bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognositc Inpact of Tumor-Infiltrating Cells Especially CD163 Positive Macrophage in DLBCL Treated with R-CHOP
Authors: Goto Naoe , Kanemura Nobuhiro , Tsurumi Hisashi , Nakamura Nobuhiko , Kasahara Senji , Hara Takeshi , Moriwaki Hisataka , Takami Tsuyoshi 
Published: October 2019

Abstract
Abstract 1594

Background:
Tumor-infiltrating immune cells perform important functions in host immune reaction against tumor cells including diffuse large B cell lymphoma (DLBCL). Recently, variable tumor-infiltrating cells were reported to give a influence for prognosis, for example, regulatory T cell (T reg), cytotoxic T cell, macrophage and mast cell etc. Among these microenvironmental cells, we focused on Treg, cytotoxic T and macrophage cell, and we assessed the distribution and prognostic significance of these cells in DLBCL. Patients and Methods: We examined samples from 124 patients with DLBCL (69 men and 55 women; median age, 70 years) at diagnosis who were prospectively enrolled between 2002 and 2008. All patients were treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone). FOXP3 protein expression as Treg cells, CD8 expression as cytotoxic T cells, and CD163 expression as activated macrophage cells were evaluated by using immunohistochemistry in paraffin-embeded tissue samples. Results: The median count of FOXP3+ cells was 15.2/mm2 (×400) (range 1– 350/mm2), the median of CD8+ cells was 72/mm2 (8−402) and the median of CD163+ cells was 24/mm2 (0−114). Patients with high count of FOXP3+ cells (>15/mm2) have better prognosis than those of low count (5 year (5-y) overall survival (OS); 72.1%, 49.7% p=0.024, respectively). No significant difference was observed for progression free survival (PFS) of FoxP3 expression. No significant difference was observed for OS and PFS of CD8 expression. Patients with low count of CD163+ cells (<15/mm2) have better prognoses than those of high count (5-y OS; 80.1%, 52.5% p=0.009, 5-y PFS: 84.3%, 42.9% p=0.0019, respectively). Multivariate analyses employing factors such as poor risk group of revised International Prognostic Index (R-IPI), non-GCB type of subtype and low counts of FoxP3, low count of CD8, and high count of CD163 demonstrated that CD163 and R-IPI for OS and PFS were independent prognostic factors (OS; CD163 odd's ratio: 2.56, p=0.038, R-IPI: 2.66, p=0.015, PFS; CD163: 2.73, p=0.03, R-IPI: 2.56, p= 0.012). Conclusion: The count of tumor-infiltrating cells especially CD163+ macrophage might predict prognosis of DLBCL treated with R-CHOP.

Disclosures:
No relevant conflicts of interest to declare.
Prior Rituximab Exposure Does Not Appear to Affect Time to Treatment Failure After Radioimmunotherapy
Authors: Burnette Brian L. , Wiseman Gregory , Habermann Thomas M. , Ansell Stephen M. , Porrata Luis F. , Inwards David James , Johnston Patrick B. , Micallef Ivana , Macon William R , Witzig Thomas E. , Nowakowski Grzegorz S. 
Published: October 2019

Abstract
Abstract 1640

Background:
The introduction of radioimmunotherapy (RIT) into clinical practice for the treatment of follicular lymphoma (FL) occurred at a time at which many patients did not have prior exposure to rituximab. Clinical trials in the relapsed/refractory setting, as well as consolidation in the upfront setting have included a small number of patients that had been previously treated with rituximab or a rituximab containing treatment regimen. We evaluated the effect of prior rituximab therapy on the efficacy of RIT.

METHODS:
The prospective lymphoma database was queried for all patients having received a single dose of yttrium-90 ibritumomab tiuxetan for relapsed/refractory FL which had previously been treated with systemic therapy (patients receiving only prior external beam radiation therapy were excluded). The database includes all consecutive adult patients diagnosed with lymphoma seen at Mayo Clinic Rochester. The diagnosis of follicular lymphoma was as by WHO classification and centrally reviewed. Patients with evidence of histologic transformation to diffuse large B cell lymphoma prior to RIT were excluded. Time to treatment failure (TTF) was defined as the time from RIT to next anti-lymphoma therapy.

