bluuebunny/crossref_metadata_2025_split huggingface dataset:
Autologous stem cell transplant in older patients with multiple myeloma (MM): Analysis of the nationwide inpatient sample (NIS).
Authors: Wildes Tanya Marya , Hellstrom Anita , Vij Ravi , Owens Pamela , Colditz Graham A. 
Published: March 2020

e18551 Background: Autologous stem cell transplant (ASCT) improves survival in MM patients <65 years and is applied to select patients ≥ age 65. We hypothesized that comorbidities (CM) are associated with increased length of stay (LOS), hospital charges, toxicity, and in-hospital mortality in older patients with MM undergoing ASCT. Methods: This is a retrospective cohort study of patients over the age of 65 with MM admitted to U.S. hospitals for ASCT in the 2008 NIS. CM were coded using the Comorbidity Software; toxicities were determined by ICD-9-CM codes. Relationships between CM and toxicities, LOS, hospital charges, and in-hospital mortality were analyzed. Results: 206 patients MM ≥ 65 years who underwent ASCT were identified. Median age was 68 years (range 65-82). As defined by Elixhauser (Medical Care 1998), 83.5% of patients had ≥ 1 CM. Median LOS was 17 days (range 1-152). Median total charges were $162,998 (range $4289-$953,789). The most common complications coded were: neutropenic fever (29.6%), diarrhea (28.6%), bacteremia (13.6%), mucositis (8.7%) and pneumonia (6.8%). In-hospital mortality was <5% (precise percentage cannot be reported due to cell size <10). Elixhauser CM did not predict LOS, total charges, in-hospital mortality, or toxicities. When CM were restricted to those in the Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI, Sorror et al 2005), only 35.4% of patients had CM. The presence of CM using a modified HCT-CI was associated with longer LOS (23.5 vs 17.6 days, p=0.0047) higher mean total charges [$189,896 (95% CI $154,333-225,459) vs $148,234 (95%CI $121,887-174,581), p=0.02] and increased risk of “complications of transplant” or “delirium” codes (p=0.035; precise percentage cannot be reported due to cell size <10). Conclusions: ASCT was well-tolerated with low in-hospital mortality in a population-based cohort of older patients with MM.The Elixhauser CM method did not predict outcomes. Using a modified HCT-CI CM index predicted longer LOS, greater hospital charges, and some toxicities, highlighting differences in the utility of different CM indices. Further investigation must define the optimal CM index for studying hematopoietic cell transplantation using administrative data.
Efficacy and safety of biosimilar epoetin alpha in treated patients with multiple myeloma.
Authors: Antolino Giusy , Moscetti Alessandro , Saltarelli Francesca , Monarca Bruno , Resci Federica , De Benedittis Daniela , Naso Virginia , Bianchi Maria Paola , La Verde Giacinto 
Published: March 2020

e18563 Background: The biologic drugs are pharmaceutical products derived from living organisms through biotechnology. For some of the biotech drugs patent coverage is now decayed. This has allowed other companies to produce, at lower costs, similar products called biosimilar pharmaceuticals. Among the first biosimilar products marketed there were two growth factors, epoetin alpha and filgrastim. Methods: We retrospectively analyzed 15 chemo-treated patients with Multiple Myeloma (MM) referred to UOS Diagnosi e Cura delle Discrasie Plasmacellulari e delle Amiloidosi of Sant’Andrea Hospital in Rome, who were treated with biosimilar epoetin alpha between November 2010 and November 2011. In particular, 6 males and 9 females (median age 70 years) had started therapy with subcutaneous biosimilar epoetin alpha 40,000 IU weekly for haemoglobin level below 10 g/dl. In these patients, we evaluated the Hb levels before treatment, after 4 weeks and, in those who continued therapy, after 8 weeks from the drug administration start. Results: In all cases there was a significant and steady increase of Hb values: we observed an increase of 1 g/dl after 4 weeks in 80% of patients. In 5 of 11 patients the data are not available at 8 weeks because it was observed a so quick increase in Hb values as to cause discontinuation of treatment; in 100% of the remaining patients we observed an increase ≥2 g/dl after 8 weeks. None of patients needed supportive therapy with red blood cells transfusion. Although the duration of treatment in our patients was limited, we did not observe any adverse event in the short and medium term by the administration. Conclusions: The results reported do not fall in a comparative study and our initial data are still limited, however in our analysis biosimilar epoetin alpha was effective in increasing Hb values in MM patients against lower costs. It should be emphasized that this growth factor has been used in overtreated patients with impaired bone marrow reserve. In our analysis biosimilar epoetin alpha has shown efficacy and safety data to suggest the possibility of their use in alternative to biotech generators.
