bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Prospective, Randomized, Chemoprevention Trial of Celecoxib for High Risk Monoclonal Gammopathy of Undetermined Significance and Asymptomatic Multiple Myeloma
Authors: Horwitz Leonard J. , Faiman Beth , Elson Paul , Baz Rachid , Hussein Mohamad , Lust John A , Mehta Paulette , Reu Frederic J. , Habecker Becky , Reed Janice , Karam Mary Ann , Dean Robert M , Sobecks Ronald , Hsi Eric D. , Kaushal Varsha , Kalaycio Matt 
Published: October 2019

Abstract
Abstract 5045
Observation remains the standard approach to patients with monoclonal gammopathy of undetermined significance (MGUS) and asymptomatic multiple myeloma (AMM) who lack end-organ impairment characteristic of symptomatic MM. Institution of early MM therapy has not been shown to improve survival or alter the natural progression of the disease. Cyclooxygenase-2 (COX2) inhibitors inhibit proliferation and induce apoptosis in drug resistant MM cell lines. 23 asymptomatic adult patients with a serum monoclonal protein >1g/dL, from Cleveland Clinic, Mayo Clinic, or University of Arkansas Medical Center between August 2005 and April 2008 were randomized to either celecoxib or placebo in a double-blind, 1:1 fashion. The primary end point was change in the monoclonal protein concentration after 6 months. Correlative biomarkers, including IL6 and IL-6R, CD4/CD8+ T-cell ratios, and beta-2 microglobulin, were examined before and after treatment. Celecoxib had no significant effect on the median monoclonal protein concentration, which went from a median of 1. 44 to 1. 65 g/dL with placebo and 2. 42 to 2. 24 g/dL with Celecoxib (p=0. 36), or on any of the analyzed correlative markers (all p-values >0. 34). One patient's monoclonal protein concentration increased on placebo, but he did not require treatment for symptomatic MM. There were no adverse events of Grade 2 or higher. Celecoxib was well tolerated in contrast to previous reports when given in higher doses and in combination with thalidomide. Although accrual was limited we conclude that celecoxib has no clinical or immunologic effect on high risk asymptomatic plasma cell disorders. This study does not support using celecoxib for preventing progression to symptomatic MM. Future studies on progression of MGUS to symptomatic MM would require more patients and a longer follow-up period.

Disclosures:
Off Label Use: Celecoxib for chemoprophylaxis. Hussein:Celgene: Employment. Reu:Celgene: Research Funding.
Combination Therapy Based on Bortezomib for Newly Diagnosed Multiple Myeloma Patients
Authors: He Jingsong , Yang Li , Jin Dian , Lin Xuanru , Yang Qianqian , Han Xiaoyan , Zheng Gaofeng , Zheng Weiyan , Wei Guoqing , Wu Wenjun , Ye Xiujin , Shi Jimin , Xie Wanzhuo , Zhang Jie , Lin Maofang , Huang He , Cai Zhen 
Published: October 2019

Abstract
Abstract 5048

Introduction:
Novel drugs, such as bortezomib, have significantly improved the response rates in multiple myeloma (MM), but little has been reported on bortezomib-based therapies in Chinese patients.

Methods:
In the initial eight 28-day cycles, newly diagnosed ymptomatic patients were treated with combination therapy including bortezomib plus dexamethasone (PD) and the triplet combinations of PD with adriamycin (PAD), cyclophosphamide (PCD), thalidomide (PDT) between February 1, 2006 and May 31, 2012. Among the above regimens, bortezomib (1. 3 mg/m2) was given intravenously on days 1, 4, 8, 11, while dexamethasone (20 mg/m2/day) was given intravenously on days 1–2, 4–5, 8–9, 11–12, adriamycin (10 mg/m2) was given intravenously on days 1–4, cyclophosphamide (200 mg/m2) was given intravenously on days 1–4 and thalidomide (100 mg) was administered orally each day.