RESULTS:
111 patients were identified. 57 (51%) were male. Median age at time of RIT was 58 (19–88). Median time from diagnosis to RIT was 35 (6–281) months in patients having received prior treatment with rituximab and 47 (12–272) months in those who had not (p=0.19). 63 (57%) of patients received prior treatment with rituximab or rituximab containing chemotherapy. Median number of prior therapies was 2 (1–10), which was not different between the rituximab treated or untreated groups [2(1–6) vs 2(1–10) p=0.12]. Median TTF was 10.0 months in the patients having received prior rituximab and 10.1 months in those that had not (p=0.29). Figure 1. The median overall survival from RIT was not reached, but appeared similar (Kaplan-Meier estimate 125 months without prior rituximab exposure vs 95 months with prior rituximab exposure; p=0.33).

CONCLUSIONS:
Prior rituximab exposure does not seem to adversely impact the time to treatment failure or overall survival in those patients treated with RIT. While the data leading to the approval of RIT were accrued prior to the routine clinical use of rituximab, our data demonstrate similar clinical benefit of RIT in patients with prior exposure to rituximab or rituximab containing therapy.

Disclosures:
No relevant conflicts of interest to declare.
Allogeneic Hematopoeitic Stem Cell Transplantation (AHSCT) Versus Hypomethylating Agents (HMA) in Patients (pts) with Myelodysplastic Syndrome (MDS): A Case-Control Study
Authors: Tanaka Maria F , Jabbour Elias , Kantarjian Hagop M. , Pierce Sherry , Champlin Richard , Lima Marcos De , Garcia-Manero Guillermo 
Published: October 2019

Abstract
Abstract 1707

BACKGROUND:
Treatment of pts with higher-risk MDS revolves around AHSCT and HMA. Although AHSCT is thought to be the only curative approach for pts with MDS, only a small percentage of pts are appropriate candidates and this procedure carries significant morbidity and mortality rates. We wanted to assess outcomes in pts with higher risk MDS treated with AHSCT or HMA. To study this, we performed a retrospective analysis comparing the outcome of pts with previously untreated MDS who received AHSCT or HMA therapy at M.D. Anderson Cancer Center (MDACC).

METHODS:
From a database of pts with MDS who received AHSCT (N=152) at MDACC between 01/1988 and 04/2008, we selected those with untreated MDS prior to receiving the transplant. A total of 53 (29%) pts were identified. We compared them with a control group of 40 pts treated with HMA among 1748 referred to MDACC. All controls were selected to match at least 3 of the following 5 criteria: 1) age, 2) year of diagnosis, 3) percentage of blasts at the time of diagnosis, 4) IPSS cytogenetic risk, and 5) time from diagnosis to treatment. The primary endpoint was survival.

RESULTS:
A total of 53 pts with untreated MDS who received AHSCT and 40 pts treated with HMA were identified (Table 1). Median age was 51 (range 20–62) and 54 (range 38–79) years for pts treated with AHSCT or HMA respectively. There were more pts greater than 60 years old in the HMA group compared to those in the AHSCT group (58% vs. 1% p>0.001). The median follow up time was 64 months. Donors were HLA matched related (n=37), matched unrelated (n=11), 1 antigen mismatched related (n=4) or 1 antigen mismatched unrelated (n=1). Of the 40 pts treated with HMA, 31 were evaluable for response; of those 31, 19 (61%) responded, 16 (52%) achieving a complete response. The median survival was 26 and 25 months for pts receiving AHSCT or HMA, respectively (p=0.41) (Figure 1). The 8-year overall survival rates for pts receiving AHSCT or HMA were 24% and 23% respectively.

CONCLUSION:
AHSCT did not offer a significant survival improvement in a retrospective analysis of pts with MDS. Treatment with a HMA offers an adequate alternative in older patients or those who cannot tolerate or receive an AHSCT and should be used as a bridge in younger pts who are candidates for AHSCT

Disclosures:
No relevant conflicts of interest to declare.
Impact of a Venous Thromboembolism Prophylaxis “Smart Orderset”: Improved Compliance, Fewer Events
Authors: Zeidan Amer M. , Streiff Michael B. , Ahmed Syed-Rafay , Kraus Peggy S , Hobson Deborah , Horn Paula B , Shermock Kenneth , Tinoco Gabriel , Haut Elliott R 
Published: October 2019

Abstract
Abstract 172FN2

Introduction:
Venous Thromboembolism affects 900,000 Americans annually. Prophylaxis reduces the risk of VTE by 60% but many patients do not receive risk-appropriate VTE prophylaxis. We developed mandatory computer decision support “smart ordersets” (i.e. electronic menus with DVT prophylaxis recommendations) to improve our institution's VTE prophylaxis performance. The ordersets require providers to respond to 2 questions that assess VTE risk factors and contraindications to pharmacologic prophylaxis. Using these answers along with known patient demographics, the orderset gives providers an evidence-based risk-appropriate VTE prophylaxis recommendation.

