bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparison of Referring and Final Pathology for T-Cell Lymphomas in the NCCN
Authors: Herrera Alex F , Crosby-Thompson Allison , Friedberg Jonathan W. , Abel Gregory A. , Czuczman Myron S. , Gordon Leo I. , Kaminski Mark S. , Millenson Michael , Nademanee Auayporn , Niland Joyce , Rodriguez Maria A. , Zelenetz Andrew D. , LaCasce Ann S. 
Published: October 2019

Abstract
Abstract 1610

Background:
T-cell lymphomas (TCL) are an uncommon group of diseases recently updated in the WHO classification. Accurate diagnosis requires immunophenotyping and molecular techniques. Diagnostic accuracy of TCLs utilizing the WHO classification has not previously been evaluated.

Methods:
The NCCN NHL database prospectively collects clinical, treatment, and outcome data for patients seen at 7 comprehensive cancer centers. Using this unique resource, we evaluated diagnostic concordance between referring and NCCN centers for TCLs, including peripheral T-cell lymphoma, NOS (PTCL NOS), angioimmunoblastic T-cell lymphoma (AITL), ALK-positive anaplastic large cell lymphoma (ALK+ ALCL), and ALK-negative ALCL utilizing pathology reports, immunohistochemical stains, flow cytometry, fluorescence in situ hybridization/cytogenetics, T-cell gene rearrangement, and progress notes.

Results:
Of 98 eligible patients enrolled from April 2007 to March 2011, 38 (39%) cases were concordant and 60 (61%) were non-concordant. Among non-concordant cases, 34 (57%) had a provisional diagnosis before referral, 6 (10%) were discordant with no additional studies performed, 17 (28%) were discordant with additional studies performed, and 3 (5%) required an additional biopsy. Concordance was highest for ALK+ ALCL at 73%, while the remaining subtypes had low concordance: PTCL NOS 28%, AITL 28%, ALK- ALCL 47%. In 13 (13%) discordant cases (referral diagnosis was benign, a B-cell NHL, or ALK status was undefined) patients may have experienced a significant change in treatment with pathologic reclassification.

Conclusions:
In patients with TCL, the likelihood of a concordant final diagnosis at a referring institution was low. Among non-concordant cases, the majority were referred with provisional diagnoses, and many referral diagnoses were discordant. Establishing a precise diagnosis is critical for prognosis and impacts both therapeutic decisions and clinical trial enrollment. As current and future therapies, such as brentuximab vedotin, target subsets of TCLs, our data suggest that all suspected TCLs may benefit from evaluation by an expert hematopathologist.

Disclosures:
Kaminski: Allos: Consultancy, Honoraria.
Combination of ACY1215, a Selective Histone Deacetylase 6 (HDAC6) Inhibitor with the Bruton Tyrosine Kinase (BTK) Inhibitor, Ibrutinib, Represents a Novel Therapeutic Strategy in Mantle Cell Lymphoma (MCL)
Authors: Sahakian Eva , Rock-Klotz Jennifer , Shah Bijal D. , Powers John , Cultrera Jennifer L. , Deng Susan , Woods David M , Nguyen Michael , Cheng Fengdong , Wang Hongwei , Perez-Villarroel Patricio , Lienlaf Maritza , Knox Tesa , Chen-Kiang Selina , Villagra Alejandro , Tao Jianguo , Pinilla-Ibarz Javier , Jones Simon S , Sotomayor Eduardo M. 
Published: October 2019

Abstract
Abstract 1660
Recently, we have found that HDAC6 is overexpressed in MCL cell lines and in primary human MCL cells. Knocking-down HDAC6 in MCL cells with a shRNA lentiviral system resulted in cell cycle arrest and apoptosis induction. Interestingly, MCL cells lacking HDAC6 displayed a significantly decreased STAT3 phosphorylation and abrogation of IL-10 gene transcriptional activity. ACY1215 is a novel, selective, orally bioavailable HDAC6 inhibitor. Treatment of MCL cell lines with this agent resulted in decreased cell viability and proliferation. In addition, ACY1215 inhibits IL-10 production in a dose dependent manner.
Bruton tyrosine kinase (BTK) is a member of Tec family of kinases with a very distinct role in B-cell antigen receptor (BCR) signaling. The selective BTK-inhibitor PCI-32765 has shown promising pre-clinical and clinical activity in MCL. In addition to their direct anti-lymphoma effects, disruption of BTK also induces positive immunological changes such as inhibition of the immunosuppressive STAT3/IL-10 signaling pathway1.
The above observations led us to determine whether the direct antitumor effects and the immunological properties of ACY1215 and PCI-32765 could be potentiated when these agents are used in combination. First, the viability of MCL cells was decreased when they were treated in vitro with either PCI-32765 or ACY1215. However, combination of these two agents resulted in a 3-fold increase in apoptosis induction, pointing to a synergistic effect of BTK and HDAC6 inhibition in MCL. The additional findings that this approach can increase the immunogenicity of MCL cells and anti-MCL immune responses has provided the proper framework for combining the selective HDAC6 inhibitor ACY1215 with BTK inhibition as a novel therapeutic strategy in MCL.