Results:
The overall response rate (¡Ý partial response, PR) of all the 151 eligible patients was 88. 7% (including 29. 8% very good partial response (VGPR) and 25. 8% complete response/near complete response (CR/nCR). The responses per IMWG criteria for patients are shown in Table 2. The median PFS was 20. 3 months (95% CI: 14. 8–25. 8 months) in the patients who received PDT, 24. 8 months (95% CI: 20. 0–30. 0 months) in the patients who received PCD, 22. 9 months (95% CI: 17. 6–28. 2 months) in patients who received PAD and 21. 8 months (95% CI: 15. 3–28. 3 months) in the patients who received PD with no significant differences between the groups. The median OS for PD arm was 42. 0(95% CI: 20. 1–63. 9 months) months while other arms were not reached, but the median OS for PDT, PCD and PAD was significant longer than PD (P=0. 042, 0. 039, 0. 010). PFS and OS for patients with favorable cytogenetics were significantly longer than those with unfavorable cytogenetics by FISH. The frequently observed hematologic toxicities (Grade 3/4) were: thrombocytopenia (17. 00%), neutropenia (15. 00%) and anemia (8. 61%). The most common non-hematologic toxicities included (all Grades) peripheral neuropathy(57. 61%), fatigue(27. 15%), infection(23. 84%), constipation(22. 52%), herpes zoster(17. 22%) and diarrhea(15. 23%).

Conclusions:
Our experience indicated that bortezomib-based regimens were active and well-tolerated for MM patients, and triplet combinations were superior to PD. Serious Adverse events were rare in the Chinese patients with MM who received bortezomib-based chemotherapy.

Disclosures:
No relevant conflicts of interest to declare.
Role of the Somatic Mutation Rate in Patients with Classical Myeloproliferative Neoplasms (MPN) with and without Other Neoplasms
Authors: Berardi Margherita , Rondelli Tommaso , Susini Maria Chiara , Pellecchia Annamaria , Antonioli Elisabetta , Boni Luca , Luzzatto Lucio , Vannucchi Alessandro M. , Notaro Rosario 
Published: October 2019

Abstract
Abstract 5055
Classical chronic myeloproliferative neoplasms (MPNs) are amongst the best-characterized neoplasms associated with one of a set of specific somatic mutations, the most common of which is in the JAK2 gene. MPN is a relatively rare condition, and it could be surmised that it develops preferentially in people who have an increased tendency to somatic mutations, i. e. an increased somatic mutation rate (μ). Since measuring μ is rather labor-intensive, in this study we have measured instead the frequency of peripheral blood granulocytes that have inactivating mutations in a reporter gene, namely the gene PIG-A, a gene whose protein product is required for numerous glycosyl-phosphatidylinositol-anchored proteins to become surface bound. Since several such proteins are displayed by normal granulocytes, mutant cells can be numbered accurately by flow cytometry; and the frequency (ƒ) of such mutant cells may be a good surrogate of μ (Peruzzi et al. Mutation Research. 2010, 705:3).
We have determined ƒ in 74 patients with MPN (including 29 with polycythemia vera (PV), 17 with essential thrombocythemia (ET), 16 with primary myelofibrosis (PMF) 12 with post-PV/post-ET (PPV/PET) MF. Overall the proportion of those with a JAK2(V617F) mutation was 90%. In a subset of 59 of these patients, who had “uncomplicated” MPNs, the median of ƒ was no different compared to 142 healthy controls (4. 74×10−6vs. 4. 87×10−6: Figure 1). However, in a subset of 15, consisting of patients who in addition to MPN had at least one primary malignancy (2 had lymphomas and 13 had one of several types of solid tumors), the median value of ƒ was 15. 22×10−6, i. e. significantly elevated (Mann Whitney test: MPNs vs. MPNs with a second neoplasm, p<0. 013; Healthy controls vs. MPNs with a second neoplasm, p<0. 005: Figure 1).