Preclinical activity of the JAK1/2 inhibitor ruxolitinib on malignant plasma cell growth and survival.
Authors: Burger Renate , Bugdahn Tim , Staudinger Matthias , Peipp Matthias , Günther Andreas , Gramatzki Martin 
Published: March 2020

e18565 Background: In multiple myeloma, cytokines in the tumor environment, in particular interleukin-6 (IL-6), support the growth and survival of malignant plasma cells. Binding of IL-6 to its receptor leads to gp130 dimerization and activation of JAKs and STAT3. Ruxolitinib (INC424)is the first small molecule JAK inhibitor approved for the treatment of patients with myelofibrosis. The aim of our study was to evaluate the effects of ruxolitinib on malignant plasma cells. Methods: Cell growth was studied in seven myeloma cell lines including the IL-6 dependent INA-6. Ruxolitinib was tested at 0.0625 µmol/L to 8 µmol/L. Proliferation of plasma cell enriched patient samples was measured by [3]H-thymidine uptake, apoptosis by flow cytometry upon annexin V/7-AAD staining. Levels of STAT3 and ERK1/2 phosphorylation were determined by Westernblot analysis. IC50 concentrations and combination index were calculated with CalcuSyn. IL-6 levels were determined by ELISA. Results: A significant inhibition of plasma cell growth with ruxolitinib was achieved in IL-6 dependent INA-6 cells (IC50 0.22 µmol/L). Complete growth inhibition at 1 µmol/L was seen in the absence and presence of bone marrow stromal cells. Stromal cell viability and IL-6 production were not affected. The number of apoptotic INA-6 cells upon treatment with ruxolitinib at 1 µmol/L increased 3.6- and 7.2-fold (after 48 and 72 hours, respectively), consistent with the reduction of IL-6 induced STAT3 phosphorylation. A similar strong inhibitory activity of ruxolitinib (IC50 0.16 µmol/L) was observed in tumor cells of a patient with plasma cell leukemia proliferating in response to IL-6. In contrast, none of the myeloma cell lines that grow autonomously were sensitive, pointing to the kinase specificity of the drug. Using INA-6 as a model, combinations with other signaling inhibitors revealed additive to synergistic effects with PI3K, mToR and IGF-1R inhibitors. Conclusions: In multiple myeloma, ruxolitinib has a strong cytotoxic activity against malignant plasma cells that require IL-6 for growth and survival. This warrants further clinical testing but also points to the need of identifying molecular markers to predict benefit from JAK inhibitor treatment.
Epigenetic inactivation to target the arginine biosynthetic pathway in multiple myeloma.
Authors: Hatzimichael Eleftheria , Dasoula Aggeliki , Syed Nelofer , Szlosarek Peter Wojciech , Dranitsaris George , Crook Tim , Briasoulis Evangelos C. 
