined as day 1. We used the DIC criteria of the Japan Welfare and Health Ministry. We evaluated the overall survival at day 28 after anti-DIC treatment, the cumulative incidence of DIC resolution, and the total fresh frozen plasma (FFP) and platelet transfusion volumes during the course of DIC.

Results
Clinical outcomes are summarized in the Table. Both groups showed comparable overall survival (95.2% in the rTM group and 95.0% in the control group). In addition, the cumulative incidence of DIC resolution in the rTM group (90.5%) was not different from that in the control group (70.0%) (p=0.210) (Figure). However, the median FFP and platelet transfusion volumes in the rTM group (0 U/kg and 0.28 U/kg) were lower those in the control group (0.14 U/kg and 0.76 U/kg) (p=0.041 and 0.063, respectively).

Conclusion
The use of rTM in children with DIC should reduce the social and ethical problems as well as the biological risks associated with human-derived blood products. Although the limited advantages of rTM were shown, the present study was limited by the small and heterogeneous patient population. Therefore, larger prospective studies are warranted to fully evaluate the efficacy of rTM.

Disclosures:
No relevant conflicts of interest to declare.
Passage-Dependent Cancerous Transformation Of Human Mesenchymal Stem Cell Of Adipose Origin During In Vitro Culture
Authors: Kim Jung Ah , Choi Qute , Im Kyong Ok , Kwon Ji Seok , Park Si Nae , Kim Seon Young , Hwang Sang Mee , Oh Yeon-Mok , Lee Dong Soon 
Published: October 2019

Abstract

Introduction
In vitro culture of adult human mesenchymal stem cells (hMSCs) can induce cancerous transformation, depending on environmental factors. To evaluate the passage dependent chromosomal changes of hMSCs toward malignant transformation, we passaged adipose origin hMSC to 9th passage and analyzed cytogenetic change, molecular cytogenetic changes, and telomere length variations on every passage.

Methods
On each passage, in situ karyotyping was performed on 3 separate batches with subsequent Giemsa staining. Karyotyping was analyzed using Metafer system (MetaSystems, Altlussheim, Germany). For analysis of nonproliferating interphase cell, each chromosome were counted with centromere fluorescent in situ hybridization (FISH) using Same Day OligoFISH™(Cellay Inc., Cambridge, Massachusetts, USA). Telomere length was analyzed using FISH technique with a Cy3-lableled Telomere peptide nucleic acid (PNA) FISH kit (DakoCytomation Denmark A/S, Glostrup, Denmark). To confirm the chromosomal translocation appeared by in situ karyotyping, we made home-brew FISH probe with bacterial artificial chromosome(BAC) clone and quantitated the proportion of abnormal cells by interphase FISH.

Results
On 5th passage, translocation and polysomy of chromosome 7 and 9 appeared, and on 6th passage, additional translocation t(6; 10) appeared. ISCN Karyotypes of chromosomal changes from 5th passage to 7th passage were 48,XX,+7,t(7;22)(q11.22;q13.3),+9[4]/46,XX[21] → 47,XX,+7[2]/47,XX,t(6;10)(q21;q25.1),+7[2]/46,XX[13] → 48,XX,+7,t(7;22)(q11.22;q13.3),+9[6]/ 47,XX,+7[5]/46,XX[9]. Telomere length was decreased on late passages. Fusion signal of t(7;22) on passage 5(fig 1) and that of t(6;10) on passage 6(fig 2) were confirmed by BAC clone.

Conclusions
The behavior of late passage (from passage 5) follows a cytogenetic profile similar to that of transformed cancer cells. Cytogenetic abnormalities which were not observed in earlier passage, showed up and disappeared, but eventually persisted during passages. We suggest in vitro environment cause hMSCs to undergo cancer-like cytogenetic changes. It is of great importance to test safeguards for clinical applications of human stem cells manufactured in vitro.

Disclosures:
No relevant conflicts of interest to declare.
Thrombotic Thrombocytopenic Purpura Associated With Hodgkin Lymphoma
Authors: Chao Ju-Hsien , Kloecker Goetz H 
Published: October 2019

Introduction
Thrombotic thrombocytopenic purpura (TTP) is characterized by microangiopathic hemolytic anemia and thrombocytopenia with usually less than <5% ADAMTS13 (a disintegrin and metalloprotease with thrombospondin repeats) activity level. Hodgkin lymphoma (HL) comprises 10% of newly diagnosed lymphoma cases.