Clearly we cannot automatically extrapolate from our reporter gene, PIG-A, to the actual probability that another gene undergoes somatic mutation; besides, the rate of mutation of JAK2 is influenced by the local genomic context. With that proviso, our data suggest that JAK2 mutations are unlikely to result from an overall increased mutation rate. In keeping with this notion, we found no correlation between the value of ƒ and the allelic burden of JAK2(V617F) (R2= 0. 001): i. e., there is no evidence for genetic instability in MPNs (although, once there is a JAK2 mutation, this may produce a mutator phenotype). On the other hand, an intrinsically increased mutation rate does play a significant role in subjects with multiple neoplasms. This is not surprising: but, to the best of our knowledge, for patients who did not otherwise appear to be ‘cancer-prone’, direct evidence for this is provided here for the first time.

Disclosures:
No relevant conflicts of interest to declare.
Interleukin-15 Levels in Patients with Essential Thrombocythemia
Authors: Cacciola Emma , Francesco Ernesto Di , Cipolla Antonino , Ferlito Carmen , Pezzella Francesca , Seria Elisa , Cacciola Rossella Rosari 
Published: October 2019

Abstract
Abstract 5071
The essential thrombocythemia (ET) is a myeloid neoplasm characterized by a inflammatory component responsible for myeloproliferation and hypercoagulability. It has been showed that interleukin-15 (IL-15) affects myelopoiesis and coagulation. Therefore, we evaluated platelets, hematocrit (HCT), as myeloproliferative indicator, tissue factor (TF), as marker of coagulative activation and IL-15. We recruited 25 patients with ET (10 males and 15 females, mean age 58 years) who fulfilled WHO criteria. Their mean duration of disease was 8 years (range, 5–21 years). All patients were on aspirin. None of the patients had thrombotic risk factors. Platelets and HCT were measured by automated analyser. IL-15 and TF were measured by ELISA. All patients had thrombocytosis (961±235×109/L), high HCT (42±4 vs 37±1 %) (p<. 0001), increased TF (214±266 pg/ml vs 5±3 pg/ml) (p<. 0001) and elevated IL-15 (21±8 pg/ml vs 2±1 pg/ml) (p<. 0001). A correlation there was between IL-15 and HCT (p=0. 076) and a strong correlation was found between IL-15 and TF (p=0. 046). These results suggest a novel relationship between IL-15 and myeloproliferation and thrombosis that might mean worse prognosis.

Disclosures:
No relevant conflicts of interest to declare.
Long-term Use of Anagrelid in Essential Thrombocythemia Treatment of a Child Under 12 Months
Authors: Laguna Pawel , Klukowska Anna , Pawelec Katarzyna , Matysiak Michal 
Published: October 2019

Abstract
Abstract 5072
Essential thrombocythemia (ET) is currently classified as a chronic myeloproliferative disorder. Anagrelide is a novel platelet lowering agent that has recently been approved for use n ET.
We present the case of ET in an 8 –month- old girl, who was treated with Anagrelid for 13 months.
The girl was admitted to hospital because of elevated platelet count. She had stomach pains periodically. On admission the child's condition was good but on palpation her stomach was sore and her spleen was enlarged. Laboratory investigations showed an elevated platelet count (1. 5m) and hypercalemia (6. 3mEq/l). Thrombopoetin was normal.
Acesan was added to the treatment. A morphology performed after 1 month revealed further elevation of platelets (up to 2. 65m). On the basis of laboratory investigations, bone-marrow biopsy and trepanobiopsy, we eliminated an oncological disease and infectious diseases of connective tissues.
On bone-marrow investigation, acquired mutation of JAK2 (V617F) tyrosine kinase was diagnosed, which confirmed ET.
On account of the growing number of platelets, which was life - threatening, we decided to administer anagrelid, starting with a dose of 0. 25 mg per day. The number of platelets decreased to 1. 4m, so the dose was increased to 0. 25 mg twice daily after 3 weeks.
At present, after 37 months of anagrelide treatment, the number of platelets in the child ranges between 400 and 650.
The patient visits our, department for monthly check-up (morphology, biochemical tests, ECG and echocardiography).
In international literature there is no information on the use of Anagrelid in ET treatment of children under 12 months old. However, on the basis of our observations and initial results of treatment, it seems that the above protocol for Anagrelid administration is safe for infants of this age.

