bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic impact of bone marrow CD138 immunohistochemistry (IHC) prior to autologous stem cell transplant (ASCT) for multiple myeloma (MM)
Authors: Foster M. C. , Christensen R. , Egan J. , Whitley J. , Chiu W. K. , Serody J. , Gabriel D. , Ivanova A. , Dunphy C. H. , Shea T. C. 
Published: August 2020

8600 Background: Low bone marrow plasma cell (BMPC) burden prior to ASCT for MM is associated with favorable outcomes, but is usually determined by morphologic evaluation of marrow aspirates, a method subject to variability in sampling and interpretation. It is unknown if CD138 IHC, a more sensitive measure of BMPC, predicts progression-free survival (PFS), overall survival (OS) or post-ASCT response. Methods: Consecutive patients (n=93) who underwent single ASCT for MM from 2001 to 2008 and had available, stainable bone marrow core biopsies (BMB) obtained <90 days prior to ASCT were included in this single-center retrospective cohort study. BMB and/or clot CD138 IHC staining were reviewed by blinded hematopathologists. Post-ASCT response, PFS, and OS were determined using the International Myeloma Working Group uniform response criteria. Results: Patients were highly cytoreduced prior to ASCT, with 50.5% of pts having 0–5%, 21.5% having 6–10%, 20.4% having 11–20%, and 7.5% having >20% BMPC by CD138 analysis. BMPC% by CD138 IHC correlated with aspirate BMPC% [Pearson correlation coefficient=0.48, 95%CI (0.30, 0.63)]. In 12.6% of patients, BMPC% by CD138 IHC was ≥10% more than the aspirate count. Patients with ≤5% BMPC were more likely to achieve or maintain a CR or VGPR at initial post-ASCT restaging than those with >5% BMPC: Odds Ratio (95% CI) 6.91 (2.12, 22.57), p=. 0005 (chi-squared). With median follow up of 15.4 months for the ≤5% BMPC group and 19.3 months for the >5% BMPC group, 34/93 patients have progressed or died, with no difference between groups. By Kaplan-Meier analysis, PFS was similar regardless of BMPC [3 year estimated PFS (95%CI): ≤5%BMPC, 49.9% (29.4, 70.4) vs. >5%BMPC, 45.5% (26.7, 64.3); HR=1.24 (0.62, 2.49), p=.55, log-rank]. There was no difference in OS [3 year estimated OS (95%CI): ≤5%BMPC, 71.0% (49.7, 92.3) vs. >5%BMPC, 81.8% (66.2, 97.4); HR=0.61 (0.21, 1.78), p=.36, log-rank]. Conclusions: Detection of ≤5% BMPC by CD138 IHC prior to ASCT predicts attainment or maintenance of post-transplant CR/VGPR and correlates with plasma cell morphology. Differences in PFS or OS may emerge with additional follow-up, or if more patients with a higher content of residual plasma cells were transplanted. [Table: see text]
Plasma cell leukemia: A SEER database analysis
Authors: Ramsingh G. , Mehan P. , Luo J. , Vij R. , Morgensztern D. 
