bluuebunny/crossref_metadata_2025_split huggingface dataset:
PI3K/AKT Pathway Is Activated By MYD88 L265P and Use Of PI3K-Delta Inhibitors Induces Robust Tumor Cell Killing In Waldenstrom’s Macroglobulinemia
Authors: Yang Guang , Liu Xia , Zhou Yangsheng , Xu Lian , Cao Yang , Manning Robert , Patterson Christopher , Tripsas Christina K , Hunter Zachary , Buhrlage Sara , Gray Nathanael S , Treon Steven Peter 
Published: October 2019

Abstract

Background
MYD88 L265P is a somatic mutation present in >90% of Waldenstrom's Macroglobulinemia (WM) patients. The downstream signaling pathways that promote malignant cell growth and survival remain to be fully clarified but include IRAK 1/4 and BTK (Treon et al, NEJM 2012; Yang et al, Blood 2013).

Methods
To further clarify the downstream signaling associated with MYD88 L265P in WM cells, we employed Phospho Explorer Antibody Arrays in MYD88 L265P expressing BCWM.1 and MCWL-1 WM cells following lentiviral mediated knockdown of MYD88, or over-expression of MYD88 wild type or L265P; or the use of MYD88 homodimerization inhibitor that block MYD88 signaling. Arrays were scanned by Axon GenePix Microarray Scanner and data analyzed by Ingenuity Pathway Analysis. Western blot analysis was performed using total and phospho-specific antibodies in WM cells. CellTiter-Glo® Luminescent cell viability assay (Promega) was used to assess cell survival following treatment with the PI3K-delta inhibitors, CAL101 and PIK-294 (Selleck Chemicals).

Results
Ingenuity pathway analysis demonstrated significant enrichment for B-Cell Receptor, PI3K/AKT, LPS-stimulated MAPK and ERK/MAPK signaling following MYD88 modulation in both BCWM.1 and MWCL-1 WM cells. Signal proteins that demonstrated the greatest changes in phosphorylation following MYD88 modulation are shown in Table 1. Western blot analysis confirmed the activation of ATK as downstream of PI3K in WM cells. Use of a MYD88 inhibitor significantly decreased phosphorylation of ATK-pS473 and AKT-pY308 in both BCWM.1 and MCWL-1 WM cells. Cell viability analysis demonstrated robust tumor cell killing (EC50 30-50nM) in BCWM.1 and MWCL-1 WM cells following treatment with both PI3K-delta inhibitors (CAL-101 and PIK-294).

Conclusion
In addition to activation of NF-kB through IRAK and BTK signaling, MYD88 L265P promotes survival of WM cells by activation of PI3K/AKT signaling. Inhibition of PI3K-delta is associated with robust killing of WM cells. These studies provide the framework for the investigation of PI3K-delta inhibitors in WM.

Disclosures:
No relevant conflicts of interest to declare.
Argonaute2 promotes myeloma angiogenesis by deregulation of microRNAs
Authors: Lijuan Chen , Jiaren Xu , Wu Shuang , Wang Rong , Xiaoyan Qu , Wenjun Yu , Li Jianyong 
Published: October 2019

Abstract
Dysregulation of miRNAs expression contributes to cancer cell proliferation, apoptosis and angiogenesis. Angiogenesis is a hallmark of multiple myeloma development and progression. Argonaute 2 (AGO2) protein, the core component of RNA-induced silencing complex (RISC), can directly bind miRNAs and mediate target mRNAs degradation. Previous study showed that AGO2 knockdown suppressed the growth and tube formation of HUVECs. In current study, the supernatant of AGO2 over-expression MM lines could induce HUVECs migration and accelerated tube formation. Conversely, the supernatant of AGO2 knockdown MM lines could suppress cell migration and tube formation of HUVECs. Moreover, CAM assay also demonstrated AGO2 can drive neovessel formation of MM in vivo. Using miRNAs microarray, we observed that 25 miRNAs were up-regulated and 14 miRNAs were down-regulated by AGO2 protein. Among these AGO2-associated miRNAs, most Let-7 family and two miR-17-92 cluster members (miR-17a and miR-92-1), known as pro-angiogenetic miRNAs, were the dominant positively regulated miRNAs by AGO2, and the anti-angiogenetic miRNAs, such as miR-145 and miR-361 were inversely regulated by AGO2 protein, which play crucial role in AGO2 mediating angiogenesis.