Disclosures:
No relevant conflicts of interest to declare.
Association of Renal Cell Carcinoma and B-Cell Hematological Malignancy
Authors: Chintapatla Rangaswamy , Varella Leticia , Wiernik Peter , Rusciano Valerie , Dutcher Janice P. 
Published: October 2019

Abstract
Abstract 5086

Purpose of the study:
We observed an increased frequency of hematologic malignancy (HM) in patients and family members of patients with renal cell cancer (RCC) and sought to characterize the association further in terms of frequency and characteristics of HM, and the importance of such an association.

Methods:
We performed a chart review of our data base of approximately 700 RCC patients seen by us from 2004 to the present in an effort to determine the frequency of HM in patients and in the families of patients diagnosed with RCC.

Results:
Of the 700 charts reviewed, both HM and RCC occurred in 19 individuals. [11 males and 8 females]. HM diagnosis included acute myeloid leukemia in 1 patient, Hodgkin's lymphoma (HL) in 4 pts, non-Hodgkin lymphoma (NHL) in 7 pts, (3 small cell and 4 large B-cell lymphoma), chronic lymphocytic leukemia (CLL) in 2 pts and hairy cell leukemia (HCL), monoclonal gammopathy of undetermined significance (MGUS) myelodysplasia (MDS) in one patient each. A family history of HM was found in 71 relatives involving 56 families of patients with RCC. Of these, 48/71 cases of HM were in first degree relatives and 18/71 were in second degree relatives. The most common HMs were lymphoma and leukemia: 24 NHL, 9 HL, 6 lymphoma not further specified (NOS), 11 CLL, 1 acute myeloid leukemia, 5 acute leukemia NOS and 6 leukemia NOS. Other HM observed once were multiple myeloma, Waldenström's macroglobulinemia, chronic myeloid leukemia, myelofibrosis and polycythemia vera. In addition, 2 family members had blood cancers that were NOS. Thus, of 77 patients/family members with known HM diagnosis 94% were B-cell malignancies. Clear cell histology was the most common subtype of RCC, and all subtypes of RCC occurred in the study population with expected frequency. RCC and HM occurred in the same patient in this study more frequently at 2. 7% than would be expected from a SEER database. In that database the observed to expected (O/E) ratio of NHL and RCC was 1. 86 to 2. 07% [Kunthur et al. Am J Hematol 2006; 81:271–80].

Conclusions:
Increased incidence of B-cell malignancy has been reported in individuals with RCC [Dutcher et al. Proc Am Fed Clin Res, Eastern Division, April 2011]. Wiernik et al. [Cancer J 2000] reported a similar increase was noted between adenocarcinoma of the breast and B cell malignancies in same individual and mouse mammary tumor virus was proposed a potential causative agent. There is a preponderance of B-cell malignancy in both the individuals and in the families of the patients with RCC noted in this study. The etiology of this association between RCC and HM is unclear and suggests a common etiopathogenesis for RCC and B-cell tumors, or a familial immunologic defect that facilitates both malignancies. We plan to further explore the relationship of HM to RCC.