Published: March 2020

e18567 Background: Argininoosuccinate synthetase-1 (ASS1) catalyses the rate-limiting step in arginine biosynthesis, the conversion of citruline to arginine. Argininosuccinate lyase (ASL) is an enzyme that catalyses the reversible breakdown of arginosuccinate producing arginine and fumerate. Arginine deprivation using arginine deiminase (ADI-PEG20) is currently considered as a novel therapeutic intervention for cancer. In this perspective, we investigated the methylation status of the ASS1 and ASL CpG islands in multiple myeloma (MM) and analyzed for clinical relevance. Methods: Genomic DNA was extracted from bone marrow aspirate samples from 46 MM patients (28 male, 18 female, median age 64 years) obtained at diagnosis. Methylation-specific PCR was employed to study the methylation in the ASS1 and ASL CpG islands. DNA was isolated and bisulphite modified using commercially available kits. Logistic regression analyses were used to measure the association between gene methylation and sex, age>65, ISS stage, presence of extramedullary disease, renal failure and bone disease. Kaplan-Meier curves were used to estimate the probabilities of survival and the Log-rank test to assess the statistical significance of differences in event rates. Results: Methylation in the CpG island of ASS1 was detected in 71.7% patients and of ASL in 37% patients, while simultaneous methylation in both genes was present in 10 patients. None of the two genes was detectably methylated in the control group. Patients with ASS1 methylation were less likely to have bone disease (p=0.04, OR=0.22) and extramedullary disease (p=0.05, OR=0.22) and a trend was also noted that these patients were less likely to be >65 years of age (p=0.2, OR=0.37). We did not detect any statistically significant difference in overall survival by methylation status of the studied genes in this small study size. Conclusions: We demonstrate for the first time that arginine biosynthesis genes ASS1 and ASL are methylated in MM.Methylation of ASS1 was found to be more frequent and negatively associated with bone or extramedullary disease. Further evaluation of ASS1 and ASL is warranted in MM and supports the expansion of arginine deprivation trials in these patients
Comparative response assessment by total serum IgM and IgM M-component in Waldenstrom’s macroglobulinemia.
Authors: Tripsas Christina , Ioakimidis Leukothea I , Hunter Zachary R , Patterson Christopher J , Manning Robert J , Sheehy Patricia S , Turnbull Barry , Treon Steven P. 
Published: March 2020

e18575 Background: Changes in total IgM and the electrophoretically determined IgM M-component are used as surrogate serum response markers in Waldenstrom’s Macroglobulinemia (WM). Their ability to reflect underlying disease burden changes have not been compared. Methods: 73 rituximab-naïve patients were studied who underwent rituximab-based therapy on a study, and for whom serial total serum IgM levels, IgM M-component, and bone marrow (BM) assessments were available. Baseline: Median age 61 years; serum IgM 3,960 mg/dL; IgM M-component 2.55 g/dL; BM disease by core biopsy 60%. 5 patients had serum IgM levels <1,000 mg/dL, and 23 > 5,000 mg/dL. 39 patients had adenopathy and/or splenomegaly by baseline CT scans. Post-therapy, serum IgM declined from 3,960 to 1,800 mg/dL (p<0.0001); IgM M-component from 2.55 to 1.28 g/dL (p<0.0001); and BM involvement from 60% to 10% (p<0.0001). Among 39 patients with extramedullary disease, post-therapy CT scans were improved for 18, unchanged for 14, and worse for 7. Results: By linear regression analysis, reductions in serum total IgM and IgM M-component correlated with decreased BM disease involvement, though were relatively moderate (r=0.4490, p<0.0001; and r=0.4051; p=0.0004, respectively). To assess the difference between serum IgM and IgM M-component for correlation with BM response, an r to z transformation was performed. Serum IgM and IgM M-component were not significantly different as predictors for BM response (p=0.3745). Moreover, total serum IgM and the IgM M-component were poor estimators of BM response in patients with IgM levels <1,000 mg/dL (r=0.3635, p=0.2815 for serum IgM; r=0.1869, p=0.4672 for IgM M-component) or >5,000 mg/dL (r=0.0762, p=0.2022 for serum IgM; r=0.0306, p=0.4246 for IgM M-component). Extramedullary disease presence had no impact on serum IgM or IgM M-component correlations with BM disease involvement. Conclusions: Serum IgM levels and IgM M-component show similar correlations to changes in BM disease burden following therapy in WM patients, though overall the strength of these correlations are moderate, and particularly poor among patients with either low (<1,000 mg/dL) or high (>5,000 mg/dL) serum IgM levels.