Disclosures:
Chen-Kiang: Bristol Myers Squibb: Consultancy; Pfizer: Research Funding. Jones:Acetylon Pharmaceuticals, Inc: Employment.
Microtransplantation with Decitabine and Cytarabine Improves Patient Outcomes in Myelodysplastic Syndromes
Authors: Ai Huisheng , Hu Kaixun , Sun Qiyun , Li Xiao , Guo Mei , Yu Changlin , Qiao Jianhui , Qiao Junxiao , Liu Guangxian , Dong Zheng , Qiao Zhenhua 
Published: October 2019

Abstract
Abstract 1709
The outcome of myelodysplastic syndromes (MDS) still remains unsatisfactory, with a low complete remission (CR) rate and a poor overall survival rate. Decitabine improved the overall responses of MDS as a hypomethylating agent, but CR rates remain low and prolonged pancytopenia. Our recently study showed that infusion of G-CSF mobilized HLA-mismatched peripheral blood stem cells (G-PBSC) can improve the outcome of chemotherapy for acute myeloid leukemia in elderly patients. However, whether G-PBSC combining decitabine and cytarabine chemotherapy will improve outcomes in MDS patients is unknown.

Material and methods:
Total of 72 patients with MDS, from 16 to 82 years of age, were assigned to receive decitabine 25–30 mg/m2daily for 4 days with cytarabine 150 mg/m2 daily for 7 days by intravenous followed to infusion of G-PBSC on 24 hours after each completion of the cytarabine therapy (Microtransplantation-group, n=28) or decitabine 20 mg/m2 daily for 5days (Decitabine group, n=27) or 15 mg/m2 daily for 5days (low decitabine group, n=17). The infused cells of mononuclear cells and CD34+ cells with HLA-mismatched in 3 loci (n=22) and 2 loci (n=5) and 1 loci (n=1) were 3.33(3.04–10.8)108/kg, 2.26(0.68–5.25)106/kg and no any GVHD prophylactic treatment was used in the Microtransplantation-group.

Results:
Total CR rate of was 42.9%#x2610;#x0025; A14.8% and 29.4% in the three groups, respectively. That of MST-group is significantly higher than that of B group (P=0.02). The CR rate after first course in MST group is 21.5% which was higher the other two groups (10% and 0%, P=0.14#x2610;#x0025; GP=0.04). The complete cytogenetic response rate in the Microtransplantation-group was 90.9% which is highest than the other two groups (10% and 11%, P<0.001,P<0.001). The progress free survival(PFS) of Microtransplantation-group in 12 months is 50.1% which is higher than other two group (9.9%,9.6%, P=0.01#x2610;#x0025; GP=0.008). Median times of neutrophil recovering over 1×109/L in three groups after 1 course therapy was 17,19 and 13 days and median times of platelet recovering over 50×109/L was 17,26 and 28days, respectively. These of MST group recovered more fastly than those of the other groups. The severe infection rate and early phase mortality rate in three groups had no differences. No donor chimerism, no graft-versus-host disease were observed in all of the patients in the MST group.

Conclusion:
Our clinical results suggested that decitabine with cytarabine and microtransplantation may improve clinical response CR rate early, especially on complete cytogenetic response and PFS, no increase infection rate and early phase mortality rate. The MST may provide an new method for MDS treatment. Further studies with much more patients and long-term follow-up should be conducted.