Published: August 2020

8605 Background: Primary plasma cell leukemia (PCL) is a rare plasma cell disorder with clinical information limited to small series of patients. Methods: We analyzed the Surveillance Epidemiology and End Results (SEER) database to evaluate the patient characteristic and survival data for patients with PCL. Patients were divided into cohorts based upon age, gender, race and time period of diagnosis. Kaplan-Meier product limit method was used to estimate survival functions for group in each risk factor. Demographics and survival over different periods of time from 1973 and 2004 were compared with multiple myeloma. Results: Among the 291 patients with PCL, median age was 67 years (range 19–98), and the male/female distribution was equal and the most common race was white (79.4%). Median overall survival (OS) and disease specific survivals (DSS, defined by interval from diagnosis to the event of death from PCL) were 4 months and 6 months respectively. The 1 year, 2 year and 5 year overall survival rates were 22.7%, 10.2% and 3.8% respectively. The survival did not differ between gender and race. Patients ≤60 years had a better median overall survival compared to older patients (median OS: 7 months Vs 3 months, p=0.007), although 5-year overall survival was equally poor for either group (6.9% Vs 6.7%). During the same period, we identified 49,106 patients with MM. Demographics for MM showed a slightly increased median age of 70 years, but similar race and gender distribution. Unlike MM, where there has been a modest but statistically significant survival improvement over time, both OS and DSS remained stable in PCL ( Table ). Conclusions: This is the largest study to analyze demographic and survival data on patients with PCL. The poor long term outcome and the lack of improvement in survival of patients with PCL despite small gains in MM suggest a more aggressive disease, for which further therapeutic agents are needed. [Table: see text] No significant financial relationships to disclose.
Phase I study of PLX4032: Proof of concept for V600E BRAF mutation as a therapeutic target in human cancer
Authors: Flaherty K. , Puzanov I. , Sosman J. , Kim K. , Ribas A. , McArthur G. , Lee R. J. , Grippo J. F. , Nolop K. , Chapman P. 
Published: August 2020

9000 Background: PLX4032 is an oral, selective inhibitor of the oncogenic V600E mutant BRAF kinase with preclinical activity. V600E BRAF is the most common kinase mutation in melanoma (60%), also found in colorectal carcinomas (10%), most anaplastic and papillary thyroid carcinomas, and low-grade serous ovarian carcinomas. Methods: Phase I, dose-escalation study designed to determine maximum tolerated dose (MTD), safety, pharmacokinetic (PK) / pharmacodynamic (PD), and efficacy (RECIST evaluation every 8 wks) of PLX4032 in sequential cohorts of 3 to 6 patients (pts). Plasma PK samples were collected on days 1, 8 and 15. Results: 54 pts have been enrolled: metastatic melanoma (n=49), thyroid (n=3), rectal (n=1), or ovarian carcinoma (n=1). 26 pts received a crystalline formulation (CF) continuously at doses from 100 mg BID to 1600 mg BID with associated exposures below target plasma levels. 28 pts received an optimized formulation with increased bioavailability, predicted to have 10-fold greater bioavailability, at doses from 160 mg BID to 1120 mg BID. AUC was dose-proportional and above target levels at 240 mg BID and higher. There was 1 DLT at 720 mg BID (G4 pancytopenia); treatment was restarted at 360 mg BID without myelosuppression. At 1120 mg BID, 3 of 5 pts had DLT (rash and fatigue). One pt had grade 3 increased ALT at 360 mg BID. 13 melanoma pts (77 %M1C) treated at doses of 240 mg BID or higher of the increased bioavailability formulation have a minimum follow-up of 8 weeks. 5 of the 7 BRAF V600E+ pts treated at ≥ 240 mg BID had tumor regression, up to 83%, with 1 confirmed partial response (PR) and 1 unconfirmed PR (too early); 2 of 4 pts with unknown V600E status had tumor regression, up to 50%, with 1 confirmed PR; 2 BRAF wild-type pts had progressive disease. All 7 pts with tumor regression remain progression-free, ranging from 4 to 14 months. 3 thyroid cancer pts with V600E mutations have tumor regression (range 9–16%) and are progression-free (4–7 months). Conclusions: Dose escalation of PLX4032 reached DLTs at 1120 mg BID. 720 mg BID is the current MTD, but 960 mg BID may be explored. PLX4032 exhibits antitumor activity in V600E BRAF mutant tumors. These observations confirm that V600E BRAF is a valid therapeutic target in human cancer. [Table: see text]
A phase II trial of dasatinib in advanced melanoma
Authors: Kluger H. M. , Dudek A. , McCann C. , Rink L. , Ritacco J. , Adrada C. , Phouyaphone N. , Southard N. , Sznol M. 