Case Report
A 45 year old healthy African American male presented with diffuse abdominal pain with associated nausea and constipation. Labs showed decreased hemoglobin, platelets, and haptoglobin with elevated bilirubin, lactate dehydrogenase, and creatinine. ADAMTS13 level was <1%. Peripheral smear revealed schistocytes. CT imaging demonstrated multiple lesions of liver, pleura, and bone, as well as diffuse adenopathy, all later confirmed to be hypermetabolic by PET scan. Pleura biopsy suggested HL. TTP was diagnosed, prompting start of high dose prednisone and plasma exchange (PE). Labs normalized after 5 exchanges, allowing for outpatient steroid and PE tapers. A pleura biopsy was suspicious but not definitive for HL. Three weeks later, he was admitted for opioid-induced constipation. He was still on PE. Despite labs without evidence of TTP, his ADAMTS13 persisted at <1%. A definitive excisional cervical lymph node biopsy yielded classical nodular sclerosing HL. Patient started systemic chemotherapy with doxorubicin, bleomycin, vincblastine, and dacarbazine (ABVD). PE was discontinued 7 days later. At follow-up 3 weeks from cycle #1, ADAMTS13 was 55% without evidence of TTP.

Conclusion
A 2012 review notes 4 cases of microangiopathic hemolytic anemia associated with HL, proposing an underlying immune component to this uncommon entity. Though rare, management of TTP associated HL can be challenging due to underlying cytopenias delaying systemic chemotherapy and yet refractoriness of ADAMTS13 to correct, portending a high risk of TTP relapse, without chemotherapy. Supportive measures to stabilize TTP and prompt initiation of chemotherapy can be an effective approach.

Disclosures:
No relevant conflicts of interest to declare.
Subcutaneous panniculitis-like T-cell lymphoma presented with full facial edema, hemophagocytic syndrome and Epstein-Barr Virus infection:A case report
Authors: Li Lin , Chen Jianyi , Zhang Bing , Zhu Xuejun , Sun Xuemei 
Published: October 2019

Abstract

Background
Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare and distinct type of T-cell lymphoma. It is frequently associated with hemophagocytic syndrome (HPS), whose etiologic factors always involve Epstein-Barr Virus(EBV) infection. Although EBV is absent in many cases of sporadic SPTCL, we found a case of SPTCL with full facial edema, HPS and EBV infection as the first symptom.

Patient and treatment
A 36-year-old female had presented with fever, full facial edema for 20 days before hospitalization. Remarkable abnormalities were found as hypersplenotrophy, pancytopenia, hypofibrinogenemia, high ferritin and soluble interleukin-2-receptor level, hemophagocytosis in bone marrow smear, which indicated HPS. Detection by PCR of EBV-DNA in peripheral blood was 9.73×104 copies. On the next day of her hospitalization, HLH-2004 protocol (VP-16+dexamethasone+cyclosporine A) was performed. Her temperature fell to normal on the 4th day. Full facial edema vanished gradually in the following days. After 8 weeks’ treatment, all the abnormalities in the laboratory examination returned to normal. Despite of cyclosporine A and prednisone were used as continual treatment, facial edema and fever relapsed accompanied by multiple skin lesions on her back, upper and lower limbs 4 months later. Reexamination of the laboratory index related above were abnormal once again. Copy number of EBV-DNA was 5.52×105. Histologic and immunohistochemical features of tissue biopsy from the skin lesion on her right arm revealed the evidence of SPTCL. Then, she was treated by asparaginase plus DICE regimen. The facial edema and skin lesion vanished gradually during the course of treatment. Now (one month after the first course of chemotherapy), the patient is in her second course of asparaginase plus DICE regimen and SPTCL remains remission.

Conclusion
This was not a typical case of SPTCL. The patient presented with overt skin lesion 4 months after the first symptom of full facial edema, which suggested SPTCL is a heterogenous disease with variable presentations. Awareness of this rare entity is critical to both ensure timely diagnosis and treatment. In addition, the pathogenesis of SPTCL remains unclear. Some malignant lymphomas are induced by chronic inflammation due to viral or bacterial infection. It is well known that EBV infection often causes malignant lymphomas of B-cell type, particularly in elderly peoples and immunocompromised individuals. Although EBV is absent in many cases of sporadic SPTCL, the virus appears to be implicated in the etiology of variant SPTCL occurring in the Asian population.

