bluuebunny/crossref_metadata_2025_split huggingface dataset:
Osteoblast Ablation Causes an Imbalance of the HSC Population
Authors: Garcia Mayra 
Published: October 2019

Abstract
The hematopoietic stem cell (HSC) niche is composed of many different types of support cells including endothelial cells, stromal cells, and osteoblast. Studies that ablated mature osteoblast showed that they might be important to support maintenance of HSCs. These studies used Col2.3ΔTK to ablate differentiated osteoblast with daily treatments of ganciclovir after which the samples were analyzed immediately. Two opposing studies have been done using this system one showing a decrease in HSC and another showing an increase thus the role of osteoblast in HSC maintenance is still unclear. We have used a different method of ablating cells using Osteocalcin (Oc) and Osterix (Osx) Cre to drive expression of a diphtheria toxin receptor (iDTR), in mature osteoblast and osteoprogenitors, respectively. We injected eight week old mice with three doses of diphtheria toxin and analyzed the LSK and LT-HSC populations a month after cell ablation. There was no effect when the osteoprogenitors were ablated using Osx-Cre; suggesting ablation at postnatal stages is likely necessary to see an effect using Oxs-Cre. On the other hand, we found that a month after ablation of the Oc expressing cells the osteoblast population had recovered but the LSK and LT-HSC populations were still affected with an increase in both populations, suggesting that being exposed to a defective niche might have long-term effects on the HSC population.

Disclosures
No relevant conflicts of interest to declare.
Long Term Follow up of SWOG S0313: Ibritumomab Tiuxetan Consolidation after 3 Cycles of CHOP Plus Radiotherapy for High Risk Limited Stage Aggressive B-Cell Lymphoma
Authors: Persky Daniel O , Miller Thomas P. , Unger Joseph M , Spier Catherine M. , Puvvada Soham D. , Stea B. Dino , Press Oliver W. , Constine Louis , Barton Kevin , LeBlanc Michael , Smith Sonali , Fisher Richard I. , Friedberg Jonathan W. 
Published: October 2019

Abstract
Introduction: Patients with limited stage aggressive B-cell non-Hodgkin lymphoma (LS-NHL) and at least one stage-modified adverse risk factor have an excessive relapse rate leading to a 5-year overall survival (OS) of 50-77% and 10-year OS of 0-50%. In SWOG S0014 we have shown that the addition of rituximab to 3 cycles of CHOP plus involved field radiation therapy (IFRT) resulted in an improved estimated 4-year progression-free survival (PFS) of 88% and OS of 92%. Relapses were largely systemic (5 of 6 evaluable) and continued to be seen with longer follow-up. Ibritumomab tiuxetan (Zevalin ®) is a radiolabeled anti-CD20 antibody that has excellent single agent activity in diffuse large B-cell lymphoma and could prevent systemic relapse of disease. We now report long term results of SWOG S0313, a phase II study of ibritumomab tiuxetan consolidation after 3 cycles of CHOP plus IFRT in patients with LS-NHL.
Methods: Patients with LS-NHL and at least one stage-modified adverse risk factor (non-bulky stage II, age > 60 years, elevated LDH, or WHO performance status of 2) were treated with CHOP on days 1, 22, and 43, followed 3 weeks later by 40-50 Gy of IFRT. Ibritumomab tiuxetan regimen was initiated 3 – 6 weeks following IFRT.
Results: Forty-six patients were registered and eligible, with median follow-up of 7.3 years. Median age was 61, 37% of patients had elevated LDH, and 20% had systemic symptoms. Grade 4 adverse events occurring more than once included neutropenia (8 patients), leukopenia (5), and lymphopenia (2). Febrile neutropenia was observed in 4 patients. No cases of treatment-related myeloid neoplasms were noted. Eleven patients progressed and 8 patients died. The PFS estimate is 89% at 2 years, 82% at 5 years, and 75% at 7 years. OS estimate is 91% at 2 years, 87% at 5 years, and 82% at 7 years. These outcomes compare favorably to matched cohorts on prior SWOG trials, with 7-year PFS estimate of 68% on S0014 and 65% on S8736 (original pre-Rituximab trial); and 7-year OS estimate of 80% on S0014 and 73% on S8736 cohorts.
Conclusions: Patients with high-risk LS-NHL treated with 3 cycles of CHOP plus IFRT followed by ibritumomab tiuxetan consolidation had outcomes that compare favorably to our historical experience. A US cooperative group study of R-CHOP and response-adapted IFRT followed by consolidative ibritumomab tiuxetan is ongoing.

