bluuebunny/crossref_metadata_2025_split huggingface dataset:
Carfilzomib Exerts Anti-Neoplastic Activity in Waldenstrom Macroglobulinemia.
Authors: Sacco Antonio , Roccaro Aldo M. , Aujay Monette , Ngo Hai , Azab Feda , Azab Abdel Kareem , Melhem Molly R , Runnels Judith M. , Quang Phong , Demo Susan , Ghobrial Irene 
Published: October 2019

Abstract
Abstract 4916

Introduction
Proteasome inhibition represents a valid therapeutical approach in several tumors and its use has been validated in Waldenstrom's macroglobulinemia (WM), where single-agent Bortezomib has been successfully tested in phase 2 clinical trials. Nevertheless, a significant fraction of patients relapse, or develop significant toxicity due to high toxicity in non-transformed cells. Therefore preclinical evaluation of new proteasome inhibitor with a more selective inhibition of neoplastic cells is needed in order to increase efficacy and improve patient outcome. We tested Carfilzomib, a tetrapeptide epoxyketone selective inhibitor of the chymotrypsin-like activity of the immunoproteasome and constitutive proteasome in WM.

Methods
WM and IgM secreting low-grade lymphoma cell lines (BCWM.1, MEC1, RL) were used. Expression of imunoproteasome and constitutive proteasome subunits (beta1, beta2, beta5; LMP2, MECL1, LMP7) were detected primary WM cells and cell lines by an ELISA-based assay. Cytotoxicity and DNA synthesis were measured by thymidine uptake and MTT, respectively. Cell signaling and apoptotic pathways were determined by Western Blot. Determination of the additive or synergistic effect of drugs combination was calculated using the CalcuSyn software based on the Chou-Talalay method.

Results
Primary CD19 bone-marrow derived WM cells express higher level of the immunopreoteasome as compared to the constitutive proteasome. Carfilzomib inhibited the chymotrypsin-like activity of both the immunoproteasome (LMP7) and the constitutive proteasome (beta5) and in WM cells, in a dose-dependent manner; leading to inhibition of proliferation (IC50: 5nM; 48h) and induction of cytotoxicity (IC50: 7.5nM; 48h) in WM cells. Carfilzomib mediated apoptosis in WM by increasing PARP-, caspase-9- and -3-cleavage; as well as by inducing activation of c-jun-N-terminal kinase and ER-stress in a dose-dependent manner. Moreover, combination of Carfilzomib and bortezomib induced synergistic cytotoxicity in WM cells, as shown by enhanced PARP-, caspase-9- and -3-cleavage; and synergy in inhibiting the chymotrypsin-like activity of the immunoproteasome and constitutive proteasome.

Conclusion
Taken together, these findings provide the pre-clinical rational for testing Carfilzomib in Waldenstrom Macroglobulinemia.

Disclosures
Aujay: Proteolix: Employment, Equity Ownership. Demo:Proteolix: Employment, Equity Ownership. Ghobrial:Millennium: Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau.
Continuous Infusion Cyclophosphamide as Salvage Therapy for Relapsed or Refractory Multiple Myeloma.
Authors: Malhotra Binu , Porter David L , Stadtmauer Edward A. , Schuster Stephen J. , Vogl Dan T. 
Published: October 2019

Abstract
Abstract 4942

Background
Patients with relapsed or refractory multiple myeloma (MM) are resistant to most therapies. In this study, we assess the efficacy and tolerability of continuous infusion (CI) cyclophosphamide in a group of heavily pre-treated patients with relapsed/refractory MM.

Methods
Charts of all patients treated with CI cyclophosphamide for relapsed/refractory MM between 01/2003 and 12/2008, at the Hospital of University of Pennsylvania, were identified and reviewed. Patients who had received at least one cycle of CI cyclophosphamide were included for the analysis. The dose of cyclophosphamide ranged between 200-300 mg/m2/day CI for 4 days. Duration of each cycle was planned at 28 days. Response was assessed using the international uniform response criteria for MM. Toxicity was assessed using the National Cancer Institute Common Toxicity Criteria, version 4.