Disclosures:
No relevant conflicts of interest to declare.
A Mendelian Predisposition to B Cell Lymphoma Caused by IL-10R2 Deficiency
Authors: Neven Benedicte , Mamessier Emilie , Bruneau Julie , Kaltenbach Sophie , Suarez Felipe , Doz Francois , Orbach Daniel , Minard Veronique , Frange Pierre , Canioni Danielle , Radford-Weiss Isabelle , Asnafi Vahid , Casanova jean-Laurent , Blanche Stephane , Picard Capucine , Rieux-Laucat Frederic , Davi Frederic , Brousse Nicole , Nadel Bertrand , Ruemmele Frank , Fischer Alain 
Published: October 2019

Abstract
Abstract 5092

Background
The fact that monogenic interleukin (IL)-10 and IL-10 receptor deficiencies cause very early-onset, severe inflammatory bowel disease demonstrates the IL-10 pathway's crucial role in preventing microbiota-driven gut inflammation. However, no other severe complications of IL-10/IL-10R deficiencies have been reported to date.

Methods
A cohort of six patients with IL-10/IL-10R deficiency was retrospectively surveyed for phenotypic expression. The identification of a number of cases of lymphoma prompted an in-depth characterization of available biopsy material, with immunohistochemical staining, cytogenetic studies and gene expression profiling.

Results
Four patients (all with a complete IL-10R2 deficiency) had developed B cell non-Hodgkin's lymphoma between the ages of 5 and 6 years. Cytogenetic and IgH clonality analyses suggested that one of the patients developed at least 3 distinct lymphomas. The patients' tumors had the characteristics of diffuse large B cell lymphomas and contained monoclonal, Epstein-Barr-virus-negative germinal center B cells. Nuclear expression of the NF-κB factor c-REL was detected in all of the six lymphomas tested.

Conclusions
IL-10R deficiency is associated with a high risk of developing a B cell lymphoma with an unusual phenotype. Our results highlight an unexpected role of the IL-10R pathway in the control of lymphomagenesis.

Disclosures:
No relevant conflicts of interest to declare.
The Mir-17∼92 Cluster Activates mTORC1 Signaling in MCL by Targeting Multiple Regulators of the LKB1/AMPK/mTOR Pathway
Authors: Bi Chengfeng , Jiang Chunsun , Jiang Xiaoxing , Huang Xin , Fernandez Mario R , Iqbal Javeed , Lewis Robert E , Chan Wing Chung , McKeithan Timothy , Fu Kai 
Published: October 2019

Abstract
Abstract 5118
Mantle cell lymphoma (MCL) is an aggressive hematological malignancy with a median survival ranging between 3 and 5 years. Novel therapeutic strategies are urgently needed to improve the outcome. Mammalian target of rapamycin (mTOR) pathway which plays a central role in controlling cell growth, proliferation and metabolism has been shown to be deregulated in MCL. mTOR inhibitors, such as rapamycin and its analogues, have been approved for treatment of relapsed/refractory MCL. However, the molecular mechanism of mTOR activation in MCL has yet to be defined. MiRNA (miR)-17∼92 is a cluster of six miRNAs which are frequently overexpressed in MCL cases and overexpression of the miR-17∼92 cluster in MCL predicts poor prognosis. Our previous study demonstrated that miR-17∼92 activated the PI3K/AKT pathway by directly targeting PTEN and PHLPP2; and knock-down of miR-17∼92 expression inhibited MCL tumor growth in a xenograft/SCID MCL mouse model. In the present study, we further demonstrated that knock-down miR-17∼92 decreased the cell size, similar effect as seen in cells treated with mTORC1 inhibitors. Knockdown of miR-17∼92 expression also decreased the glycolysis, protein synthesis and glucose uptake in MCL cells. We found that knockdown miR-17∼92 activated AMPK signaling as demonstrated by increased phosphorylation of AMPK at Thr172, especially under low glucose condition. Activated AMPK further phosphorylated TSC2 and Raptor at S1387 and S792, respectively, thereby inhibiting mTORC1 signaling as evidenced by decreased phosphorylation of RPS6 and 4E-BP1. Using TargetScan and other prediction algorithms, we found that several factors in the LKB1/AMPK/mTOR pathway, such as LKB1, CAB39, PRKAA1 and TSC1, are predicted the targets of miR-17∼92. In this study, we validated these factors as direct targets of the miR-17∼92 by 3'UTR luciferase assays using reporter plasmids containing the 3'UTR of the targets or the 3'UTR with mutations in the predicted miRNA binding sites. The protein levels of these targets decreased in MCL cells with the miR-17∼92 overexpression. Conversely, the levels of these factors were increased upon knockdown of miR-17∼92 cluster. Our results indicate that overexpression of miR-17∼92 in MCL plays important role in mTORC1 activation by inactivating the LKB1/AMPK signaling, in addition to its effect on the PI3K/AKT pathway activation.