The National Cancer Data Base report on the utilization of an adjuvant immunotherapy in stage III melanoma in relation to age.
Authors: Fredeking Arden , Venna Suraj S. , Jang Sekwon 
Published: March 2020

e19000 Background: The 5-year survival of Stage III melanoma ranges from 30-70%. High dose interferon alfa-2b (IFN) is an adjuvant immunotherapy approved in 1995 for stage III melanoma, however, its use has been limited by its significant toxicity and modest benefit. We hypothesized the utilization of adjuvant immunotherapy is less in older age group compared to younger patients. Methods: Using the National Cancer Data Base (NCDB) aggregate data, demographic, socioeconomic, insurance information, and treatment data were analyzed. Proportions were compared using Pearson Chi squared tests. Results: From 2000-2008, 27,365 cases of stage III melanoma were reported to NCDB. Most patients were male (63%) and Caucasian (94.2%). Twenty-nine percent were over the age of 70. Educational and socioeconomic factors across all age groups were not significantly different. The primary insurer for patients younger than 60 was a managed care plan (54.3%) as compared to Medicare with supplemental insurance for patients older than 60 (47.4%). In terms of systemic therapy, 23% received immunotherapy alone, 6% received chemotherapy alone, 2% received both, and 66% received no therapy. When compared to patients under age 39, older age groups were significantly less likely to receive adjuvant immunotherapy as shown in the table below. Conclusions: There is an inverse relationship between age and the use of adjuvant immunotherapy. Further study is planned to adjust for comorbidity, socioeconomic status using patient-level data. [Table: see text]
Determination of the BRAF V600E mutation in Uruguayan melanoma patients.
Authors: Mazzei Maria Eugenia , Hochman Jimena , Manrique Gonzalo , Marino Ana Luisa , Delgado Lucia Beatriz , Martínez Miguel Angel ,   Cátedra de Dermatología
Published: March 2020

e19007 Background: Vemurafenib approval by the FDA determines a new era for the treatment of metastatic melanoma in those patients with BRAF V600E mutation. This mutation is reported in about 50% of melanomas and is more common in melanomas on skin without chronic sun induced damage. The aim of this study was to evaluate the frequency of BRAF V600E mutation in Uruguayan melanoma patients, in order to analyze whether the use of vemurafenib would impact on our population. Methods: Formalin fixed, paraffin embedded tissues from 27 primary cutaneous melanomas, were obtained from files of the the Dermatopathology Unit, Department of Dermatology, Hospital de Clínicas in Montevideo, Uruguay. Most were Superficial Spreading Melanomas from skin without chronic sun induced damage. Microdissection of melanoma cells from paraffin embedded tissue was performed under microscopic visualization using a micromanipulator equipment. ADN extraction was performed and the BRAF V600E was detected by ASO-PCR. Results: Of the 27 melanoma samples analyzed, we detected the BRAF V600E mutation in 21. This determines a 77.8% frequency of mutation, a higher percentage than reported in the literature. This could be explained in different ways. The demographic characteristics of Uruguayan population are very peculiar, complying with a genetic admixture of Europeans(mostly from Spain), Amerindians (10%) and alow percentage of Africans (6%), which could explain the high incidence of BRAF V600E mutation. On the other hand, these melanomas were from skin without chronic sun induced damage, this type of melanomas have the highest rate of mutation. Finally, this mutation was analyzed in samples microdissected from melanoma biopsies, the fact that the cells were precisely removed from the tumor could also explain the high frequency of mutation. Conclusions: In this study we found a high frequency of BRAF V600E mutation in Uruguayan malignant melanoma patients, this could be explained by population genetic admixture, the melanoma subtype or technical characteristics. Further studies comparing techniques should be performed in our country to clarify this point.