Disclosures
Off Label Use: ibritumomab tiuxetan in diffuse large B-cell lymphoma.
Antiviral Efficacy Analysis of Telbivudine Concurrent with the First Cycle of Chemotherapy in HBsAg-Positive Lymphoma Patients
Authors: Li Wenyu , Huang Ling , Guo Hanguo , Wei Xiaojuan , Liang Zhanli 
Published: October 2019

Abstract
Background: HBV reactivation is a common complication in HBsAg-positive lymphoma patients with chemotherapy or immunotherapy. There is no standard antiviral treatment for these patients undergoing chemotherapy or immunotherapy. The initial time, the agent and the duration time are confused at present.
Objective: This study aimed to investigate the antiviral efficacy of telbivudine concurrent with initiation of chemotherapy in HBsAg-positive patients with lymphoma.
Study design: Between April 2008 and October 2012, 359 patients with pathological diagnoses of lymphoma were admitted to the hospital. Among those, a cohort of 60 HBsAg-positive cases were enrolled in this retrospective study,and telbivudine was taken at the same day or one day prior to the first cycle of chemotherapy. The rates of HBV reactivation, virological response, undetectable HBV DNA, the relationship between HBV reactivation and its clinical characteristics were investigated.
Results: The rate of HBV reactivation was 11.7% (7/60), while it was 17.5% (7/40) and 75% (3/4) in patients treated with rituximab based chemotherapy and rituximab maintenance therapy, respectively. The fulminant hepatitis rate was 6.6%. The rates of virological response, undetectable HBV DNA and ALT normalization were 88.3%, 61.7% and 83.3%, respectively. HBV reactivation was associated with rituximab (P=0.013), and HBeAg-negativity (P=0.016), but not correlated with age, gender, clinical stages, extranodal disease, bone marrow involvement, B symptoms, HBV viral loads or serum LDH level.
Conclusion: Concurrent telbivudine treatment with initial chemotherapy can effectively reduce HBV reactivation in HBsAg-positive lymphoma patients, and the efficacy is independent of the baseline HBV viral loads.

Disclosures
No relevant conflicts of interest to declare.
Ocular Adnexal Marginal Zone Lymphomas (OAMZL): Lack of Evidence for Chlamydia Psittaci (C. Psittaci) Infection in a Clinicopathologic Study from a Single Institution
Authors: Merchán Brayan Marcel , Jaramillo Anny , Tortola Teresa , Abrisqueta Pau , Castellvi Josep , Medel Ramón , Flores Katia , Hernandez Javier , Gironella Mercedes , Lopez-Hernandez Andres , Bosch Francesc 
Published: October 2019

