bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Senescence-Associated Secretory Phenotype In Multiple Myeloma
Authors: Wildes Tanya M , Paasch Jacob , Fiala Mark A. , Chen Ling , Vij Ravi , Stockerl-Goldstein Keith E. , Stewart Sheila , Colditz Graham A. , Tomasson Michael 
Published: October 2019

Abstract

Introduction
The incidence of multiple myeloma (MM) increases with age, yet some cytogenetic changes are actually more common in younger patients with MM (Avet-Loiseau J Clin Oncol 2013). This suggests that a mechanism other than chromosomal changes underlies the increased incidence with age. Senescent cells secrete a number of proinflammatory cytokines, chemokines, growth factors and proteases resulting in the senescence-associated secretory phenotype (SASP), which can promote tumor growth. Preclinical data suggests that myeloma bone marrow stromal cells express the SASP (Andre PLOS ONE 2013). We hypothesized that SASP factors correlate with age in patients with MM.

Methods
Peripheral blood serum and matched bone marrow aspirate plasma from patients with multiple myeloma were evaluated for selected factors associated with the SASP using quantitative multiplex immunoassay (Rules Based Medicine, Austin TX USA). SASP factors with a known role in MM [interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-15 (IL-15), granulocyte-macrophage colony-stimulating factor (GMCSF), intercellular adhesion molecule 1(ICAM1), osteoprotegerin (OPG), hepatocyte growth factor (HGF), insulin-like growth factor-binding protein(IGFBP-1), interleukin-1 beta (IL1b), monocyte chemotactic protein 1(MCP-1), macrophage inflammatory protein-1 alpha(MIP-1a), angiogenin, leptin, vascular endothelial growth factor receptor 1(VEGFR1) and stem cell factor(SCF)] were selected. The relationship between age and SASP factors were analyzed using Kendall tau rank correlation coefficient.

Results
Samples from 25 patients (each with peripheral blood serum and matched bone marrow aspirate plasma) were analyzed. The median age was 62 (range 47 - 74). Disease states were as follows: 36% newly diagnosed/untreated, 24% pretransplant and 40% relapsed. ISS stage included 40% stage I, 28% stage II and 32% stage III. Three of the selected SASP factors in the peripheral blood correlated with age: IL-8 (Kendall Tau 0.334, p=0.027), OPG (Kendall Tau 0.289, p=0.046) and MCP-1 (Kendall Tau 0.332, p=0.022). No SASP factors tested in the bone marrow plasma were significantly correlated with age.

Conclusions
We demonstrated age-associated differences in the SASP factors IL-8, OPG and MCP-1 in the peripheral blood of myeloma patients. Future research will examine differences between patients with myeloma and age-matched controls without cancer.

Disclosures:
Vij: Celgene : Honoraria, Research Funding, Speakers Bureau; Millennium: Honoraria, Speakers Bureau; Onyx: Honoraria, Research Funding, Speakers Bureau. Stockerl-Goldstein:Celgene : Speakers Bureau; Celgene : Speakers Bureau; Millennium: Speakers Bureau; Millennium: Speakers Bureau.
Observational Study Of VMP (Bortezomib, melphalan, prednisolone) Regimen For Newly Diagnosed Korean Myeloma Patients Who Are Not Eligible For Transplantation
Authors: Kim Kihyun , Lee Mark , Kim Hyo Jung , Kim Yang Soo , Park Keon Woo , Bae Sung Hwa , Shin Ho Jin , Lee Won Sik , Lee Jung-Hee , Lee Jeong Ok , Yoon Sung-Soo , Kim Ki Hwan , Nam Sung-Hyun , Min Chang-Ki , Bae Sang Byung , Park Joon Seong , Hyun Myung Soo , Mun Yeung-Chul , Kwak Jae-Yong , Lee Je-Jung 
Published: October 2019

Abstract

Background
VMP regimen for newly diagnosed myeloma patients is well-documented treatment. However patients in real practice generally have worse performance status and less attention than those in clinical trials. Thus we conducted observational study to evaluate the efficacy and toxicity of VMP treatment in newly diagnosed Korean myeloma patients.