Phase I study of nab-paclitaxel (NP) in combination with biochemotherapy (BCT) in patients (pts) with metastatic melanoma (MM).
Authors: Alrwas Anas , Papadopoulos Nicholas E. , Cain Suzanne , Patel Sapna Pradyuman , Kim Kevin B. , Deburr Tawania L , Bassett Roland , Hwu Wen-Jen , Bedikian Agop Y. , Davies Michael A. , Woodman Scott Eric , Hwu Patrick 
Published: March 2020

e19009 Background: NP has shown anti-tumor activity in MM in a phase II trial. The objective of this study was to determine MTD of NP as part of BCT, consisted of cisplatin (C), temozolomide (T), interleukin-2 (IL2) and interferon-alpha (IFN). Secondary objectives were to evaluate the anti-tumor activity of this combination in MM, and its benefit in preventing central nervous system (CNS) metastasis (mets). Methods: Previously untreated MM patients evaluable by RECIST 1.0 with no history of CNS mets between the ages of 18 and 65 and with ECOG 0-1 were enrolled. NP was given intravenously (IV) on Day (d) 1 and 5 of each cycle. The starting dose on d1 was 100 mg/ m2, and the dose on d5 was 70 mg/ m2, if toxicities permitted. The remainder of the regimen consisted of IV C 20 mg/ m2 daily d1-4, oral T 250 mg/ m2 d1-3, 9 million international units (MIU)/m2 of IL2 via continuous IV infusion for 96 hours, and IFN 5 MIU/m2 via subcutaneous injection d1-5. Treatment was repeated in cycles of 21 d to a maximum of 6 cycles. Prophylactic hematologic growth factors were not allowed in the first cycle. A standard 3+3 escalation method was used for NP d1 dose. Results: Ten pts were enrolled and evaluable for toxicities. Five completed six courses. Because 2 of 5 pts at the starting dose level had dose-limiting toxicities (DLTs) (diarrhea; transaminasemia-TA), the next cohort received d1 NP dose of 80mg/m2. Two of 5 pts at that dose level had DLTs (TA; neutropenia). Overall, the day 5 dose was omitted in 3 patients post third cycle due to thrombocytopenia (TP). There was no grade 5 toxicity. Common grade 3 and 4 toxicities were leucopenia, neutropenia, lymphopenia, anemia, TP, hyponatremia, diarrhea, skin rash, infection, tinnitus, neuropathy and TA. Five of 9 evaluable pts had partial response (PR). The median time-to-progression was 5.3 months (m). The median overall survival was 8.73 m. Six pts developed CNS mets with an overall median time of 5.33 m from treatment start. Conclusions: Additional studies are needed to determine the optimal dosing and schedule of NP as a part of BCT. Despite significant antitumor activity on sites outside the CNS, this combination therapy did not prevent the development of CNS mets.
Identification of melanoma-specific alterations in cell surface glycosylation.