Disclosures:
No relevant conflicts of interest to declare.
Elevated Neutrophil: Lymphocyte Ratio Does Not Predict Survival In Multiple Myeloma Patients
Authors: Atallah Jean Paul , Azab Basem , Vivekanandarajah Abhirami , Naboush Ali , Sater Houssein Abdul , Farhan Mohammad , Patel Nileshkumar J , Elkosseifi Myriam , Fares Elias , Boumitri Christine , Zaraket Vera , Saad Marc , Hassan Samer , Odaimi Marcel , Terjanian Terenig 
Published: October 2019

Abstract

Background
Cancer associated inflammation is one of the key determinants of outcome in patients with cancer. An elevated neutrophil: lymphocyte ratio (NLR) has been identified as a predictor of worse survival in patients with various solid tumors compared to hematologic malignancies but no reports yet examined its impact on multiple myeloma. The aim of this study was to examine the prognostic value of an elevated NLR in multiple myeloma.

Methods
We had approval by our institutional review board to collect the data on patients diagnosed with multiple myeloma at Staten Island University Hospital between year 2000 and 2012 identified from our local cancer database. Data on demographics, conventional prognostic markers, laboratory analyzes including blood count results, and histopathology were collected and analyzed. A cox proportional survival analysis was carried out to assess the relationship between NLR and mortality. NLR was assessed as a continuous variable as well as categorical variable (quartile 0.5-1.5, 1.6-2.2, 2.3-3.8, and 3.9-22.3).

Results
A total of 96 patients were identified with a median age at diagnosis of 70 (IQR of 61 to 79) years. The median neutrophil count was 3.5 (2.5—5.1) x 10-9/liters, median lymphocyte count 1.5 (1.05-2.4) × 10-9/liters, while the NLR was 2.28 (1.53-3.88). The median overall survival was 147.5 weeks, IQR (88.5-320). NLR did not prove to be a significant predictor of death as a continuous variable (0.95 (0.85-1.06), p =0.35). Furthermore, there was no significant difference in survival with any of the quartiles of NLR. Compare to lowest quartile of NLR, Hazards ratio for the consecutive quartiles were 1.25 (0.56-2.79, p 0.55), 1.36 (0.61-3.04, p=0.45) and 0.89 (0.36-2.22, p=0.80).

Conclusion
NLR does not appear to offer useful predictive ability for outcome and survival in multiple myeloma patients. Our study is limited with small sample size, further studies are needed to validate our results.

Disclosures:
No relevant conflicts of interest to declare.
The Presence Of Spine Bone Plasmacytomas At The Time Of Multiple Myeloma (MM) Diagnosis Confers Poor Prognosis
Authors: Kyrtsonis Marie-Christine , Nikolaou Eftychia , Maltezas Dimitrios , Sarris Katerina , Koulieris Efstathios , Iliakis Theodoros , Vyniou Nora , Vardounioti Ioanna , Karali Vassiliki , Pessach Ilias , Bartzis Vassiliki , Tzenou Tatiana , Dimou Maria , Vassilakopoulos Theodoros P. , Angelopoulou Maria K. , Tsaftaridis Panagiotis , Katodritou Irene , Panayiotidis Panayiotis 
Published: October 2019

Abstract
The negative prognostic consequences of extramedullary plasmacytomas in the context of symptomatic MM is well known. On the contrary, the clinical impact of bone plasmacytomas (BP) has not been extensively studied, although their presence is one of Duries’ major MM diagnostic criteria.
The aim of the present study was to study eventual differences between MM patients presenting at diagnosis with or without BP.