Patients and Methods
Data were prospectively collected from 39 hospitals. One hundred seventy three patients who started VMP as first line from 2011 May to 2012 April were included for analysis.

Results
Median age was 71 and 22.5% were more than 75 years old. Fifty-seven per cent were male sex. IgG type was most common (61.9%) and IgA 24.9%. ISS stage I was 13.8% and III was 51.5%. Patients with high risk FISH (Del17p, t(4;14), and t(4;16)) were 4.1%, 4.1%, and 2.3% respectively. Dose and schedule was followed original VISTA trial except for use of prednisolone instead of prednisone. Median 5cycles (range 1-9) were given and 105 patients stopped in the course of treatment. Most common cause were adverse event (28.8%) followed by disease progression or no response (19.6%). Twenty-five mortality cases were reported and 22 were in the course of treatment. The most common cause of mortality was infection (61%) followed by disease progression (13%). Overall response rate was 72.3% and response more than VGPR was 37.6%. Median progression free survival is 455 days and median OS was 504 days. One year PFS was 80.9 % and one year OS was 83.4%. Most common toxicity was cytopenia, peripheral neuropathy, and gastrointestinal toxicities such as nausea and diarrhea. Peripheral neuropathy of all grade and grade 3 or more was 58.6% and 6.36%, respectively

Discussions
Even though patients with higher proportion of ISS stage, efficacy of VMP regimen was considerable in Korean patients. With relatively high mortality due to infection in the course of treatment prophylactic measures for infection need to be developed. To reduce the incidence of peripheral neuropathy, close observation and intervention are needed to prevent aggravation of neuropathy.

Disclosures:
Off Label Use: lenalidomide in newly diagnosed myeloma. Kwak:celgene: Research Funding.
CMV Infection Alone Does Not Affect The Survival In Patients After Umbilical Cord Blood Transplantation: Can We Put Off The Time Of Preemptive Therapy?
Authors: Tong Juan , Sun Zimin , Liu Huilan , Ding Kaiyang , Geng Liangquan , Zheng Changcheng , Tang Baolin , Liu Xin 
Published: October 2019

Abstract

Objective
Analysis and discuss the time of cytomegalovirus (CMV) preemptive therapy after umbilical cord blood transplantation (UCBT). Analysis the risk factors of CMV infection and the effect on survival of CMV infection after UCBT.

Method
From April 2000 to March 2013, 176 cases of patients undergo UCBT who were detected plasma CMV-DNA twice a week routinely. Preemptive antiviral therapy was initiated with ganciclovir or foscarnet for positive PCR of 103 DNA copies or more per ml.

Results
125 of 176 patients developed CMV infection (71%) at a median of 32d (range 19 to 98) post-transplant and only 4 patients developed CMV disease (2.3%). The 5-year overall (OS) was 59.4% in the patients with CMV infection and 64.9% in patients without CMV infection (P=0.193). The study identified that younger age, high-risk disease, infused little CD34 positive cells, developed III-IV degree acute graft-versus-host disease (GVHD), high-dose methylprednisolone, and treated with basiliximab and other strong immunosuppressive agent as significant risk factors for developing CMV infection. It had nothing to do with the gender of patients, transplantation of UCB units, the conditioning regime, the day of neutrophil recovery and chronic GVHD. Preemptive therapy when the CMV-DNA copies are greater than 103 does not increase the incidence of CMV disease, and the survival has not been impacted.

Conclusion
Preemptive therapy can be initiated when CMV-DNA copies are greater than 103 which can achieve the same effects in UCBT.