Abstract
Ocular adnexal lymphomas (OAL) represent up to 55% of all orbital tumors, being extranodal marginal zone lymphoma (OAMZL) the most frequent histological subtype reported in approximately 50% of patients and its etiology and pathogenesis are still not well understood. There are conflicting reports regarding the association between C. Psittaci infection and ocular adnexal lymphoma (OAMZL), in part because this association may vary between different geographical regions. Herein, we analyzed the clinical features and the presence of C. Psittaci infection in a cohort of 28 patients with OAMZL diagnosed from a single Spanish institution. All tumor samples were centrally reviewed by two pathologists, and C. Psittaci infection was determined in tumor specimens by a Semi-nested PCR method. Between January 1984 and April 2009, 28 patients were diagnosed with primary OAMZL. The median age was 70 years (range: 31- 89) and 40% were male. The great majority of patients (79%) were diagnosed in stage I-extranodal (IE), and six patients (21%) had bilateral ocular involvement. IgH rearrangement was confirmed in 25 out of 28 cases with OAMZL. PCR for C. Psittaci infection was negative in all 28 tumor specimens analyzed. Most patients (82%) were treated with immunochemotherapy combinations, being chlorambucil based regimens the most frequently used. Overall, 18 out of 24 patients (75%) achieved a complete response after first-line treatment. Median PFS was of 79 months (IC 95% 36 - 121). Whereas C. Psittaci infection in OAMZLs has been proved in up to 90% of patients in Northern Italy, in this Spanish cohort OAMZLs were not associated with C. Psittaci infection. These findings confirm that the association between C. Psittacci infection and OAML is highly heterogeneous even between the same geographic regions. In these regions where C. Psittaci infection is not prevalent, the search for alternative antigenic stimuli driving the appearance of this lymphoma is warranted.

Disclosures
No relevant conflicts of interest to declare.
Fasudil, a Rho-Associated Protein Kinase (ROCK) Inhibitor, Decreases Disease Burden in a Cbl/Cbl-b Deficiency-Driven Murine Model for Myeloproliferative Disorders
Authors: William Basem M. , Feng Dan , An Wei , Nadeau Scott , Mohapatra Bhopal , Storck Matt , Band Hamid 
Published: October 2019

Abstract
Myeloproliferative disorders (MPDs) are heterogeneous clonal diseases with variable clinical courses. Mutations in the Cbl family genes have been reported in multiple independent studies to be present in about 10% of patients with MPDs and these patients tend of have a poorer prognosis. We have previously demonstrated that Cbl-flox/flox, Cbl-b-null mice rendered Cbl/Cbl-b double knockout (DKO) in the hematopoietic compartment with MMTV-Cre develop a disease phenotypically similar to human MPDs. An in vitro kinase inhibitor screen identified fasudil, a ROCK inhibitor, with relatively selective anti-proliferative activity against Cbl/Cbl-b DKO vs. control murine bone marrow cells. We established a mouse model with a uniform time of MPD onset by transplanting Cbl/Cbl-b DKO bone marrow cells (2x106 per recipient) into 21 busulfan-conditioned NOD/SCID/gamma chain-deficient (NSG) mice. All recipients showed donor cell engraftment. Four weeks post-transplant, we treated 13 mice with 100 mg/kg fasudil daily by gavage. By two weeks of treatment, total white cell and monocyte counts were significantly lower in mice treated with fasudil (p=0.02 and 0.04 respectively). For the entire group, we observed a trend towards improved survival in fasudil-treated mice that didn't reach statistical significance (p=0.07). However, analysis of male recipients only (n=12) revealed a significant survival advantage in fasudil-treated group (p=0.04). The gender difference may stem from a currently unexplained more severe disease phenotype we observed in female recipients. Notably, while all untreated mice succumbed to MPD, prolonged survival was observed in 2 mice beyond 27 weeks, nearly twice the average life-span in the Cbl/Cbl-b DKO MPD model (16 weeks). The 2 long-term survivors had undetectable levels of myosin light chain (MLC), a downstream target of ROCK phosphorylation (figure) suggesting that inhibition of downstream signaling of ROCK is associated with improved disease control and survival. Taken together, our data suggest a therapeutic potential for fasudil in the treatment of MPDs or other mutant Cbl-driven myeloid disorders.
Figure: Fasudil activity in mouse model of Cbl/Cbl-b DKO MPD. Total WBC (A) and monocyte (B) counts over time in untreated and fasudil-treated mice (mean+/-SEM), C: MLC levels by Western Blot in peripheral blood of control vs. fasudil-treated mice; those surviving longer than 27 weeks are indicated. Figure:. Fasudil activity in mouse model of Cbl/Cbl-b DKO MPD. Total WBC (A) and monocyte (B) counts over time in untreated and fasudil-treated mice (mean+/-SEM), C: MLC levels by Western Blot in peripheral blood of control vs. fasudil-treated mice; those surviving longer than 27 weeks are indicated.