Results
We treated 24 patients with CI cyclophosphamide. The median age was 60.5 years (range 33-75 years) and 66% were male. Patients had received a median of 5 prior regimens (range 2.0 to 11.0) and the median duration of time from diagnosis to treatment with CI cyclophosphamide was 5 yrs (range 0.38-22 yrs). Cyclophosphamide was started in 19 patients for management of progressive disease, and in 5 patients for lack of response or adverse effects from prior therapies. Prior therapies included: bortezomib (in all patients), lenalidomide (in 96% of patients) and autologous stem cell transplant (ASCT - once in 46%, and twice in 29%) among others. The median number of cyclophosphamide cycles administered until the time of last follow up was 4.0 (range 1.0-43.0). Treatment was ongoing in 4 patients at the time of last follow up, and two patients with stable disease were being observed without therapy. Median overall survival for all patients was 22.3 months (95% CI 10.04-34.53) and median progression free survival (PFS) was 7.4 months (95%CI 4.12-10.69). Partial response was noted in 4 patients, who had a median duration of response of 4.2 months and median time to best response of 0.8 month. Disease was stabilized in 14 additional patients. Disease progressed despite therapy in 6 patients, and in 4 of those progressive disease was evident from cycle one. Cytopenias were noted in 8 patients, with 4 related to the treatment with cyclophosphamide, but in only one case did this lead to discontinuation of therapy.

Conclusion
In our experience with 24 patients, monthly cycles of continuous infusion cyclophosphamide was a safe and effective method of treating relapsed or refractory multiple myeloma resulting in a prolonged progression free survival in very heavily pretreated patients.

Disclosures
No relevant conflicts of interest to declare.
Malignant Lymphoma in Primary Sjögren Syndrome: Incidence and Risk Factors.
Authors: López Andrés , Solans-Laque Roser , Bosch-Gil Josep A , Gironella Mercedes , Purroy Noelia , Marta Campillo , Vallespi Teresa 
Published: October 2019

Abstract
Abstract 4991

Background
Primary Sjögren Symdrome (PSS) is the second common systemic autoimmune rheumatic disease whose main histological feature is a focal infiltration of the exocrine glands by activated B and T lymphocytes. PSS is considered a benign autoimmune condition with a chronic indolent course. However, several reports have noted an increased incidence of malignant lymphoma with an estimated risk of up to 44 times greater than in the normal population. The aims of the present study are to assess the cumulative incidence of lymphoma in patients diagnosed of PSS, as well as to identify risk factors for developing this condition.

Methods
All patients diagnosed since 1988 and followed-up for longer than 2 years at our institution, were included. The pathological, immunological, and clinical features of each case of PSS were retrospectively examined. These data were cross-examined with the cumulative incidence of lymphoma in this group of patients, in order to determine common findings in patients later developing lymphoid malignancies.

Results
272 patients had been diagnosed as having a PSS in this time period, of which 244 [9 males, 235 females; median age 58 years (range 17 to 88)] had been followed for more than 2 years. After a median follow up of 9.6 years, 11 (4.5%) patients developed a lymphoma, after 6 to 171 months from diagnosis. The cumulative risk for developing lymphoma at 5, 10 and 15 years was 3.4, 4.1, and 9.3%, respectively. Risk factors associated with the development of lymphoma were skin purpura/vasculitis, lymphopenia and low levels of C3 and C4 complement fractions. Low levels of C3 and C4 were also found to be associated with an earlier development of lymphoma. Conversely, skin purpura/vasculitis and lymphopenia were both associated with the development of lymphoma at a later stage. The hystological analysis showed mucosal-associated lymphoid tissue lymphoma in 5 patients, diffuse large B cell in 3, and follicular lymphoma in 3 cases. Clinically, lymphomas had extranodal presentation in 8 out of the 11 cases, involving the salivary glands in 5, lacrimal glands in 1, and soft tissues and lung in 1 case, respectively. Only 3 patients had received immunosuppressive therapy prior to the diagnosis of lymphoma, and EBV was not found in the histological examination of any of these cases.