Disclosures:
No relevant conflicts of interest to declare.
Low Incidence Of Severe Cgvhd and Late NRM In a Phase II Trial Of Thymoglobulin®, Tacrolimus and Sirolimus For Gvhd Prevention
Authors: Al-Kadhimi Zaid , Eghtedar Alireza , Gul Zartash , Chen Wei , Smith Daryn , Deol Abhinav , Abidi Muneer H. , Lum Lawrence G , Bhutani Divaya , Ayash Lois , Ratanatharathorn Voravit , Uberti Joseph P. 
Published: October 2019

Abstract

Introduction
Chronic graft-versus-host disease (cGVHD) is a major factor determining long term outcome and quality of life following allogeneic hematopoietic cell transplantation (AHSCT). In fact, cGVHD is the leading cause of late non-relapse mortality (NRM) and morbidity after AHSCT. The rates of severe cGVHD using NIH consensus criteria reported in the literature are 15-38%. Effective regimens are needed to reduce the severity of cGVHD and improve NRM. We analyzed and updated the long term outcomes of our phase 2 trial evaluating the efficacy of intermediate dose rabbit anti-thymocyte globulin (Thymo) in combination with tacrolimus and sirolimus for the prevention of acute and chronic GVHD after unrelated donor transplantation.

Methods
In a Phase II trial, 47 adult patients (pts) underwent AHSCT from unrelated donors using Thymo, tacrolimus, and sirolimus for GVHD prophylaxis. Thymo was given as follows: 0.5 mg/kg day -3, 1.5mg/kg day -2, and 2.5mg/kg day -1. Chronic GVHD was measured using NIH consensus criteria.

Results
Twenty-two pts received 8/8 and 25 received 7/8 HLA matched unrelated grafts. Thirteen pts received a reduced intensity preparative regimen, while 34 pts received a full intensity regimen. The median follow-up duration was 45.2 months (95% CI 37.7-48.8), with minimum follow up of 30 months. At 4 years of follow up, the cumulative incidence of NIH severe cGVHD a, was 6.4 % (95% CI 1.6-15.9), and overall cumulative incidence of cGVHD was 48.9% (95% CI 33.6-62.6). Of 20 pts who are alive and disease free, only 4 pts continue to need systemic immune suppression at the last follow up. At 4 years of follow-up, the cumulative incidence of NRM and disease relapse were 27.7% (95% CI 15.7- 41.0) and 30.0% (95% CI 17.5- 43.6), respectively. There has been one non relapse death beyond 12 months and none after 18 months of follow up. Only one pt died from cGVHD and bronchiolitis obliterans, while two other pts had minimal symptoms from bronchiolitis obliterans. Progression free survival (PFS) and overall survival (OS) at 2 years were 50% (95% CI 35-64) and 56% (95% CI 42-70). Median OS is 33.9 months [95% CI (9.8 -*) *the upper limit of the CI was not calculated due to the pattern of censoring] All patients were censored after 40 months, so PFS and OS could not be calculated at 48 months. The median karnofsky performance status at 2 years was 90%.

Conclusion
At long term follow up, the combination of Thymoglobulin, Tacrolimus, and Sirolimus was associated with low incidence of severe cGVHD, low incidence of late NRM, and good performance status. Further validation of these results in randomized phase III trials is needed.

Disclosures:
Al-Kadhimi: Genzyme: Research Funding. Off Label Use: The use of Thymoglobulin® for GVHD prevention.
Extracorporeal Photophoresis (ECP) For Chronic Graft Versus Host Disease (cGVHD): A Systemic Review and Meta-Analysis
Authors: Hashmi Shahrukh K , Malik Mohsin , Murad Hassan , Prokop Larry , Hogan William , Patnaik Mrinal M , Winters Jeffrey L. , Litzow Mark R. 
Published: October 2019

Abstract

Introduction
Steroid refractory chronic graft-versus-host-disease (SR-cGVHD) is the leading cause of late morbidity and mortality in allogeneic transplant patients. Safety of extracorporeal photophoresis (ECP) has led to multiple studies evaluating its role in SR-cGVHD. Overall and organ specific response rates (RR) of SR-cGVHD have varied significantly between studies. We conducted a systemic review and meta-analysis to assess the efficacy of ECP in SR-cGVHD.