Disclosures
No relevant conflicts of interest to declare.
First-Line Prescribing Preferences of U.S. Hematology-Oncology Physicians for Patients with CLL: Impact of Novel Agents
Authors: Green Mark R. , Williams Michael E. , Willey Joanne , Buettner Arden , Neely Douglas , Lankford Maria 
Published: October 2019

Abstract
Background: In November, 2013 obinutuzumab (obin) was approved in combination with chlorambucil (chlor), as 1st line therapy (Rx) for patients (pts) with chronic lymphocytic leukemia (CLL). In February, 2014, ibrutinib was approved in CLL for pts who had received > 1 prior therapy. In April, 2014 ofatumumab (ofa) + chlor was approved as 1st line Rx for pts with CLL for whom fludarabine-based therapy is considered inappropriate. During 2014 we studied PPrefs of 180 U.S-based hematology-oncology physicians (HOPs) for 1stline Rx across a range of clinical scenarios varying by age, co-morbidities, and selected laboratory features.
Methods: PPrefs were assessed through a validated, proprietary, live, case-based market research tool (Challenging Cases®). Assessment dates were 3/08/14 and 4/26/14. Data were acquired using blinded, audience-response technology. A core scenario (CS) and 3 variant scenarios (VS) were utilized to evoke physician PPrefs. CS: 63-year-old male; 1-2 cm diffuse adenopathy, spleen 3 cm below costal margin. Presented with recent fatigue/ low grade fevers; no relevant co-morbidities; CD 38=12%. No FISH abnormalities. PS1. VS1: All equal except 17p deletion and CD 38 = 42%; VS2: CS (age 63; no abnormal FISH) plus co-morbidities (medication-controlled hypertension, type II diabetes, and mild COPD); VS3: VS2 BUT age 73 with same co-morbidities.
Results: PPrefs by scenario shown below: Abstract 4676. Table 1PPref CS VS1 VS2 VS33/8/144/26/143/8/144/26/143/8/144/26/143/8/144/26/14Bendamustine + rituximab[BR]61%63%52%51%72%68%66%64%Bendamustine + Obinutuzumab0%2%2%6%0%1%3%2%Chorambucil + Obinutuzumab1%3%2%3%2%5%8%17%FCR20%16%25%19%5%8%1%2%Ibrutinib + additional agent(s)2%3%11%16%7%8%6%7%Other2%2%4%2%2%2%3%2%Observe14%10%3%3%11%6%12%5%
Conclusions: As of March-April 2014 BR is the 1st line PPref of 51% -72% of US-based HOPs across 4 plausible newly diagnosed CLL scenarios. In VS1 (age 63; 17p deletion) ibrutinib based Rx is emerging despite lack of 1st line indication. In VS 3 (age 73, multiple co-morbidities present, neither high risk FISH nor CD 38 positivity) 1st line PPref for Chlor + Obin is emerging. Prior to ASH 2014, we will assess PPrefs of approximately 180 additional HOPs related to these scenarios (with ofatumumab + chlorambucil added as a treatment option) and have aggregate PPref data (N > 350) across all of 2014 for ASH.

Disclosures
Williams: Pharmacyclics, Janssen: Consultancy, Research Funding.
A Novel PI3K Inhibitor Identified By a High Throughput Virtual Screen Displays Potent Activity Against Multiple Myeloma
Authors: Cao Biyin , Zhu Jingyu , Wang Man , Yu Yang , Qi Huixin , Han Kunkun , Zhang Zubin , Zeng Yuanying , Qiao Chunhua , Zhang Hongjian , Hou Tingjun , Mao Xinliang 
Published: October 2019