Disclosures:
No relevant conflicts of interest to declare.
CD30/CD123 Expression in Systemic Mastocytosis Does Not Correlate with Aggressive Disease
Authors: Moonim Mufaddel T , Kossier Thibaud , van Der Walt Jon , Wilkins Bridget , Harrison Claire N , Radia Deepti H 
Published: October 2019

Abstract
Abstract 1746

Introduction:
Systemic Mastocytosis (SM) is a myeloproliferative neoplasm (MPN) with heterogeneous clinical manifestations and limited treatment options for patients with aggressive disease. The WHO Classification sub divides SM patients into Indolent (ISM: evidence of clonal mast cells in bone marrow), Smouldering (SSM: Trypstase > 200ng/ml;organomegaly without dysfunction; bone marrow mast cell burden > 30% ), Aggressive (ASM: organomegaly with laboratory evidence of dysfunction), Mast Cell Leukaemia (MCL; > 20% mast cells on aspirate and >10% on blood film) and Associated Haematological Non-Mast Cell Disorders (AHNMD). The c-kit mutation (D816V) is present in > 90% of SM patients. Tryptase levels reflect total mast cell burden. To date there is no discriminatory marker to allow for identification of SM patients with more aggressive disease. CD30 (Ki-I antigen) has been reported as a potential marker for mast cells in high grade mastocytosis (Sotlar et al, 2011).We present preliminary data on 43 SM patients seen at Guys and St Thomas' Hospitals NHS Foundation Trust looking at CD30 and CD123 expression with clinical correlates.

Methodology:
43/58 SM patients who have a full set of clinical records and bone marrow trephine samples have been evaluated. Bone marrow trephine processing: fixation in a neutral buffered formalin < 24hours; EDTA decalcification for 48 hours;Immunochemistry on an automated immunostainer (Leica Bondmax)using standard protocols: CD 30 (Dako dilution 1:75, antigen retrieval ER2). CD123 (BD Sciences, Novacastra, dilution 1:400,antigen retrieval ER2). Bone Marrow trephine samples were reviewed by haematopathologists at diagnostic MDM. Disease bulk was estimated as a percentage of the trephine sample. Immunocytochemistry review of the CD30/CD123 was reviewed by a single haematopathologist for this study. Clinical information was reviewed for laboratory results, tryptase levels, clinical symptoms and SM diagnosis.

Results:
43 patients: M:F(18:25). SM diagnoses: 26 ISM (60%), 2 SSM (5%),3 ASM (7% ), 12 AHNMD (28%). Data on 43 patients for CD30 expression and 40 for CD123 expression.
Tryptase: 20 CD30(+) patients median 74.9ng/ml (range 16.6–285ng/ml): 23 CD 30(−) patients median 43.6ng/ml (range 15.1–386ng/ml).

Conclusions:
Our preliminary data on 43 patients with SM/ CD30/123 expression suggests:

Disclosures:
Harrison: Novartis: Honoraria, Research Funding, Speakers Bureau; YM Bioscience: Consultancy, Honoraria; Sanofi Aventis: Honoraria; Shire: Honoraria, Research Funding.
The PD-1/PD-L1 Axis Contributes to T Cell Dysfunction in Chronic Lymphocytic Leukemia
Authors: Brusa Davide , Serra Sara , Coscia Marta , Rossi Davide , Gaidano Gianluca , Inghirami Giorgio , Vaisitti Tiziana , Deaglio Silvia 
Published: October 2019

Abstract
Abstract 1778
Chronic lymphocytic leukemia (CLL) is characterized by a progressive accumulation of mature B lymphocytes and it is marked by profound defects in T cell function. The mechanisms responsible for T cell dysfunction remain unclear, even if several observations show that T cells from CLL patients express markers of chronic activation. One of this marker is Programmed death-1 (PD-1), a cell surface molecule that inhibits activation of immune cells and it is involved in tumor escape mechanisms through binding of the specific PD-L1 ligand. The aim of this work is to evaluate the expression and function of the PD-1/PD-L1 axis in the CLL context.
Using multiparameter flow cytometry, we showed that CD4+ and CD8+ T lymphocytes from CLL patients (n=117) express significantly higher levels of the PD-1 receptor, as compared to the same cell subpopulations purified from age- and sex-matched normal donors (n=33; 52% vs 34%, p <0.001). In keeping with the notion that PD-1 is a marker of cell exhaustion, CD4+ and CD8+ T lymphocytes from CLL patients displayed increased numbers of effector memory and terminally differentiated cells, respectively, with a concomitant decrease in naïve and central memory cells, when compared to controls. The number of effector memory and terminally differentiated cells positively associated with a more advanced stage of disease, treatment requirements and unfavorable genomic aberrations. Moreover, leukemic lymphocytes expressed higher levels of PD-L1 than circulating B lymphocytes from normal donors. PD-1 and PD-L1 expression significantly increased when T or B lymphocytes were treated with mitogenic signals, suggesting that this interaction might work efficiently in an activated environment. This hypothesis was tested by immunohistochemical analyses determining PD-1 and PD-L1 expression in the proliferation centers of lymph nodes sections from CLL patients. The results obtained indicate that PD-L1+ proliferating CLL cells are in close contact with CD4+/PD-1+ T lymphocytes. Lastly, functional experiments performed using anti-PD-1 antibodies or recombinant soluble PD-L1 clearly indicate that the PD-1/PD-L1 axis contributes to driving IL-4 secretion and to the inhibition of IFN-g production by CD8+ T cells.
In conclusion, these results show that CD4+ and CD8+ T lymphocytes from CLL patients express high levels of the surface marker PD-1 and exhibit an exhausted phenotype, while B leukemic cells express the PD-L1 ligand. Functional data suggest that PD-1/PD-L1 interactions are critical in skewing the T cell compartment towards a Th2 phenotype, by impairing IFN-g secretion by CD8+ cells. Taken together, these observations suggest that pharmacological manipulation of the PD-1/PD-L1 axis might be relevant in restoring T cell functions in the CLL microenvironment.