Conclusion
Patients with PSS are at a higher risk for developing lymphoma. Our study suggests low levels of C3 or C4, as well as the presence of purpura or lymphopenia delimitates a group of patients at a higher risk, so that such patients may benefit from a closer follow up.

Disclosures
No relevant conflicts of interest to declare.
Primary Mediastinal Large B-Cell Lymphoma: A Single Center Experience in Korea.
Authors: Ahn Heui June , Cho Yoo Jin , Kang Myoung Joo , Choi Dae Ro , Kim Shin , Lee Dae Ho , Kim Sang We , Lee Jung Shin , Huh Jooryung , Suh Cheolwon 
Published: October 2019

Abstract
Abstract 5013

Introduction
Primary mediastinal large B-cell lymphoma (PMBCL) was formally established as a distinct subtype of diffuse large B-cell lymphoma (DLBCL). Some studies indicated that patients with PMBCL have an aggressive clinical course with short median survival but more recent studies reported a relatively good response rate and survival. Therefore, controversies still exist regarding the response to therapy and prognosis of patients with PMBCL.

Patients and methods
Between July 1993 and July 2008, a total of 26 patients with PMBCL were identified at Asan Medical Center, Seoul Korea. We retrospectively reviewed the clinic-pathologic features and clinical outcomes of them in comparison with 597 patients diagnosed with non-mediastinal DLBCL during the same period.

Result
Out of the 26 patients, 17 (65.4%) were females and 9 (34.6%) males, while out of the 597 patients, 257 (43.0%) were females and 340 (57.0%) males (p=0.025). The median age of the PMBCL patients was 31.5 years old (range 15-78 years old), while that of the DLBCL patients was 56.0 years old (range 15-85 years old). Out of the 26 patients, 14 (53.8%) had a Ann Arbor stage III or IV disease, 7 (26.9%) had B symptoms, and by the IPI, 11 were in low, 9 in low intermediate, 2 in high-intermediate and 4 in high risk group. Out of 24 patients treated with front-line therapy CHOP or R-CHOP, 17 (70.8%) reached a CR, while 1 PR patient reached a CR after being treated with high-dose chemotherapy followed by autologous stem cell transplantation. Five refractory patients were treated with high-dose chemotherapy followed by autologous stem cell transplantation, but among them only one reached a CR and 4 died of disease progression. With a median follow-up of 41.5 months (range 1-92 months), 5-year survival rates of PMBCL and non-mediastinal DLBCL patients were 69% and 65.7%, respectively (p=0.982, Log Rank).

Conclusion
There was no difference between PMLBL and non-mediastinal DLBCL in terms of clinical features and outcomes.

Disclosures
No relevant conflicts of interest to declare.
Is Skull-Base to Proximal Thigh PET/CT Enough? Do We Need Vertex to Toe PET/CT Imaging for Cutaneous T-Cell Lymphoma (CTCL) Patients?.
Authors: Woodward Catherine S , King Nassoma , Prince Kenneth , Parker Sareeta , Halkar Raghuveer , Lechowicz Mary Jo 
Published: October 2019

Abstract
Abstract 5020

INTRODUCTION
Positron emission tomography (PET) imaging using [F-18] fluorodeoxyglucose (FDG) provides metabolic information valuable to staging and restaging lymphoma patients. The Society of Nuclear Medicine recommends skull-base to proximal thigh imaging to survey the body and recommends vertex to toe PET/CT when the tumor may be in the extremities, e.g. melanoma (Delbeke 2006). As CTCL may develop in any region of the body, we aimed to assess the usefulness of vertex to toe PET/CT images in evaluating CTCL patients.