Patients and Methods
Two hundred and twelve symptomatic MM patients were studied from diagnosis to last follow-up. Their median age was 66 years and 60% were men. Twenty-three percent, 27% and 50% of patients were in ISS stage 1, 2 and 3 respectively; MM type was IgG in 59% , IgA in 26%, light chain only in 12%, IgD in 1,5% and non- or oligo-secretory in 1,5%. All patients required treatment and BP ones were additionally given radiotherapy. The median follow-up time of the whole cohort was 46,4 months.

Results
Forty patients (19%) had a BP at the time of their diagnosis. BP was located in the spine (BP-S) in 19 out of 40 and in other sites (BP-O: skull, pelvis, long bones, and ribs) in 21 patients. BP patients had equivalent demographics, stage and MM type as the others. Non-BP patients tended to have a better survival than BP ones but the difference was not statistically significant (p=0.1). However, BP-S patients had a significantly worse outcome than BP-O patients (24±6 versus 48±11 months, p<0.00001), and indeed worse than non-BP patients. It is worthwhile to outline that 17 out of 19 BP-S patients had received new drugs (thalidomide, lenalidomide, Bortezomib) during their course while 8 of them underwent high dose treatment with autologous stem-cell transplantation. In addition, the ISS staging has absolutely no prognostic impact in these patients (p=0.5), on the contrary to the whole cohort (p=0.03).
In conclusion, MM patients presenting spine plasmacytoma at diagnosis constitute a distinct subgroup with adverse outcome that is difficultly predictable, given that the current staging system does not separate them. Further confirmation of this finding in larger cohorts is needed, as well as exploration of the biologic background.

Disclosures:
No relevant conflicts of interest to declare.
Once-Weekly Subcutaneous Bortezomib Plus Oral Cyclophosphamide and Dexamethasone Therapy For Relapsed Or Refractory Multiple Myeloma
Authors: Takamatsu Yasushi , Imamura Yutaka , Nakazato Tomonori , Uike Naokuni , Miyashita Kaname , Saburi Yoshio , Harada Naoki , Ota Shuichi , Imamura Rie , Miyamoto Toshihiro 
Published: October 2019

Abstract

Background
We previously reported that twice-weekly intravenous bortezomib plus doxorubicin and intermediate-dose dexamethasone (iPAD) therapy induced a high complete response (CR) rate of 30% and prolonged remission duration of median 12.1 months in patients with relapsed or refractory myeloma. However, sensory neuropathy was observed in 78% of the patients with grade 3 neuropathy in 22%. To reduce the toxicity, we conducted once-weekly subcutaneous bortezomib therapy given in combination with oral cyclophosphamide and dexamethasone (sVCD).

Methods
This was a phase 2 multicenter study conducted by the Kyushu Hematology Organization for Treatment Study Group (K-HOT). sVCD regimen consists of bortezomib 1.3 mg/m2 administered subcutaneously, and cyclophosphamide 300 mg/m2 and dexamethasone 40 mg given orally on days 1, 8, 15 and 22. The treatment was repeated at a 5-week interval for 6 cycles. The primary endpoint was to determine the complete response rate. The toxicities including sensory neuropathy and injection site reaction were analyzed as the secondary endpoint. The study was approved by the Institutional Review Board at each participating center and was registered in University hospital Medical Information Network (UMIN000006490). All patients provided a written-informed consent.

Results
Thirty-one patients with median age of 69 (range, 43-87) were entered into this study. The numbers of prior chemotherapy line were 1 in 39%, 2 in 23%, and more than 3 in 39% of the patients. Bortezomib, lenalidomide and thalidomide had been given in 52%, 26% and 16%, respectively. CR was achieved in 16%, partial response (PR) in 26%, and minimal response (MR) in 29%, resulting in overall response rate of 71%. Grade 3/4 neutropenia was observed in 35%/3%, thrombocytopenia in 16%/13%, and anemia in 45%/0% of the patients. Grade 3 to 4 non-hematological toxicities were uncommon; the highest incidence of grade 3 events were rash, hyponatremia and hyperglycemia observed in 6%, while no grade 4 events were reported. Grade 3 sensory neuropathy developed in 3% and grade 2 in 19%. Injection site reactions were observed in 39%, but all of them were grade 1.