Methods:
To study the impact of Medicine service-specific orderset on compliance with the 2008 American College of Chest Physicians (ACCP) VTE prophylaxis guideline and clinical outcomes, we conducted a retrospective cohort chart review of consecutive patients admitted to the Medicine service during one month immediately prior to (November 2007) and a single month subsequent to (April 2010) orderset launch. Data collection included patient demographics, VTE risk factors, and use and type of VTE prophylaxis. Patient characteristics before and after implementation of the protocol were compared. The primary outcome measures were compliance with thromboprophylaxis guidelines in patients at risk for VTE and the 90-day VTE rate. Secondary outcomes were bleeding events and 30-day mortality. Outcomes were compared by Student's t-test and Fisher's exact test.

Results:
The before and after cohorts contained 1,025 and 1,057 patients, respectively. Demographic characteristics and contraindications to pharmacologic prophylaxis were similar between groups. (Table 1) Some VTE risk factors were more prevalent in the before group. (Table 1) ACCP compliant prophylaxis increased significantly from 68.3% to 85.9% (p <.0001). Provider choices for prophylaxis changed with an increase in mechanical prophylaxis and twice daily heparin in the post-orderset implementation cohort. (Table 2) Radiographically-documented symptomatic VTE by day 90 post-hospital discharge declined from 2.8% to 0.7% after orderset implementation (p=0.001). There was also a trend toward fewer in-hospital VTE (0.8% versus 0.2%, p=0.06). (Figure 1) Major bleeding remained unchanged (0.3% to 0.1%, p=0.47).

Conclusion:
A VTE prophylaxis computerized decision support “smart orderset” improves ACCP-compliant VTE prophylaxis and results in lower risk of symptomatic VTE without an increase in major bleeding.

Disclosures:
Streiff: BristolMyers Squibb: Research Funding; sanofi-aventis: Consultancy; Daiichi-Sankyo: Consultancy; Eisai: Member of study outcome adjudication committee; sanofi-aventis: Honoraria.
Expression of the CAMPATH-1 Antigen (CD52) on CD34+/CD38- Progenitor Cells in Patients with 5q- MDS and in a Subset of AML
Authors: Blatt Katharina , Herrmann Harald , Cerny-Reiterer Sabine , Herndlhofer Susanne , Sperr Wolfgang R. , Valent Peter 
Published: October 2019