Methods
A comprehensive search of several databases (Ovid Medline In-Process & Other Non-Indexed Citations, MEDLINE, EMBASE, Cochrane Central register of Controlled Trials,, Scopus) for articles published in any language between 1984-2012 was conducted. Unpublished studies using electronic databases from the annual meetings abstracts of hematology/transplant societies were searched. Experts in the field were also contacted for selection of studies and missing data from selected trials. End points included complete response rate (CR), overall RR (ORR), and organ-specific RR's.

Results
Initial search generated 312 studies, out of which 18 studies (4 prospective) met selection criteria (N=595). Random effects model was used for pooled rates. Pooled CR rate (11 studies) was 29% (CI 19%-42%). Pooled ORR (16 studies) was 64% (CI 65-82%). 1 year overall survival was 49% (CI 29-70%). There was significant heterogeneity between studies (I²=72) likely due to differences in ECP schedules utilized, and a variety of scales used to measure outcomes. Pooled RR's for SR-cGVHD of skin was 74% (CI 60-85%), liver was 68% (CI 57-77%), ocular was 60% (CI 40-78%), oral was 72% (CI 51-86%), lung was 48% (CI 33-63%), gastrointestinal (GI) was 53% (CI 21-83%), and musculoskeletal (MSK) was 64% (CI 18-94%). No significant differences in responses to ECP for pediatric and adult populations were found. Sensitivity analysis could not be done due to limited number of prospective studies.

Conclusions
ECP is an effective therapy for oral, skin & liver SR-cGVHD, with modest activity in lung and GI SR-cGVHD. Further studies must report standardized outcomes with a uniform schedule of ECP.

Disclosures:
No relevant conflicts of interest to declare.
A Lower Dose Of Melphalan (140 mg/m2) As Preparative Regimen For Multiple Myeloma In Patients >65 Or With Renal Dysfunction
Authors: Saunders Ila Maewal , Gulbis Alison M , Champlin Richard E , Qazilbash Muzaffar H. 
Published: October 2019

Abstract

Background
Melphalan at a dose of 200 mg/m2 IV (MEL 200) is considered the standard preparative regimen for autologous hematopoietic stem cell transplantation (auto-HCT) for multiple myeloma. However, reduced doses of melphalan such as140 mg/m2 (MEL 140) are often used in older patients or patients with renal dysfunction.

Methods
The purpose of this retrospective analysis was to determine if there was a difference in toxicity, treatment-related mortality (TRM), response rate, progression- free survival (PFS) or overall survival (OS) in patients that received 140 mg/m2 of melphalan (MEL 140) compared to those receiving MEL 200 for auto-HCT. From June 1, 1996 through December 31, 2012, 63 patients received MEL 140. We compared their outcomes with 252 patients that received MEL 200.

Results
Patient characteristics and outcomes are shown in the attached Table. Patients in the MEL 140 group were older, had a higher β2 microglobulin (β2M) level both at diagnosis and auto-HCT, and had a higher serum creatinine (Cr) at auto-HCT (Table). A higher proportion of patients in MEL 140 were older than 65 with serum Cr > 2 mg/dL. There was no significant difference in disease status or high-risk cytogenetics between the 2 groups (Table). NCI CTCv3 > III non-hematologic toxicity was not significantly different between MEL 140 and MEL 200. Transplant-related mortality (TRM) at 100 days and at 1 year was 0% and 0.4% in MEL 140 and 200 (p=1.0), respectively. Complete remission (CR) rates in MEL 140 and MEL 200 were 16% and 29%, respectively (p=0.03). There was no significant difference in (CR) + very good partial remission (VGPR), or overall response (CR + VGPR + PR) between MEL 140 and MEL 200. Median follow up in surviving patients in MEL 140 and 200 was 7.6 and 25 months, respectively. Fifteen (24%) and 64 (25%) patients died in MEL 140 and MEL 200 groups, respectively, with >90% of deaths due to recurrent disease. Median PFS was 26.4 and 30.6 months in MEL 140 and MEL 200 groups, respectively (p=0.46). Median OS was 38.4 and 93.0 months in MEL 140 and MEL 200 groups, respectively (p=0.02). However, there was no significant difference in PFS or OS in patients older than 65 or with serum Cr > 2 mg/d between MEL 140 and MEL 200.