METHODS
We retrospectively analyzed 79 PET/CT scans from 33 CTCL patients (15 men, 18 women, age range: 7-83, median: 56) who were imaged between 2004 and 2008. All studies were performed on GE Discovery LS 8 slice MDCT PET/CT scanner or GE Discovery DST 16 slice MDCT PET/CT scanner (Milwaukee, WI) and the images were interpreted on a GE AW or Xeleris workstation by four board certified nuclear medicine physicians.

RESULTS
The length distribution of the 79 scans is detailed in Figure 1. The 79 scans showed an average maximum SUV of 8.6 +/- 5.2 (range: 2.3 – 21.7). Of the 79 scans, 15 scans showed only cutaneous involvement; 25 scans showed lymph node involvement (as defined by radiologic criteria of lymph node > 1.5 cm, and SUV > 2.5); 10 scans showed likely benign, non-specific uptake in the lymph nodes; 8 scans showed hypermetabolic lymphadenopathy (as defined by SUV> 2.5, lymph node measurement <1.5 cm); 4 scans suggested organ involvement; and 18 scans showed no FDG uptake suggestive of malignancy, usually representing post-treatment patients. 71% of patients with elongated scans (17 of 24 patients) had FDG uptake suggestive of malignancy in areas of the body that would not have been imaged following the standard of skull-base to mid-thigh procedure. For 14 of these 17 patients, the elongated scans demonstrated systemic involvement which did not affect disease management, due to widespread uptake. However, in 3 patients, focal cutaneous uptake noted in the upper or lower extremities played a critical role in staging as there was no FDG uptake suggestive of malignancy in the skull-base to mid-thigh region. These results are demonstrated in Figure 2.

CONCLUSION
3 patients (13% of patients with at least one elongated scan) had FDG uptake only in the extremities. If these patients had been imaged from skull-base to proximal thigh, no suspicious FDG uptake would have been noted, and treatment plan may have been altered. Further studies prospective PET studies are necessary to determine its role in the staging and management of CTCL.

Disclosures
No relevant conflicts of interest to declare.
Prognostic Factors in Aggressive, Non-Primary Cutaneous Peripheral T-Cell Lymphoma in Peru: A Study of 227 Cases.
Authors: Beltran Brady , Morales Domingo , Quinones Pilar , Desposorio Carlos , Sokol Lubomir , Castillo Jorge 
Published: October 2019

Abstract
Abstract 5021

Background
Peripheral T-cell lymphoma (PTCL) is a heterogeneous family of entities with a worse prognosis, stage by stage, than their B-cell counterparts. We have previously reported that Peruvian population has a higher incidence of PTCL, akin to the Asian population. The goal of this study is to therefore investigate the clinical characteristics and prognostic factors in patients with PTCL in a reference center in Peru.

Methods
A total of 227 cases of aggressive, non-primary cutaneous PTCL diagnosed between January 1997 and December 2008 were reviewed, reappraised according to their morphological, immunological and clinical characteristics, and reclassified according to the new WHO classification of lymphoid neoplasms. Kaplan-Meier method was used to estimate survival curves, which were compared using the log-rank test. The multivariate analysis was performed using the Cox proportional-hazard regression test.