Disclosures:
Inghirami: OncoEthix SA: Research Funding.
The Broad Kinase Inhibitor Dasatinib in Combination with Fludarabine in Patients with Refractory Chronic Lymphocytic Leukemia: A Multicenter Phase 2 Study
Authors: Kater Arnon P. , Spiering Marjolijn , Liu Rob D , Beckers Marielle M , Tonino Sanne H. , Daenen Simon M. G. J. , Doorduijn Jeanette K , Lankheet Nienke A , Luijks Dieuwertje M , te Raa Doreen , Eldering Eric , Van Oers Marinus H.J. 
Published: October 2019

Abstract
Abstract 1798

Introduction
Development of chemoresistance in chronic lymphocytic leukemia (CLL) is at least partly mediated by protective stimuli within the lymph node (LN) microenvironment. Dasatinib has activity against multiple kinases which have been reported to be activated by the microenvironment, including SRC, c-Abl and BTK. We have recently shown that Dasatinib can effectively inhibit the anti-apoptotic program and as a consequence, restore fludarabine sensitivity in vitro.

Patients and methods
We conducted an open-label phase 2 trial of Dasatinib combined with fludarabine in twenty refractory CLL patients. Patients were treated with Dasatinib 100 mg once daily for 28 days. In patients who did not reach at least a PR, fludarabine was added (40 mg/m2 for 3 consecutive days q28) for at least 2 and a maximum of 6 cycles. Response assessments included CT-scans at baseline, following 4 weeks of Dasatinib monotherapy, after 2 cycles of combination therapy and at the end of protocol. In a subset of patients with high numbers of circulating lymphocytes at baseline, RNA expression profiles of apoptosis regulator genes as well as inflammation genes were analyzed prior and during treatment by MLPA analysis.

Results
Toxicities were comparable to those observed in fludarabine containing regimens and as expected in heavily pre-treated refractory patients.
Three patients (18%) reached a PR. Although most patients did not reach a formal nodal response, most patients showed reduction in lymph node (LN) size with a median of −20% as best response. Subsequent dasatinib fludarabine treatment following dasatinib monotherapy induced additional clinical effects but primarily in patients without del11q or del17p. Patients with a LN reduction of at least 20% had a significant improved PFS (256 days) and OS (510 days) as compared to non-responders (80 days and 158 days respectively). Also, in responding patients PFS was superior to PFS after last prior treatment.
NF-κB expression levels decreased while expression levels of the pro-apoptotic gene NOXA increased both after Dasatinib treatment and combination treatment.

Conclusion
In conclusion, Dasatinib fludarabine combination treatment has clinical efficacy in heavily pretreated refractory patients which correlated with decreased NF-κB and increased NOXA expression. As recently showed with other targeted agents, improvement of PFS and OS is also observed in patients with tumor responses less than 50%. These data do encourage further studies on a broad-spectrum kinase inhibitor like Dasatinib in combination with other classes of drugs in relapsed and refractory CLL.