Conclusion
sVCD therapy containing bortezomib administered subcutaneously in once-weekly schedule successfully reduced the incidence and severity of sensory neuropathy with moderate response rate.

Disclosures:
Miyamoto: Kyushu University Hospital: Employment.
Description Of The Hematological Toxicity Of Different Regimens Using Bortezomib In Multiple Myeloma (CyborD, Vel-Dex and VMP)
Authors: Duquette Dominic , Laroche Vincent 
Published: October 2019

Abstract

Introduction
The use of bortezomib has evolved since the APEX study published in 2005. It remains, however, the only study providing a detailed account of the changes in hematological parameters in response to bortezomib-based chemotherapy. The APEX trial enrolled multiple myeloma patients in relapse. In first-line transplant eligible multiple myeloma patients, we use bortezomib twice weekly with low-dose dexamethasone (VelDex) or bortezomib once weekly with dexamethasone and cyclophosphamide (CyBorD). For patients non-eligible to transplant, we use bortezomib once or twice weekly with melphalan and prednisone (VMP). The goal of this study is to describe changes in platelet counts during these three types of bortezomib-based induction therapys.

Methods.
We conducted a retrospective chart review to examine the complete blood count (CBC) results during treatment with VelDex, CyBorD or VMP. Neutrophil count, hemoglobin and platelet count were measured before every bortezomib infusion. Patients not receiving the anticipated protocol or less than 3 cycles of VelDex or CyBorD or 6 cycles of VMP were excluded from this review.

Results
30 patients were included in this review (VelDex = 11, CyBorD =10, VMP = 9) Results are showed in the following graphs. The use of twice weekly bortezomib is associated with a more pronounced drop in platelets. CyborD once weekly is associated with less severe drop in platelets.

Conclusion
These findings show that once weekly bortezomib is associated with less severe thrombocytopenia. This suggests that the blood monitoring could be less frequent than at each dose of bortezomib. A biweekly monitoring of blood counts could reduce significantly blood tests and waiting time for patients.

Disclosures:
Duquette: Janssen: Consultancy, Honoraria. Off Label Use: CyborD is a widely accepted regimen but has not been accepted by the FDA.
PTEN Regulated BCRP/ABCG2 and Side Population Through PI3K/Akt Pathway In Chronic Myeloid Leukemia
Authors: Huang Fang-Fang , Zhang Li , Yu Yan-Hui , Chen Fang-ping , Zeng Hui , Niu Ting , Wu Deng-shu 
Published: October 2019

Abstract
A small population of cancer stem cells named as “side population (SP)” has been demonstrated to be responsible for many solid tumor maintenance. However, the role of SP in leukemic pathogenesis is still controversial. The resistance of leukemic stem cells in response to targeted therapies such as tyrosine kinase inhibitors (TKIs) results in therapeutic failure or refractory/relapsed disease in chronic myeloid leukemia (CML). The drug pump, ABCG2, is well-known as a specific marker of SP and could be controlled by several pathways including PI3K/Akt. Our data demonstrated that compared to wild type K562 cells, the higher percentage of ABCG2+ cells corresponded to the higher SP fraction in K562/ABCG2 (ABCG2 overexpressing) and K562/IMR (resistance to imatinib) cells, which exhibited enhanced drug resistance along with downregulated PTEN and activated p-Akt. It could be abrogated by both PI3K inhibitor LY294002 and mTOR inhibitor rapamycin. Moreover, in CML patients at accelerated phase/blastic phase (AP/BP), increased SP phenotype rather than ABCG2 expression accompanied with loss of PTEN protein and up-regulation of p-Akt expression was observed. These results suggested that expression of ABCG2 and fraction of SP may be regulated by PTEN through PI3K/Akt pathway, which will be the potentially effective strategy for targeting CML stem cells.