Disclosures:
No relevant conflicts of interest to declare.
Calmodulin Inhibition Rescues the Effects of Ribosomal Protein Deficiency by Modulating p53 Activity in Models of Diamond Blackfan Anemia
Authors: Taylor Alison M. , Raiser David M. , Humphries Jessica M. , Ebert Benjamin L. , Zon Leonard I. 
Published: October 2019

Abstract
Abstract 512
Ribosomal protein mutations are common in patients with Diamond Blackfan anemia (DBA), who have red cell aplasia and craniofacial abnormalities, and rps14 deficiency has been linked to 5q- myelodysplastic syndrome. We have characterized a zebrafish mutant in rps29, a ribosomal protein in the small subunit. Rps29−/− embryos have hematopoietic and endothelial defects, including decreased hematopoietic stem cells, defects in hemoglobinization, and decreased staining of vessel markers. Heads of mutant embryos are also morphologically affected, with increased apoptosis. Consistent with other models of DBA, knockdown of p53 completely rescues the rps29 hematopoietic and apoptotic phenotypes. We wanted to identify chemicals that could rescue the rps29 mutant phenotype. Using 600 compounds from known bioactive libraries, we performed an in vivo chemical screen for rescue of the rps29 apoptotic and endothelial defects. Treatment with one compound, A-3, improved the morphology of the apoptotic embryo head. A-3 is an inhibitor of calmodulin, which interacts with a host of calmodulin-dependent enzymes and can bind to other proteins in the cell, including p21. W-7, another calmodulin inhibitor related to A-3, can rescue the endothelial defect in the rps29 mutant. Calmodulin inhibition in rps29 mutant embryos rescues the hemoglobin defect. Furthermore, structurally unrelated chemicals that inhibit calmodulin rescue the endothelial defect. We hypothesized that calmodulin inhibition was affecting some part of the p53 pathway. We tested whether A-3 had an effect on the phenotype in vitro in a cancer cell line where shRNA knockdown of RPS19 has been shown to stabilize p53 and induce p21. When rps19 is knocked down in A549 cells, treatment with calmodulin inhibitors resulted in a decrease of p21 protein, as measured by flow cytometry, although p53 protein levels were stable. This effect was also observed in primary human cord blood-derived CD34+ hematopoietic stem and progenitor cells. In situ immunofluorescence in A549s further revealed that nuclear localization of p53 and p21 upon RPS19 knockdown was disrupted by chemical treatment. Calmodulin inhibitors also rescue ribosomal protein deficiency-mediated erythroid defects both in vitro and in vivo. When RPS19 is knocked down in CD34+ cells, there is a defect in erythroid differentiation. Treatment with calmodulin inhibitors rescued production of CD71+ cells upon differentiation. In conclusion, we have demonstrated the use of calmodulin inhibitors as a novel approach for mediating p53 activation upon ribosomal protein knockdown, thereby rescuing the erythroid defects of ribosomal deficiency. Our data suggests that small molecules that inhibit calmodulin may be effective therapies for patients with ribosomal deficiency.

Disclosures:
Ebert: Celgene: Consultancy; Genoptix: Consultancy. Zon:Fate Therapeutics: Founder Other.