Disclosures:
No relevant conflicts of interest to declare.
CD44 Monoclonal Antibody-Enhanced Clearance Of Chronic Myeloid Leukemia Stem Cells From The Malignant Niche
Authors: Hellqvist Eva , Holm Frida , Mason Cayla N , Runza Valeria , Weigand Stefan , Sadarangani Anil , Jamieson Catriona H.M. 
Published: October 2019

Abstract

Introduction
Leukemia stem cells (LSC) in chronic myeloid leukemia (CML) are important in disease progression and relapse. Conventional therapy with tyrosine kinase inhibitors (TKIs), although very effective at reducing bulk CML cells, frequently fail to eliminate LSC residing in the protective bone marrow niche. Thus, there is an unmet need for combination therapy that simultaneously targets bulk disease and eliminates LSC in order to prevent disease progression and relapse. Stem cell niches are often rich in hyaluronic acid. CD44, the main receptor for hyaluronic acid, and some of its splice variants are frequently overexpressed on cancer stem cells, including LSC. In this study we aimed to evaluate the in vivo anti-LSC activity of CD44 monoclonal antibody (mAb) RG7356.

Methods and Results
For anti-CD44 LSC inhibition studies, immunodeficient RAG2-/-γc-/- neonatal mice were intrahepatically transplanted with human BC LSC from imatinib responsive and resistant patients. Once engraftment was verified, mice were treated with control IgG1 (30mg/kg/week), dasatinib (25mg/kg/day), CD44 mAb (RG7356) (30mg/kg/week) or a combination of CD44 mAb (RG7356) and dasatinib. The mice were sacrificed after two weeks of therapy and bone marrow, spleen, peripheral blood and myeloid sarcomas were analyzed by FACS to assess CML LSC burden. In the imatinib responsive patient, CD44 mAb single agent therapy showed an 85% reduction of LSC in bone marrow, 98% reduction in spleen and 91% reduction in peripheral blood. CD44 mAb therapy thus showed an efficacy equal to that of dasatinib, which showed an 87%, 98% and 98% reduction in bone marrow, spleen and peripheral blood respectively. Combination therapy (CD44 mAb + dasatinib) completely eradicated any trace of CML LSC in all tissues analyzed. In the imatinib resistant patient, dasatinib very effectively reduced the number of myeloid sarcomas and blasts but did not inhibit LSC survival in bone marrow. In contrast, CD44 mAb single agent therapy effectively reduced the number of CML LSC to 51% in bone marrow, 96% in spleen and 93% in peripheral blood.

Conclusions
This study demonstrates that a human CD44 specific mAb, RG7356, significantly reduces CML LSC survival. Notably, TKI resistance of CML LSC, can be overcome by treatment with a human CD44 specific mAb, RG7356, as it sensitizes CML LSC residing in malignant niches to dasatinib. From these results, RG7356 appears to be an excellent antibody for future combination clinical studies aimed at eradicating CML.

Disclosures:
Runza: employee of Roche Diagnostics GmbH: Employment. Weigand:Roche Diagnostics GmbH: Employment. Jamieson:J&J: Research Funding; Sanofi: Consultancy; Roche: Research Funding.
Causes and Consequences of Cancer-Associated Thrombocytosis
Authors: Sood Anil , Stone Rebecca L. , Afshar-Kharghan Vahid 
Published: October 2019

Abstract
Platelets represent one of the largest storage pools of angiogenic and oncogenic growth factors in the human body. The observation that thrombocytosis (platelet count >450,000/µL) occurs in patients with solid malignancies was made over 100 years ago. However, mechanisms of paraneoplastic thrombocytosis and the role that platelets play in abetting cancer growth are unclear. We have used clinical data coupled with sophisticated mouse models to identify the mechanisms and biological implications of paraneoplastic thrombocytosis. Thrombocytosis was significantly associated with advanced disease and shortened survival. Plasma levels of thrombopoietin and interleukin-6 were significantly elevated in patients who had thrombocytosis as compared with those who did not. In mouse models, increased hepatic thrombopoietin synthesis in response to tumor-derived interleukin-6 was an underlying mechanism of paraneoplastic thrombocytosis. Tumor-derived interleukin-6 and hepatic thrombopoietin were also linked to thrombocytosis in patients. Silencing thrombopoietin and interleukin-6 abrogated thrombocytosis in tumor-bearing mice. Anti-interleukin-6 antibody treatment significantly reduced platelet counts in tumor-bearing mice and in patients with epithelial ovarian cancer. In addition, neutralizing interleukin-6 significantly enhanced the therapeutic efficacy of paclitaxel in mouse models of epithelial ovarian cancer. The use of an anti-platelet antibody to halve platelet counts in tumor-bearing mice significantly reduced tumor growth and angiogenesis. Biologically, platelets were detected within the tumor microenvironment and affected tumor growth and response to chemotherapeutic agents. These findings support the existence of a paracrine circuit wherein increased production of thrombopoietic cytokines in tumor and host tissue leads to paraneoplastic thrombocytosis, which fuels tumor growth. Blocking the stimulatory effects of platelets may have implications for new therapeutic approaches.