Conclusion
The dose of melphalan can be safely reduced to 140 mg/m2 in patients >65 or with renal insufficiency without adversely impacting the overall response rate or PFS.

Disclosures:
Qazilbash: Otsuka Pharmaceuticals: Research Funding; Onyx Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Millennium Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Celgene Corporation: Honoraria, Membership on an entity’s Board of Directors or advisory committees.
Association Between S6K1 Phosphorylation and Cytotoxic Efficacy Of S6K1 Inhibitors
Authors: Liu Hongqi , Gallo Catherine A. , Plas David R. 
Published: October 2019

Abstract
S6K1 (ribosomal protein S6 Kinase 1) is emerging as a potential target for counteracting the glucose-dependent survival programs induced by oncogenes. In PTEN-deficient cells, previous analysis revealed that inactivating S6K1 was sufficient to reduce glycolysis and induce programmed cell death. In BCR-ABL+ cells, we found that S6K1 inactivation was cytotoxic when combined with a fatty acid oxidation inhibitor.
To begin to translate these findings, we have investigated the cytotoxic efficacy of a panel of S6K1 inhibitors. Although all compounds were efficient inhibitors of S6K1 phosphorylation of downstream substrates, there was one class of inhibitors that strongly induced the phosphorylation of S6K1 itself. These inhibitors were not cytotoxic for PTEN-deficient cells. In contrast, inhibitors that avoided strong phosphorylation of S6K1 overcame the pro-survival program in PTEN-deficient cells. These results suggest that S6K1 inhibition may be beneficial as a chemotherapeutic approach, but that inhibitors should be selected to avoid the phosphorylation of S6K1 itself while also inhibiting kinase activity.

Disclosures:
No relevant conflicts of interest to declare.
Indications For Hospital Admissions and Outcomes Of Hospitalization Among Multiple Myeloma Patients In The U.S: Data From National Inpatient Sample
Authors: Nooka Ajay K. , Kaufman Jonathan L. , Shah Nishi N , Langston Amelia , Collins Hannah , Boise Lawrence H. , Lonial Sagar 
Published: October 2019

Abstract

Introduction
A recent Spanish study suggested an impact of the type of hospital (teaching versus non-teaching) on survival of multiple myeloma (MM) patients. Such data, as well as other hospitalization parameters such as indications, length of stay (LOS), in-hospital mortality (IHM) in MM patients admitted to hospitals in the U.S are lacking. We have explored the National Inpatient sample (NIS) data to address the indications for hospitalization in MM patients and their survival outcomes of the hospitalization.

Methods
We obtained the National Inpatient Sample (NIS) data for the years 01/2001 until 12/2010 from Healthcare Cost and Utilization Project database (HCUP) database. The 2010 NIS contains all discharge data located in 45 States, approximating a 20% stratified sample of the U.S hospitals. Teaching hospital was defined as a hospital supported by AMA-approved residency program, is a member of the council of teaching hospitals or has a ratio of full-time equivalent interns and residents to beds of ≥0.25.

Results
A total of 178354 admissions reported to NIS were analyzed. Majority of admissions were to teaching hospitals (61.7% admissions: 45.8% for non-SCT and 15.9% for SCT indications) (Table 1). Among the patients that were admitted for non-SCT indications, significantly younger patients were admitted to teaching hospitals. Complicated procedures such as cancer chemotherapy were admitted to teaching hospitals (teaching vs. non-teaching: 8.3% vs. 3.4%; p=<0.0001) and simple procedures such as blood transfusions were admitted to non-teaching hospitals (teaching vs. non-teaching: 13% vs. 19.2%; p=<0.0001). The IHM is significantly increased in non-teaching hospitals (teaching vs. non-teaching: IHM: 9.8 vs. 12.5%; p=<0.0001). Among the patients that were admitted for SCT as the primary procedure, IHM for autologous SCT is 1.64% and for allogeneic SCT is 5.94%.