Disclosures:
No relevant conflicts of interest to declare.
Post-Transplant Immune Monitoring In Patients Receiving Allogeneic Stem Cell Transplantation
Authors: Park Silvia , Jung Chul Won , Jang Jun Ho , Kang Eun Suk , Kim Kihyun 
Published: October 2019

Abstract

Introduction
There are still substantial morbidity and mortality caused by insufficient immunologic recovery after allo-HSCT. In this context, we attempt to evaluate the clinical relevance of immune monitoring in allo-HSCT recipients.

Method
Fifty five patients who underwent allo-HSCT between 2008 and 2012 were included. Peripheral blood samples were drawn from recipients before transplant, and on 4, 8, 12, 24, 36 and 48 weeks after transplant. Each blood samples were analyzed by multi-color flow cytometry for determining lymphocyte subsets. MNC were separated from blood specimen, and analyzed for the quantitation of Treg with the use of real-time PCR. We also examined T cell derived IFN-r by using in vitro culture, intracellular staining, and flow cytometry analysis.

Results
The median age was 43, and AML was the most common reason for transplantation (49.1%). Grade II or more aGVHD occurred in 36.4% of cases, and 49.1% exhibited moderate or severe cGVHD. The differences in the proportion (%) and the absolute number (/uL) of CD4+, CD8+ cells, CD4+ derived IFN-r (%), CD8+ derived IFN-r (%), and Treg (%) between the groups (Gr. II or more aGVHD (+) vs (-); moderate or severe cGVHD (+) vs (-)) were compared by Two sample t-test. Patients with Gr. II or more aGVHD showed decreased CD4+ count at 4, 8 and 12 weeks, but showed rather higher CD8+ count at 8 weeks after transplant. T-cell secretion function assessed by IFN-r (%), and Treg (%) was similar between two groups within 12 weeks after transplant. In case of cGVHD, both CD4+ and CD8+ count tended to be higher in patients with moderate or severe cGVHD, and the trends lasted for up to 48 weeks from allo-HSCT. Treg (%) was almost consistently lower throughout the period in these patients. There were 12 relapses within follow up period (median 36.1 months), and higher slope of post-transplant increase in CD8+ count and CD8 derived IFN-r were identified as protective factors for disease relapse.

Conclusion
In view of the results so far achieved, slow recovery of CD8 count and function might be associated with disease relapse. However, this is still a preliminary data, and warrants further evaluation.

Disclosures:
No relevant conflicts of interest to declare.
Allogeneic Stem Cell Transplantation With Reduced Intensity Conditioning Regimen In Patients With Relapsed Hodgkin´s Lymphoma
Authors: Rivas Maria Marta , Berro Mariano , Yantorno Sebastian , Prates Maria Virginia , Milone Jorge H , Basquiera Ana Lisa , Berreta Adriana , Garcia Juan , Remaggi Guillermina , Rolon Juliana Martinez , Arbelbide Jorge , Makiya Monica , Dibar Eduardo , Requejo Alejandro , Julio Feldman Leonardo , Milovic Vera , Foncuberta Maria Cecilia , Burgos Rubén , Kusminsky Gustavo Daniel 
Published: October 2019

Abstract

Introduction
Hodgkin´s Lymphoma (HL) is a highly curable disease. However, there are still patients with primary refractory disease or who relapse after first-line treatment, or even after high-dose chemotherapy with hematopoietic cell rescue. Allogeneic stem cell transplant (ASCT) is therapeutic for this patients.

Objective
To analyze the experience with relapsed HL patients that received ASCT with reduced intensity conditioning (RIC)regimen in 8 Argentine Medical Centers.

Design and Population
We performed a retrospective multicenter analysis from data obtained from medical records. Fifty-four patients with relapsed HL who received ASCT had a median age of 26years. The relationship between male / female was 1/1. Only 3 patients (5.5%) at the time of transplant had a performance status> 1 according to ECOG. Ninety-six percent of the patients had received previously autologous transplant. Most patients 43 (80%) received an identical sibling donor transplant. All patients receiving unrelated donor transplants had in vivo lymphocyte depletion as prophylaxis of graft versus host disease. Forty-three patients (79.6%) received as a conditioning regimen Fludarabine + Melphalan. The disease status at transplant was: complete remission (CR) 33%, partial remission (PR) 54%, stable disease / progressed (SD / PD) 13%.