Disclosures:
No relevant conflicts of interest to declare.
Molecular Basis of T-Cell Exhaustion
Authors: Wherry E. John 
Published: October 2019

Abstract
T-cell exhaustion is common during chronic infections, cancer, exposure to persisting antigens, and can prevent optimal immunity. Exhausted T cells are defined by the loss of ability to perform effector functions efficiently, low proliferative capacity, and poor survival following antigen stimulation. In addition, it has become clear that exhausted T cells co-express multiple inhibitory receptors that negatively regulate their function. Indeed, receptors such as PD-1 have become major targets of clinical immunotherapies in cancer and infectious disease aimed at re-invigorating exhausted T cells. Our work has recently defined transcriptional networks of T-cell exhaustion and has focused on the role of key transcription factors, including T-bet and Eomesodermin (Eomes), in controlling the sustainability and terminal differentiation of exhausted T cell populations. Chronic infections and persisting antigen exposure often strains the sustainability or regenerative capacity of exhausted T cell populations resulting in an eventual collapse in immunity. We have found a key role for T-bet in sustaining a progenitor pool of exhausted CD8 T cells during chronic infection, while the related transcription factor Eomes governs terminal differentiation. These represent unique functions for T-bet and Eomes since these transcription factors are associated with different roles in functional memory T cells, highlighting the contextual dependence of transcriptional regulation guiding T-cell exhaustion. Additional studies are focusing on the role of other transcription factors such as BATF in T-cell activation and exhaustion, and on the role of inhibitory receptors including PD-1 in shaping the differentiation of exhausted CD8 T-cell subsets. Ultimately, a more precise molecular understanding of T-cell exhaustion should lead to novel and more robust clinical interventions to reverse exhaustion in settings of persisting infections and cancer.

Disclosures:
Wherry: Genentech: Patents & Royalties.
Bortezomib-Containing Regimens for Multiple Myeloma Maintenance Therapy: a Meta-Analysis
Authors: Wang Yucai , Zhang Wenwen , Yang Fang , Guan Xiaoxiang , Kothari Neil , Chang Victor , Wang Michael 
Published: October 2019

Abstract
Objective: To evaluate the efﬁcacy and safety of bortezomib-containing regimens in maintenance therapy of multiple myeloma through meta-analysis of randomized controlled trials (RCTs).
Patients and methods: PubMed, Web of Science and ASH databases were searched for RCTs that investigated the treatment outcomes (progression-free survival [PFS] and overall survival [OS]) of maintenance therapy with bortezomib-containing regimens in patients with multiple myeloma. Study endpoints included PFS, OS, and grade 3 or 4 adverse events. Pooled hazard ratios (HRs) for survival outcomes and risk ratios (RRs) for dichotomous data with 95% confidence interval (CI) were calculated using Comprehensive MetaAnalysis (v2).
Results: Three RCTs comprising 1396 patients were included in this meta-analysis. Compared with maintenance therapy without bortezomib and/or no maintenance therapy, bortezomib-based maintenance therapy regimens significantly prolonged PFS (HR = 0.66, 95% CI = 0.58 - 0.76, P < 0.001) and OS (HR = 0.74, 95% CI = 0.62 - 0.88, P = 0.001) in multiple myeloma patients. In patients who received high-dose chemotherapy followed by autologous stem cell transplantation (ASCT), bortezomib-based maintenance therapy increased both PFS (HR = 0.73, 95% CI = 0.61 - 0.86, P < 0.001) and OS (HR = 0.76, 95% CI = 0.61 - 0.95, P = 0.016). For transplant ineligible patients, maintenance therapy with bortezomib-containing regimen also increased PFS (HR = 0.58, 95% CI = 0.47 - 0.71, P < 0.001) and OS (HR = 0.70, 95% CI = 0.52 - 0.92, P = 0.012). However, bortezomib-based maintenance therapy increased the risks of grade 3 or 4 adverse events including thrombocytopenia (RR = 1.37, 95% CI = 1.01 - 1.87, P = 0.046), infections (RR = 1.29, 95% CI = 1.02 - 1.64, P = 0.035), cardiac disorders (RR = 2.01, 95% CI = 1.17 - 3.47, P = 0.012), and vascular events (RR = 2.02, 95% CI = 1.15 - 1.45, P= 0.015).
Conclusions: Bortezomib-based maintenance therapy results in signiﬁcant improvement in PFS and OS in multiple myeloma patients, but may increase the risk of developing some grade 3 or 4 adverse events, such as thrombocytopenia, infections, cardiac disorders, and vascular events. Further studies are needed to corroborate the above findings given the limited data on proteasome inhibitor based maintenance therapy for multiple myeloma.

Disclosures
No relevant conflicts of interest to declare.