Conclusions
This analysis suggests inferior survival outcomes in MM patients admitted to non-teaching hospitals. Despite the difference in severity of admissions, IHM is significantly increased in non-teaching hospitals. This effect is at least partially attributable to older patient admissions. IHM in SCT admissions is similar to published literature, validating our findings.

Disclosures:
Kaufman: Onyx: Consultancy; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Janssen: Consultancy; Millenium: Consultancy; Merck: Research Funding. Boise:Onyx Pharmaceuticals: Consultancy. Lonial:Millennium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; BMS: Consultancy; Sanofi: Consultancy; Onyx: Consultancy.
A Selective TNFR2 Agonist Expands Host Treg Cells in Vivo to Protect from Acute Graft-Versus-Host Disease
Authors: Beilhack Andreas , Chopra Martin , Biehl Marlene , Vaeth Martin , Brandl Andreas , Amich Jorge , Findeis Janina , Jordán Garrote Ana-Laura , Brede Christian , Bäuerlein Carina A , Schwinn Stefanie , Einsele Hermann , Berberich-Siebelt Friederike , Wajant Harald 
Published: October 2019

Abstract

Donor CD4+Foxp3+ regulatory T cells (Tregs) suppress graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HCT) while maintaining the anti-tumoral effect of transplanted conventional T cells in preclinical mouse models. Current clinical study protocols with donor Tregs for treatment or prophylaxis of GVHD rely on their ex vivo expansion and infusion in high numbers. Here we present a fundamentally novel strategy for inhibiting GVHD that is based on the in vivo expansion of recipient Tregs prior to allo-HCT, exploiting the crucial role of tumor necrosis factor receptor 2 (TNFR2) in Treg biology.
To this end we constructed a recombinant nonameric TNFR2-specific agonist, mimicking the activity of murine membrane-bound TNF on TNFR2 without TNFR1 stimulation, thereby avoiding the inflammatory side effects observed with conventional TNF. In vitro, this TNFR2-agonist expanded natural Tregs from wild type but not from TNFR2 KO mice. Accordingly, a human variant of this TNFR2-specific agonist expanded human Tregsin vitro. In vivo treatment of healthy mice with the murine TNFR2-agonist significantly increased Treg numbers in secondary lymphoid organs and peripheral tissues, particularly in the gastrointestinal tract, a prime target of acute GVHD.
Next, we pre-treated recipient mice with this novel TNFR2-agonist to expand host-type radiation resistant Tregs prior to of allo-HCT in two models across MHC barriers (C57BL/6, H-2b->Balb/c, H-2d and FVB/N, H-2q->C57BL/6, H-2b). TNFR2-agonist pre-treatment resulted in significantly prolonged survival and reduced GVHD severity when compared to TNFR2-deficient recipients or untreated allo-HCT recipients. This was accompanied by reduced donor T cell proliferation and infiltration into GVHD target organs as assessed by in vivo and ex vivo bioluminescence imaging, flow cytometry and immunofluorescence microscopy. While in vivo TNFR2-agonist pre-treatment protected allo-HCT recipients from GVHD, anti-tumor effects of transplanted T cells remained unaffected in two different murine B cell leukemia models. In vivo depletion of host derived Tregs completely abrogated the protective effect of TNFR2-agonist pre-treatment.
Our study shows that the expansion of host Tregs by selective in vivo TNFR2-activation significantly improves the outcome after allo-HCT and results in prolonged tumor-free survival.

Disclosures
No relevant conflicts of interest to declare.