Abstract
Abstract 1728
The target antigen CAMPATH-1 (CD52) is widely expressed in various hematopoietic lineages inlcuding lymphocytes, basophils, and blood monocytes. The anti-CD52 antibody Alemtuzumab is used successfully to treat patients with chemotherapy-refractory chronic lymphocytic leukemia. Based on its strong immunosuppressive effects, Alemtuzumab has also been considered for patients with aplastic anemia and hypoplastic myelodysplastic syndromes (MDS). Indeed, more recently, Alemtuzumab was found to induce major hematologic responses in a group of patients with MDS. Although the immunosuppressive effect was considered to play a role, the exact mechanisms underlying this drug effect remained speculative. In the current study, we asked whether CD34+ bone marrow (BM) progenitor cells in MDS and acute myeloid leukemia (AML) express the CAMPATH-1 antigen. Twelve patients with MDS (5 females, 7 males; median age: 70 years), 25 patients with AML (16 females, 9 males; median age: 62 years), and 34 control cases (normal reactive BM, n=12; idiopathic cytopenia of unknown significance, n=11; chronic myeloid leukemia, CML, n=4; chronic myelomonocytic leukemia, CMML, n=3; JAK2 V617F+ myeloproliferative neoplasms, MPN, n=4) were examined. Surface expression of CD52 on CD34+/CD38+ and CD34+/CD38- BM progenitor cells was analyzed by monoclonal antibodies and multicolor flow cytometry. In the group of MDS, CD52 was detectable on CD34+/CD38- stem cells in 3/4 patients with isolated 5q-. In most of the other MDS patients, CD52 was weakly expressed or not detectable on CD34+/CD38- cells. In AML, CD34+/CD38- cells displayed CD52 in 12/25 patients, namely 3 with complex karyotype including 5q-, 2 with inv(3), one with t(8;21), one with inv(16), one with del13q, one with trisomy 8, one with monosomy 7, and 2 with normal karyotype. Expression of CD52 mRNA in CD34+/CD38- AML stem cells was confirmed by qPCR in all patients tested (n=14). In addition, a good correlation was found between surface CD52 expression and CD52 mRNA expression in AML progenitor fractions. In patients with normal hematopoiesis (n=12) or idiopathic cytopenia (n=11), CD34+/CD38- cells stained weakly positive or negative for CD52. Almost in all cases tested, blood monocytes and blood basophils stained positive for CD52. Together, our data suggest that the target antigen CAMPATH-1 (CD52) is expressed on primitive CD34+/CD38- progenitor cells in MDS, preferentially in 5q- patients, and in a subset of patients with AML. These observations may have clinical implications and explain recently described effects of Alemtuzumab in patients with MDS. Our data also suggest that Alemtuzumab may be an interesting targeted drug in patients with refractory or relapsed AML in whom neoplastic stem cells express the target antigen CD52.

Disclosures:
No relevant conflicts of interest to declare.
Alternate Splicing Factor Fox2 Affects Growth and Survival of Multiple Myeloma Cells
Authors: Song Weihua , Hu Yiguo , Yang Guang , Shah Parantu K , Shan Weisong , Tai Yu-Tzu , Li Yi , Minvielle Stephane , Avet-Loiseau Hervé , Anderson Kenneth C. , Li Cheng , Munshi Nikhil C. 
Published: October 2019

Abstract
Abstract 1810
Alternative splicing of pre-mRNA plays a critical role in number of cellular processes including cell growth and survival. We have previously demonstrated significant frequency of alternate splicing in multiple myeloma (MM) that points to the need for evaluation of not only the expression level of genes but also post translational modifications. Our data utilizing exon array profile from 170 uniformly treated newly diagnosed patients with MM confirms clinical relevance of splicing as demonstrated by impact of level and extent of alternate splicing on both progression free and overall survival. We have now further studied the molecular mechanisms that may be involved in differential splicing in myeloma. We have evaluated the expression data from 170 uniformly treated newly diagnosed patients with MM and identified Fox-2, an RNA binding protein that is thought to be a key regulator of alternative exon splicing as one of the most important gene predicting clinical outcome in MM. We have now investigated the molecular effects of Fox2 and its role on myeloma cell growth and survival. Using Fox-2-directed shRNA lentivirus, we knocked-out (KO) the expression of Fox2 in MM1S and RPMI8226 cell lines. Real-time PCR and western blot analysis confirmed KO of over 90% of Fox2 expression in both cell lines. We observed significant inhibition of proliferation of both MM1S and RPMI8226 cell lines in Fox-2- KO compared to control cell lines. Using annexin V and PI staining and flow cytometric analysis we also observed induction of apoptosis in Fox-2-KO-MM1S and RPMI8226 cells. The apoptosis was Caspase 3 and caspase 8-mediated in the Fox-2-KO. A similar effect of Fox-2-KO was observed on cell survival and proliferation in Hela and 293 cells. Fox-2 also plays a crucial role in the maintenance of cytoskeleton of MM cells. We observed that actin was significantly downregulated in both MM1S and RPMI8226 knockdown cell lines compare to controls, whereas GAPDH expressions are equal in all conditions. It's been recognized that actin derangement is associated with cell apoptosis. The RNA binding specificity of Fox-2 in MM cells by CLIP-seq and changes in alternate splicing in Fox-2-KO by exon array is underway to understand the molecular events mediated by this transcriptome modifier affecting MM pathobiology. These results identify Fox-2 as a biologically important intermediate with essential function in myeloma with potential biological and clinical implications.