Disclosures:
No relevant conflicts of interest to declare.
Exposure to Novel Agents Contribute to Extramedullary Spread of Multiple Myeloma Cells and Altered Expression of Adhesion Molecules: A Clinicopathologic Study of 91 Consecutive Autopsy Cases
Authors: Mine Sohtaro , Hagiwara Shotaro , Tagashira Amane , Igari Toru , Miwa Akiyoshi 
Published: October 2019

Abstract
Abstract 1832

Background
Recent development of novel agents such as bortezomib, lenalidomide, and thalidomide improved the remission rate and survival of multiple myeloma. However, the end stage of myeloma is still uncontrollable. The extramedullary disease (EMD) progression of myeloma was frequently observed in heavily treated patients, whereas few data exist about its incidence and predictive factors. It is well known that adhesion molecules play a role in disease progression and drug resistance. We investigated factors associated with the EMD progression based on the autopsy cases. In addition, the effect of the exposure to novel agents on the expression of adhesion molecules on myeloma cells was analyzed.

Methods
We reviewed autopsy reports and medical records of 91 multiple myeloma cases between 1979 and 2012 at the National Medical Center for Global Health and Medicine in Tokyo, Japan. The sites of myeloma cell invasion, infection, hemorrhage and renal complications were studied gross and microscopically. Patient profile, duration of illness, type of monoclonal gammopathy, clinical stage and history of treatment were studied. Durie & Salmon's criteria was used for diagnosis and staging. Factors associated with EMD were statistically analyzed using Student's t-test and the chi-square test. NCAM, VCAM, ICAM, and LFA-1 immunostaining in the bone marrow was performed.

Results
In 91 autopsy cases, 62.6% was male. Mean age and the duration of illness was 63.0 (38–85) years old and 40.6 months (1–156). Eighteen patients (19.8%), 23 (25.3%), and 15 (16.4%) were treated with novel agents, SCT and both respectively. EMD progression of myeloma cells was observed in 65 patients (71.4%). Frequent sites of EMD were spleen (48.9%), liver (37.8%), kidney (31.1%), lymph nodes (28.6%), lung (25.6%), pancreas (20.0%), and gastro-intestinal tract (18.9%).
The incidence of EMD was significantly higher in patients treated with novel agents than in patients without novel agents (94.4% vs. 65.8%, p=0.016). The risk factors of EMD were novel agents, longer duration of illness, and adverse cytogenetic abnormalities.
In the cases with novel agents, the expression of NCAM was significantly low (11.1% vs. 57.4%, p=0.049) compared to the cases without novel agents. However, the expression of VCAM was significantly higher in the cases with novel agents than the cases without novel agents (40.0% vs. 0%, p=0.01).

Conclusion
Multi-organ involvement of myeloma is not rare in autopsy cases of the disease. Exposure to novel agents may contribute to extramedullary spread of myeloma cells and altered expression of adhesion molecules. Further study on other adhesion molecules is needed.

Disclosures:
No relevant conflicts of interest to declare.
Membrane Lipid Biosynthesis As a Potential Therapeutic Target in Multiple Myeloma
Authors: Bardeleben Carolyne , Lichtenstein Alan 
Published: October 2019

Abstract
Abstract 1836
Phosphatidylcholine (PC) is the most prominent phospholipid in mammalian endoplasmic reticulum (ER) membranes. The rate-limiting step in PC synthesis through the Kennedy pathway is the conversion of phosphocholine + cytidine triphosphate (CTP) to cytidine diphosphocholine, (CDP)-choline, via the enzyme CTP:phosphocholine cytidylyltransferase (CCT) (see figure).

Multiple myeloma (MM) cells may be particularly dependent on this biosynthetic reaction because of their high consistent level of ER stress and requirement to continuously replenish ER membranes. Indeed, CCT-null mice have a defect in differentiation of B lymphocytes to plasma cells and deficiencies in Ig synthesis. To test whether this pathway remains critical in survival of malignant MM cells, we exposed MM cell lines to an inhibitor shown to inhibit CCT activity, HexPC. HexPC induced apoptosis in all MM cell lines in a concentration- and time-dependent manner. The addition of lysophosphatidylcholine (LPC), presumably converted to PC independently of the Kennedy pathway, completely rescued MM cell apoptosis. In contrast, similar concentrations of LPC in the same cell lines could not rescue apoptosis induced by bortezomib. An additional intervention to inhibit phosphatidylcholine synthesis, namely inducing pyrimidine starvation, also resulted in MM cell apoptosis and down-regulation of CDP-choline levels. Apoptosis of MM cells induced by HexPC was associated with induction of ER stress as shown by enhanced phosphorylation of IRE1 and eIF-2alpha. This ER stress was also prevented when LPC was added to HexPC although LPC could not prevent similar ER stress induced by bortezomib. These results underscore the importance of this phosphatidylcholine synthesis pathway in MM cells and provide new targets for future therapy.

Disclosures:
No relevant conflicts of interest to declare.