Abstract
The phosphatidylinositol-3-kinase (PI3K) has been developed as a promising target for the treatment of many cancers, including hematological malignancies, such as lymphoma, leukemia, and multiple myeloma (MM). Recent clinical trials have demonstrated Idelalisib, a specific PI3Kdelta inhibitor, reached a total 57% of response rate in relapsed indolent lymphoma and 72% of overall complete rate in relapsed chronic lymphocytic leukemia. MM remains fatal as a cancer of plasma cells because of lack of efficient drugs. Therefore, we tried to find novel PI3K inhibitors for MM therapy. To this end, we performed a high throughput virtual screen against 800,000 small molecule compounds using PI3Kγ as the analytic model and identified C98, a function unknown compound, as a potent inhibitor of PI3Ks. The cell-free enzymatic studies showed that C98 inhibited all class I PI3Ks at nano- or low micromolar concentrations but had no effects on AKT or mTOR activity. Molecular docking analysis revealed that C98 interfered with the ATP-binding pockets of PI3Ks by forming H-bonds and arene-H interactions with specific amino residues through which C98 specifically inhibited PI3K/AKT/mTOR signaling pathway, but had no effects on other kinases and proteins including IGF-1R, ERK, p38, c-Src, and STAT3. PTEN is a key negative modulator of the PI3K signaling pathway, but KIF did not show any induction of PTEN, thus further demonstrating that KIF is a selective PI3K inhibitor. Inhibition of PI3K by C98 led to myeloma cell apoptosis as shown activated caspase cascade signaling. Furthermore, oral administration of C98 delayed tumor growth in two independent human myeloma xenograft models in nude mice but did not show overt toxicity. Pharmacokinetic analysis revealed that C98 can be found in MM tissues at an average concentration up to 622.6 ng/g, suggesting that C98 can penetrate into the tumor tissues where it exerts its anti-myeloma activity. It also suggests C98 has a reliable oral activity. Therefore, through a high throughput virtual screen we identified a novel PI3K inhibitor that is orally active against multiple myeloma with great potential for further development.

Disclosures
No relevant conflicts of interest to declare.
Chemotherapy-Induced Senescence Reprograms Lymphoma and Leukemia Cells into Latent Cancer Stem Cells That Are Susceptible to Conceptually Novel Treatments
Authors: Schmitt Clemens A. , Milanovic Maja , Daebritz Henry , Zhao Zhen , Trumpp Andreas 
Published: October 2019

Abstract
Cellular senescence is a stress-responsive cell-cycle arrest program that terminates further expansion of (pre-)malignant cells. Senescence imposes a tumor-suppressive barrier in lymphomagenesis, and acts as an effector program in response to chemotherapy in various hematological malignancies. Interestingly, many key signaling components of the senescence machinery also operate as critical regulators of stem cell functions (collectively termed ‘stemness’), among them the p53 axis and control of lysine 9 trimethylation at histone H3 (H3K9). We investigated here in vitro and in vivo whether chemotherapy-induced senescence may change stem cell-related functionalities in aggressive B-cell lymphomas and acute leukemias of murine and human origin.
Gene expression and functional analyses comparing senescent vs. non-senescent Eµ-myc transgenic B-cell lymphomas unveiled massive upregulation of an adult tissue stem cell signature, activated Wnt signaling, and de novo expression of distinct stem cell markers in senescence. Utilizing Suv39h1- (an H3K9-targeting methyltransferase) and p53-based genetically switchable ‘matched pair’ on/off models of senescence to mimic spontaneous escape (‘previously senescent’, PS), we found PS cells to re-enter the cell-cycle with strongly enhanced and Wnt-dependent clonogenic growth when compared to their equally chemotherapy-exposed but never senescent (NS) counterparts.In vivo, these PS lymphoma cells presented with a much higher tumor initiation potential, which was neutralized upon pharmacological or genetic Wnt inhibition. Strikingly, temporary enforcement of senescence in a p53-regulatable leukemia model reprogrammed non-stem bulk PS leukemia cells into leukemia-initiating stem cells, whose de novo self-renewing potential was also Wnt-dependent. In contrast, equally chemotherapy-exposed NS bulk cells (i.e. p53 always ‘off’) did not acquire stemness potential.
Our data, further supported by consistent findings in various human cancer cell lines and primary patient-derived lymphoma and leukemia samples, characterize senescence as a fundamentally reprogrammed cellular condition, and uncover senescence-associated stemness as an unexpected, cell-autonomous feature that exerts its detrimental potential upon escape from the cell-cycle block. These findings raise concerns about the long-term benefit of senescence-inducing cancer therapies, and provide new mechanistic insights into the plasticity of the “cancer stem cell” condition. In turn, we present synthetic lethal targeting of senescence-associated stemness as a conceptually novel, outcome-improving treatment strategy in lymphoma, leukemia and possibly other cancer entities as well.