Published: August 2020

9010 Background: Direct or indirect inhibition of Src kinases (non-receptor tyrosine kinase signaling intermediates) reduces melanoma cell proliferation in vitro. Dasatinib is a well tolerated, small molecule inhibitor of src kinase family members c-Src, c-Yes, Lck, and also inhibits c-KIT, PDGFβR and EPHA2. We initiated a CTEP-sponsored phase 2 trial of dasatinib in melanoma to assess response rate, PFS and toxicity. The secondary objective is to evaluate the association between clinical response and expression of dasatinib targets in tumors obtained pre-treatment. Methods: Adults with stage III/IV unresectable melanoma with a PS of 0- 1, who have not received prior chemotherapy are eligible. Dasatinib was administered at 100mg PO BID continuously to the first 18 patients. Subsequently, the starting dose was decreased to 70mg BID. Cycles are 4 weeks, tumor assessments occur q2 cycles. Results: Thirty patients have been accrued, five are too early to evaluate. Five, four and three patients had acral-lentiginous, ocular or mucosal primaries, respectively. Median age was 62, M:F 18:12, six received prior non-cytotoxic therapy. Three patients had confirmed partial responses lasting 16, 6, and 5 months, and one had a non-confirmed partial response, progressing after 4 cycles. One patient had a minor response and remains on study after 24 cycles. A patient with an exon 13 mutation in c-KIT responded to therapy, while another with a c-KIT exon 11 deletion mutation did not. Common toxicities are grade II fatigue, grade II-III dyspnea and pleural effusions. Chronic toxicities required reduction of the starting dose, and have been observed in all patients on dasatinib for over two months, all of whom required two dose reductions. Conclusions: Daily dasatinib has modest activity in melanoma. Accrual is almost complete. Toxicities are frequent, alternate schedules providing breaks in dosing might be better tolerated and should be evaluated. Combination studies may be warranted based on preclinical evaluation in molecularly defined subsets of patients. [Table: see text]
First analysis of an international pediatric melanoma and atypical melanocytic neoplasm database
Authors: Averbook B. J. , Jukic D. , Rao J. S. , Panneerselvam A. , Delman K. , Zager J. S. , Sabel M. , Pittelkow M. R. , Swetter S. , Kirkwood J. M. 
Published: August 2020

9013 Background: Pediatric melanoma (PM) care has been extrapolated from adult melanoma data. PM and atypical melanocytic neoplasms (AMNs) appear to have different biology. An international database (DB) was developed to clarify their behavior. Methods: IRB approval was obtained at 12 institutions. An SQL-DB was developed for web entry of de-identified demographic and pathologic data for PM and AMN patients (pts) < 21yr through an honest broker system at the University of Pittsburgh. Institutions retained a key of pts entered with assigned numbers for quality assurance and updates. Statistical analysis used Kaplan-Meier survival curves, univariate linear trends and log rank tests. In situ melanoma was excluded from PM survival analysis. Results: 828 pts were registered as of 31 Oct 2008 (ages 11mo-23; median 15yr). 34 pts 21–23yr entered were left in the DB for statistical comparison. Diagnosis years ranged from 1936–2008. 455 pts had complete follow-up. Too few AMN pts had complete follow-up for analysis (18/208). After excluding 32 in situ and 40 with other incomplete data, 365 PM out of 415 total PM were evaluable for OS and 351 for DFS (Stage IV removed). Mean/median age for evaluable PM pts was 16.44/17-yrs (range 1–21yr). 591 pts were age 10–20 while 203 were < 10. Sentinel lymph node (SLN) biopsy showed spread in 30.1 % PM pts (compared to 50% [4/8] of AMN SLN pts). 10-yr PM OS was 80.6%, and pts 0–10 yr had 100% 10-yr OS compared to 69.6% for pts age 10–15 and 79.49% for age 15–20 (p= 0.1473). OS did not differ significantly by gender. Stage predicted OS (p<0.0001). 10-yr OS was 94.13% for Stage I (n=174), 79.62% for stage II (n=67) & 77.14% for stage III (n=75). Thickness affected 10-yr OS: 0–1mm=97% (n=147), 1.1–2mm 70% (n=84), 2.01–4mm 78% (n=71) & >4mm 81% (n=25), p= 0.0099. Survival was similar for pts with PM > 1mm of the several T stage groupings. Ulceration adversely affected OS (p=0.022). Mitosis, defined as present/absent did not alter survival. Nodal metastasis correlated with worse OS (p= 0.170). Conclusions: Stage, thickness, ulceration, and nodal status are significant predictors of OS for PM. Further study will focus on multivariable analysis of PM and AMNs after updating pts, increasing accrual, and cleaning data. No significant financial relationships to disclose.