Results
With a median follow up of 2.7 years, actuarial overall survival (OS) at 1 and 5 years was 65% and 20% respectively and disease free survival (DFS) at 1 and 5 years was 35 % and 18% respectively. The incidence of acute GVHD grade II-IV was 31%. Patients in CR at the time of transplant showed significant differences compared with those who were not in CR in DFS (1-5 years 52-27% vs 19-14%, p=0.01), OS (1-5 years 76-38% vs 59-13%, p=0.02) and non relapsed mortality (NRM) (1-5 years 6-12% vs 34-39%, p=0.04). Age, PS, the use Fludarabine + Melphalan as conditioning regimen, unrelated donor, aGVHD, were not variables that modified the overall survival and disease-free survival.

Conclusion
The ASCT with RIC regimen is a feasible therapeutic option in patients with HL, especially in patients who can achieve CR. The low rate of DFS is still an issue in this setting, may be new drugs may help in optimizing pretransplant response status to improve patients’ outcome.

Disclosures:
No relevant conflicts of interest to declare.
Sequential R-CHOP and R-FM Chemotherapy Followed By Autologous Stem Cell Transplantation Results In High Rates Of Long Term Remission In Advanced Follicular Lymphoma
Authors: Derenzini Enrico , Stefoni Vittorio , Casadei Beatrice , Pellegrini Cinzia , Broccoli Alessandro , Fanti Stefano , Gandolfi Letizia , Stefani Giulia , Argnani Lisa , Zinzani Pier Luigi 
Published: October 2019

Abstract

Introduction
Autologous stem cell transplantation (ASCT) is a potentially curative treatment option for relapsed Follicular Lymphoma (FL) patients, but to date available data do not support the use of ASCT as first line consolidation, given the lack of overall survival (OS) advantage compared to standard therapy. R-CHOP (Rituximab-Cyclophosphamide, Vincristine, Doxorubicin, Prednisone) and R-FM (Rituximab, Fludarabine, Mitoxantrone), have comparable efficacy and are widely used as first and second line combinations. The best way to sequence the available therapies in FL is still undefined. Here we show the long term results of a phase II trial of sequential chemotherapy alternating CHOP and FM plus Rituximab followed by ASCT in patients with stage III-IV and/or bulky FL either at disease onset or first relapse, conducted in our Institution from 2002 to 2008.

Methods
Patients at diagnosis or first relapse were treated in sequence with R-CHOP for 4 cycles, Endoxan 7g/m2 followed by hematopoietic stem cell harvest, R-FM for 4 cycles and ASCT. The ASCT conditioning schedule was BEAM (BCNU, ARA-C, Etoposide, Melphalan) in all cases.

Results
24 patients were enrolled, 12 pts were male. Median age was 44 years. One patient did not undergo ASCT for insufficient left ventricular ejection fraction and was excluded from the analysis. 13 patients were treated upfront whereas 10 patients at first relapse. After a median follow-up of 10 years, progression free survival (PFS) and OS in the whole study cohort were respectively 65% and 87%, with a complete response (CR) rate after the completion of sequential treatment of 100%. PFS and OS for patients treated at disease relapse were 60 and 70% (4 relapses, 3 deaths). Remarkably PFS and OS for the 13 patients treated upfront was 70% and 100% (4 relapses). To date no secondary malignancies were observed.

Conclusions
Sequential treatment alternating standard R-CHOP and R-FM followed by ASCT results in impressive long term PFS and OS rates, both in first line and at relapse. These data represent the proof of principle of a sequential therapy containing alternating alkylating agents and purine analogs followed by ASCT in FL.

Disclosures:
No relevant conflicts of interest to declare.