Disclosures
No relevant conflicts of interest to declare.
Intravenous Administration of Liposome Encapsulated DFO Efficiently Removes Iron from the Liver and Spleen of Iron Overloaded Mice
Authors: Tran David T , Noble Charles O , Hayes Mark E , Szoka Francis C 
Published: October 2019

Abstract
Introduction: Long-term red blood cell transfusions effectively sustains patients who have β-thalassemia, sickle cell anemia, and myelodysplastic syndromes but they also lead to excess iron accumulation in the body. Iron overload is a major cause of morbidity and mortality in transfusion dependent patients. Chelation therapy reverses iron accumulation but marketed chelators have drawbacks such as: long infusions of deferoxamine (DFO, Novartis), large oral tablets with adverse effects (Exjade, Novartis), or twice daily oral dosing (Ferriprox, ApoPharma). These attributes contribute to poor compliance and poor outcomes in iron overload patients. To overcome long infusions and high doses of current therapies we have devised a stable nanoliposome encapsulated DFO (LDFO) for the treatment of iron overload.
Methods: LDFO composed of saturated soy phosphatidylcholine and cholesterol (3/2 molar ratio) is manufactured using a proprietary remote loading method that provides high encapsulation of DFO in 90 nm diameter liposomes. For pharmacokinetics and bioavailability studies, DFO and lipid concentrations in CF-1 mice plasma and tissues were analyzed by HPLC utilizing an in-house method. For iron removal efficacy studies, CF-1 mice were overloaded with iron dextran and after 10 days washout were treated with 100 mg/kg LDFO or unencapsulated DFO. Animals were sacrificed 5 days post treatment and tissue iron was measured by a ferrozine based spectroscopic assay.
Results: The manufacturing method to prepare LDFO results in a 300 g DFO/mole lipid encapsulation ratio. The formulation has greater than 6 months stability at 4 ºC. LDFO is long circulating and the DFO is bioavailable. At 24 hr post I.V. injection, there is 30% ID DFO in plasma and 10% ID DFO/g in liver whereas unencapsulated DFO is not detectable. Preclinical single dose safety studies in CF-1 mice indicate that LDFO is well tolerated at 300 mg/kg I.V. and 1250 mg/kg I.P. In the iron dextran overload model, LDFO greatly reduces iron levels in the liver and spleen. The absolute efficiency of LDFO is greater than 50% on a mole LDFO injected /mole iron removed from the liver (P<0.0004, n=4) and spleen (P<0.01, n=4). This is corroborated by an elevated iron accumulation in urine and feces from LDFO.
Conclusion: LDFO effectively removes iron from the liver and spleen with an overall molar efficiency > 50%. This high efficacy could lead to a dramatically improved treatment that increases compliance and provides substantially better management of iron overload than current treatments in patients suffering from iron overload conditions.

Disclosures
Tran: ZoneOne Pharma, Inc.: Employment. Noble:ZoneOne Pharma, Inc.: Employment, Equity Ownership. Hayes:ZoneOne Pharma, Inc.: Employment, Equity Ownership. Szoka:ZoneOne Pharma, Inc.: Consultancy, Equity Ownership.