The biology and prognostic value of lymphatic vessel density (LD) and lymphatic invasion (LI) in regression in melanoma
Authors: Yun S. , Gimotty P. , Hwang W. , Dawson P. , VanBelle P. , Elder D. , Elenitsas R. , Guerry D. , Schuchter L. , Xu X. 
Published: August 2020

9017 Background: Regression in melanoma is characterized by increased vascularity, lymphocytic infiltrate and fibroplasia in the papillary dermis, accompanied by the absence (complete regression, CoR) or presence (partial regression, PaR) of melanoma cells in the epidermis. The prognostic value of regression is controversial. We noticed that LD and LI were increased in the areas of regression (AR) or areas with brisk lymphocytic infiltration (AB). Our goal was to clarify the prognostic value of regression in melanoma. Methods: Dual immunohistochemical staining was done using antibodies to podoplanin (lymphatic vessels) and S100 (melanoma cells) on paraffin tissues from 321 patients with vertical growth phase (VGP) primary melanomas who had 10 years or more of follow-up. LD in AR (both CoR and PaR) was compared with that of normal dermis adjacent and distant, as well as LD in the AB. LI in these areas was also scored. Unadjusted and adjusted hazard rates were obtained from univariate and multivariate Cox models for time to melanoma-specific death using established melanoma prognostic factors. Results: 116 patients (36%) had regression: 75 CoR (23%) and 41 PaR (13%). LD significantly decreased stepwise from CoR (mean ± se, 23.7 ± 2.7) to PaR (15.5 ± 1.1), adjacent normal dermis (7.3 ± 0.28) and distant normal dermis (5.4±0.31) and it was significantly elevated in the AB (18.5±0.78). Melanomas with CoR had the highest percentage of LI in both AR and AB. In addition, the percentage of LI in AB was highest for men and for those with VGP tumor infiltrating lymphocytes (TILs). Both high LD in AR and more LI in AB were associated with poor prognosis (p=0.004 and p=0.002, respectively). Six factors were significant in the final multivariate model: LI in AB (HR=2.3), LD in AR (HR=1.04), thickness (HR=1.44), axial (HR=7.7), ulceration (HR=2.5) and no VGP TILs (HR=2.8). Conclusions: AR and AB were associated with increased LD and higher incidence of LI in primary melanomas. LD and LI in AR or AB are independent prognostic factors. Our data suggest that the effects of regression on prognosis are mediated at least in part through lymphangiogenesis and LI. No significant financial relationships to disclose.
Phase II trial of extended dose anti-CTLA-4 antibody ipilimumab (formerly MDX-010) with a multipeptide vaccine for resected stages IIIC and IV melanoma
Authors: Weber J. S. , Sarnaik A. , Targan S. , Yu B. , Morelli D. , Urbas P. , Maker N. , Yellin M. , Nichol G. 