Disclosures:
No relevant conflicts of interest to declare.
Risk of Second Cancers Among Multiple Myeloma (MM) Patients in the Era of Novel Agents: Analysis Using the Surveillance, Epidemiology and End Results (SEER) Database
Authors: Raghavendra Meghana , Gundrum Jacob D , Go Ronald S. 
Published: October 2019

Abstract
Abstract 1859

Introduction:
Recent data have drawn interest in the potential association of lenalidomide and the risk of developing of second cancers in patients with MM. However, available data are limited. Though there is lack of chemotherapy specification, SEER data segregated into diagnosis periods may be useful as a surrogate to detect changes in the incidence of second cancers corresponding to the introduction of novel agents.

Methods:
Patients who had MM diagnosed as a first cancer from 1973–2008 were identified in the SEER 17 database. We included only patients who survived at least 2 years after diagnosis. Time segments were created based on the era of novel agents approved for MM: before January 2000 (Period 1; control), January 2000-April 2003 (Period 2; off-label thalidomide), May 2003-April 2006 (Period 3; bortezomib approval), May 2006-September 2006 (Period 4; thalidomide approval) and October 2006-December 2008 (Period 5; lenalidomide approval). The primary outcome measure was incidence of second cancer within 2 years of MM diagnosis. All second cancers were included except for myelodysplastic syndrome and in situ cancer that were not of breast and bladder. Odds ratios (ORs) were adjusted and P values < 0.05 were considered statistically significant.

Results:
There were 29,259 eligible patients. Majority were males (53%) and the mean age at MM diagnosis was 65 years (std.+/− 12). The incidence of second cancers was associated with period of diagnosis (P = 0.048), sex (P < 0.001), treatment (P < 0.001), and age (P < 0.001), but not with race (P = 0.108). Multivariate analyses showed that higher risk of second cancers was associated with older age (OR = 1.03; P < 0.001), male sex (OR = 1.41; P < 0.001), radiation and/or surgery as compared to neither treatment (radiation and surgery OR = 1.77, radiation only OR = 0.82, surgery only OR = 2.31; P values: 0.002, 0.040, and <0.001, respectively), and Periods 3 and 4 as compared to Period 1 (Periods 2–5 ORs: 1.11, 1.22, 1.63, and 1.53, respectively; P values: 0.260, 0.033, 0.011, and 0.096, respectively).

Conclusions:
Our population-based study suggests that the risk of developing second cancers in patients with MM may be increased in the recent decade wherein novel agents were introduced. A more specific study linking SEER to Medicare database is recommended in order to further define the risk specific to novel agents.

Disclosures:
No relevant conflicts of interest to declare.
A Plasmin Inhibitor Prevents Lethal Acute Graft-Versus-Host Disease in Mice
Authors: Sato Aki , Tashiro Yoshihiko , Nishida Chiemi , Gritli Ismael , Kusubata Kaori , Takahashi Satoshi , Heissig Beate , Hattori Koichi , Nakauchi Hiromitsu 
Published: October 2019

Abstract
Abstract 1897
Proinflammatory cytokines released upon cell damage can cause excessive tissue destruction in acute graft-versus-host disease (GVHD). Certain key cytokines for GVHD like TNF-α and Fas-ligand, are secreted by ectodomain shedding from matrix metalloproteinases (MMPs). Many MMP inhibitors have been developed and used over the last three or four decades, but its widespread use is hampered by severe side effects. We reported that the fibrinolytic system, above all plasmin formation promotes the activation of several MMPs. Therefore we hypothesized that plasmin inhibition might be a novel means to control acute GVHD in part by suppressing MMP and inflammatory cytokine secretion. We found that the fibrinolytic system is activated during the development of acute GVHD in mice and in humans. Here, we examined a novel plasmin inhibitor (YO-2) that inhibits MMP activation and inflammatory cytokines release for lethal acute GVHD model in mice. Administration of YO-2 into (BALB/c × C57BL/6) F1 that received C57BL/6 spleen cells showed markedly reduced mortality and weight loss in association with minimal signs of GVHD pathology in the liver, intestine, and hematopoietic tissues. Furthermore, our results suggest that administaration of YO-2 blocked the processing of inflammatory cytokines through MMP inhibition in vitro and in vivo. These data have major implications for transplantation medicine, as pharmacological inhibition of plasmin does not require the need for intensive immunosuppression. Our results suggest that YO-2 could be a novel molecular therapeutic agent for GVHD.

Disclosures:
No relevant conflicts of interest to declare.