Authors: Friedman Erica Brooke , Rakus John Frank , Zavadil Jiri , Hernando Eva , Mahal Lara K , Osman Iman 
Published: March 2020

e19018 Background: Cell surface glycans, oligosaccharides present on proteins and lipids, play important roles in a range of biological processes. Our group recently reported on the role of aberrant glycosylation in promoting melanoma cell invasion and immunosuppression (Cancer Cell, 2011). In this study, we further exploit the ability of glycomic profiling of melanoma, using lectin microarrays, to identify differences in melanoma-associated glycosylation for new melanoma biomarkers and/or targets of treatment. Methods: We utilized a ratiometric dual colored 90-lectin microarray to examine differences in glycosylation between 13 primary and 14 metastatic melanoma cell lines, 5 human melanoma tissues and 4 human epidermal melanocytes (HEM). One HEM was used as a biological reference for hybridization. A subset of melanoma cell lines (n=4) was used for comparison with the glycomic profiles of the NCI-60 lines using a mixed reference. Hierarchical clustering of lectins with significant differences in binding to the sample sets (t-tests, p<0.05) was used to visualize and infer differences in glycosylation patterns. Results: A shift in the glycome related to reduction in expression of high mannose and core fucosylated complex N-glycans was seen in melanoma cell lines and tissues compared to HEMs. Glycomic profiles of primary and metastatic melanoma were similar. Interestingly, enrichment of high mannose and potentially a-2,3 sialic acid was seen in BRAF mutant (n=19) compared to BRAF wild type (n=8) cell lines. Our tested melanoma cell lines showed similar glycosylation patterns compared to melanoma lines of the NCI-60 panel, which all show higher expression of high mannose and complex N-glycans compared to other cancers. Comparison of melanoma cell lines to tissues shows similar glycomic profiles, suggesting that glycosylation of melanoma cells is not significantly altered (or blunted) due to culture. Conclusions: Our data suggest that alterations in cell surface glycosylation may be an early event in the malignant transformation of melanocytes to melanoma. Further analysis of the melanoma glycome will be needed to elucidate the biological implications and clinical potential of altered glycosylation.
Analysis of BRAF mutation status in high-risk malignant melanoma patients having received HD IFNa therapy in adjuvant setting.
Authors: Hlavata Zuzana , Salek Tomas , Andrezalova Iveta , Dolinsky Jozef , Svabova Veronika , Porsok Stefan , Berkovcova Jitka , Waczulikova Iveta 
Published: March 2020

e19020 Background: Mutation in BRAF gene is considered to be a predictor of response to vemurafenib. However, it still remains to be demonstrated wheter BRAF mutational status is a prognostic factor in high risk melanomas. Methods: Between May 2003 till July 2011, there were 100 patients with a wide local excision of high risk malignant melanoma removed, who received HD IFNa adjuvant treatment. We retrospectively analyzed the data of 57 patients, who had determined BRAF V600 mutation status by real-time PCR assay (Cobas 4800 BRAF V600 Mutation Test). 48 patients were identified as a high-risk melanoma initialy, 9 after locoregional recurrence. Results: We have analysed samples from primary tumors (N35), lymph nodes (N16) and mets (N6). BRAF V600 mutation was found in 35 cases (61.4%). The median age was 52 yrs (range 19-66 yrs) in the whole group, in the subgroup of BRAF MT/WT it was 52.5/51 yrs (nonsignificant). The female/male ratio was 22/35, with no sex dependent differences for the BRAF MT or WT. The most frequent tumor stage T4N0M0 (29.8%) was the most common indication to the IFN treatment. The recurrence (distant mets) of melanoma was observed in 33 patients (57.8%); BRAF MT/WT 21 vs 12, HR 0.74, (95%CI 0.37-1.48) p =0.25. We observed 24 deaths (42.1%); BRAF MT/WT 16 vs 8, HR 0.72 (95%CI 0.32-1.62) p =0.46. We found a statistically significant higher risk of death associated with lower age in the whole group (p =0.006; OR =0,92). Logistic regression in the subgroup of BRAF MT patients revealed that the positivity of lymph nodes was associated with 5.6-times higher probability of death (OR =0.89, p =0.094). Additionally, a higher age was significantly associated with better overall survival (OS) p=0.012. On the other hand, in the subgroup of BRAF WT patients neither the age nor the positivity of lymph nodes influenced OS. Conclusions: We confirmed that BRAF mutation occurs in approximately 60% high-risk malignant melanomas. There were no statistically significant differences in DFS or OS between BRAF MT/WT form. However, our analysis corroborates the notion that BRAF MT patients have higher risk of death or recurrence, which we consider to be clinically relevant.