Results
The mean age at diagnosis was 57 years (range 14 – 92 years) with a male-to-female ratio of 1:1. According to the new WHO classification of lymphoid neoplasms, 97 cases (43%) were classified as adult T-cell leukemia/lymphoma (ATLL), 84 cases (37%) as PTCL, unspecified (PTCLU), 28 cases (12%) as anaplastic large cell lymphoma (ALCL), 10 cases (4%) as extranodal NK/T lymphoma, nasal type, 4 cases (2%) as angioimmunoblastic lymphoma and 3 cases (1%) were diagnosed with more rare PTCL subtypes. Fifteen percent were stage I, 12% stage II, 16% stage III and 56% stage IV. Distribution based on the International Prognostic Index (IPI) score was: low 24%, low-intermediate 24.5%, intermediate-high 26% and high 25.5%. B symptoms were present in 64% of patients. The median overall survival (OS) for the whole group was 8.4 months, the 2-year OS was 34% and the 5-year OS was 27%. ATLL patients showed a median overall survival of 6.1 months, PTCL of 11.4 months, ALCL of 12.4 months and extranodal NK/T cell lymphoma of 7.8 months. The IPI score, the Prognostic Index for PTCLU (PIT) score and the presence of B symptoms showed statistical significance in both the univariate and the multivariate survival analysis (p=0.001, p=0.005 and p=0.005, respectively).

Conclusions
The distribution of PTCL subtypes in Peru is comparable to the series of patients reported in Asian countries. ATLL and PTCL-U are the most frequent aggressive, non-primary cutaneous PTCL subtypes found. PTCL tends to present with advanced stages and has a poor prognosis, with a 5-year OS of less than 30%. In the multivariate analysis, the IPI score, the PIT score and presence of B symptoms were independent prognostic factors for survival in PTCL.

Disclosures
No relevant conflicts of interest to declare.
Central Nervous System Involvement in Patients with Diffuse Large-B Cell Lymphoma: A Retrospective Analysis of a Single Center in Brazil.
Authors: Rocha Talita , Pinto Maeva , Fortier Sergio Costa , Campos Igor , Paes Roberto , Chiattone Carlos 
Published: October 2019

Abstract
Abstract 5029

Background
Relapse in the central nervous system (CNS) after initial treatment of diffuse large-B cell lymphoma (DLBCL) is an uncommon but serious complication. This retrospective study of a single institution in a Latin American country investigated the incidence of CNS involvement in patients with DLBCL and compared it with results in developed countries.

Patients and methods
A total of 134 patients treated for DLBCL from January 2001 to April 2008 were retrospectively analyzed for incidence of secondary CNS involvement of lymphoma.

Results
Twenty six (19,4 %) patients of this cohort had used rituximab as first line treatment and nine (6,7%) had done IT chemoprophylaxis. Seventy (52%) were stage III and IV. Forty seven (35%) had high intermediate or high international prognostic index. Nine of 134 (6,7%) developed CNS disease after a median observation of 36 months. The median time for the CNS relapse or progression was 7,7 months after diagnostic and all but one patient died despite the treatment proposed. Among the 9 patients that relapsed, seven (77,7 %) had parenquimal CNS involvement. Seven (77,7%) had stage III or IV disease. One (11,1 %) had bone marrow involvement. Two (22,2%) received IT chemoprophylaxis and 3 (33,3%) had used rituximab.

Discussion and Conclusion
We describe here our cases and emphasize that as we know, this is the only Brazilian study investigating this kind of involvement. Different than expected, we found a similar CNS infiltration compared to developed countries cohorts. This suggests that CNS disease is probably related to biologic features than circumstantial issues normally present in developing countries such as late diagnoses and treatment. The evaluation of the risk factors for CNS involvement had not been done due to the small cohort.

Disclosures
No relevant conflicts of interest to declare.
The Prohibitin 3′ Untranslated Region Polymorphisms Are Associated with AML Susceptibility.
Authors: Kim Hye-Ran , Shin Myung-Geun , Kweon Sun-Seog , Kim Hee-Nam , Kim Hyeoung-Joon , Lee Il-Kwon , Shin Jong-Hee , Suh Soon-Pal , Ryang Dong-Wook 
Published: October 2019

Abstract
Abstract 5038
The prohibitin gene, which is located on human chromosome 17q21 encodes a certain regulatory RNA molecule responsible for inhibitory effects and the respective tumor suppressor function. Common C/T and A/G polymorphisms occur at nucleotide 10701 and 10730 respectively in the 3' untranslated region (UTR) of the prohibitin gene. Recent findings indicate that presence of at least one mutant allele within the 3' UTR prohibitin gene polymorphism causes inactivation of bioactive RNA, resulting in loss of its pro-apoptotic function and subsequent risk for malignant growth. These observations led to the hypothesis that individual carrying the prohibitin T allele has increased susceptibility to acute myeloid leukemia (AML). To assess this, we carried out a case-control study of the prohibitin genotype in 381 patients with AML and 372 healthy controls. The distribution of genotypes for the prohibitin 3' UTR polymorphism in patients with AML (P=0.79) and controls (P = 0.10) were in Hardy–Weinberg equilibrium. The prohibitin 3'UTR 10701TT genotype was associated with an increased risk for AML (odds ratios (OR)=2.6; 95 percent confidence interval (CI)=1.90 to 6.19, P = 0.031). However, the prohibitin 3'UTR 10730 polymorphism was not related to AML susceptibility. Haplotype (10701T-10730A) increased risk (OR=2.11; CI=1.28-2.94) for AML. There was a significant difference in the frequency of T-allele carriers between the patients and controls (OR=1.34; CI=1.01-1.77; P=0.046). Interestingly, AML patients having 10730GG genotype had shorter overall survival rate than those with AA and AG genotypes. In conclusion, the prohibitin 3'UTR region genotyping is valuable in assessing risk of AML and estimating prognosis.

Disclosures
No relevant conflicts of interest to declare.
Effects of SHIP Over Expression On the Invasion and Migration of K562 Cells and Its Mechanism.
Authors: Yang Lin , Luo Jianmin , Liu Xiaojun , Wen Shupeng 
Published: October 2019

Abstract
Abstract 5051

Introduction
The phosphatidylinositol-3 kinase (PI3K) pathway plays a central role in regulating numerous biologic processes, including survival, adhesion, migration, metabolic activity, proliferation, differentiation, and end cell activation through the generation of the potent second messenger PI-3,4,5-trisphosphate (PI-3,4,5-P(3)). The SH2 domain-containing inositol polyphosphate 5-phosphatase (SHIP) is known to play an important role in the negative regulation by PI3K-dependent signaling cascades activated by several tyrosine-kinase coupled cytokine receptors. SHIP knockout mice display myeloproliferation and hyper-responsiveness to growth factor stimulation and have short life span with myeloid cell infiltration into vital organs. We have proved SHIP inhibits growth of leukemia cells, and it may have an important role in apoptosis of leukemia cells. However, to date the role of anti-migrated effect of SHIP and its mechanism is unclear.

Methods
Based on the results of our previous studies, with different human leukemia cell lines K562 as study samples, including K562 transfected with wtSHIP (Group A), K562 transfected with muSHIPC1076T (Group B) and K562 transfected with empty vector (Group C); Expression of SHIP at mRNA and protein level was detected by real-time PCR and Western blot, respectively; By Transwell chamber assay was used to count the numbers of Group A and Group B cells that penetrated the matrigel to the back of PVPF membrane after transfection; Primary migration associated factor FAK, p-FAK and NFκB were screened by Western blot. The expression of MMP-2 and MMP-9 was examined by zymography.

Results
Compared with Group C and Group B, the migration of Group A cells was decreased (32±6 vs 78±13 and 83±16)(P<0.01); Over expression of wild-type SHIP does not affect the MMP2 secretion in K562, but site-directed mutant in C terminus of SHIP can significantly block MMP-9 secretion in K562 cells, By Western blot analysis, the expression of p-FAK and NFκB protein in Group A cells were down-regulated to 44% and 63% of the Group C, respectively.

Conclusions
The results confirmed SHIP as a negative regulator for cell migration and invasion in bcr/abl transformed cells through decreasing the MMP-9 expression, which may be induced by reduced phopha-FAK and NFαB expression, and implied that it may function through its PXXP domain.

Disclosures
No relevant conflicts of interest to declare.