Published: August 2020

9023 Background: Ipilimumab is a human anti-CTLA-4 antibody shown to have clinical activity in melanoma that is associated with immune-related adverse events (IrAEs). Methods: 50 HLA A*0201 positive patients with resected stages IIIC/IV melanoma received MART-1/gp100/tyrosinase peptides with adjuvant Montanide ISA 51 12 times subcutaneously with Ipilimumab at 3 or 10 mg/kg intravenously every 8 weeks for 12 months, and 25 HLA A *0201 negative patients received Ipilimumab alone at 10 mg/kg. Primary endpoints were toxicity and the achievement of a 40% rate of tolerable IrAEs. Immune responses measured by ELISPOT and tetramer assays, and time to relapse were also assessed. 3 melanoma peptides were administered at 1000 mcg/dose each. Results: Median age was 58, with 44 men and 31 women. 46 patients had stage IV, and 29 had stage IIIC resected disease. 19/75 (25%) patients had grades 3–4 IrAEs that were dose-limiting. No patient with dose limiting toxicity required hospitalization and all returned to baseline status with the use of systemic steroids. Assays of induction of IL-17 secreting T cells showed a positive association with freedom from relapse (p=0.049). Change in slope of the increase in total lymphocyte count at four weeks was also associated with a trend toward freedom from relapse and development of an IrAE. 27 of 75 patients have relapsed with a median of 23 months of follow-up. 10 were again rendered NED surgically and are alive without disease. 68 patients are alive, 10 with disease. Only 1/19 patients with grade 3/4 IrAE has died of disease, compared to 6/56 without a dose limiting IBE. 23 of 27 relapses occurred without a grade 3/4 IrAE, compared with 15 IrAEs in 48 patients without a relapse. ELISPOT assays showed that patients at 10 mg/kg actually had decreased responsiveness in fresh PBMC to PHA and the CEF (CMV, EBV, FLU) pool of peptides. Conclusions: IrAEs are associated with clinical benefit in patients with resected high-risk melanoma receiving Ipilimumab with or without a peptide vaccine. Increases in IL-17 secreting CD4 T cells and the slope of increase in total lymphocytes over 4 weeks are associated with freedom from relapse. These data support testing the current regimen at 10 mg/kg in a larger randomized trial. [Table: see text]
Phase II trial of bevacizumab and everolimus in the treatment of patients with metastatic melanoma: Preliminary results
Authors: Peyton J. D. , Spigel D. R. , Burris H. A. , Lane C. , Rubin M. , Browning M. , Trent D. , Hainsworth J. D. 
Published: August 2020

9027 Background: Metastatic melanoma remains resistant to therapy. Anti-angiogenesis agents and m-TOR inhibitors have shown modest activity as single agents. In this multicenter phase II trial, we evaluated the combination of bevacizumab and everolimus in the treatment of patients with metastatic melanoma. Methods: Patients with unresectable metastatic melanoma with ECOG PS 0–2 were eligible. Up to 2 previous treatment regimens were allowed; patients previously treated with angiogenesis or m-TOR inhibitors were excluded. Additional eligibility requirements: adequate organ function, no CNS involvement, standard bevacizumab exclusions. All patients received bevacizumab 15mg/kg IV q 3 weeks, and everolimus 10mg po daily. Patients were evaluated every 6 weeks, and treatment continued until disease progression. Results: Between February 2008 and October 2008, 56 patients were enrolled; the first 31 patients are included in this interim report. The median age was 71 years (range 36 to 89 years); 19 patients (61%) had visceral metastases; 0/1/2 previous regimens, 12/11/8 patients; ECOG PS 0/1/2, 17/11/1. 28 patients (90%) received at least 6 weeks of treatment; 3 patients withdrew prior to 6 weeks (toxicity, 2 patients; intercurrent illness, 1 patient). 1 of 28 evaluable patients (4%) had a PR. However, 19 additional patients (68%) had stable disease (15 of these patients had measurable decrease in tumor size), for a disease control rate of 72%. 14 patients remain on treatment, after treatment durations of 2 - 7.5 months. After a median followup of 5 months, the median progression-free survival is 3.5 months (95% CI 2.4 - 5.4 months). Bevacizumab/everolimus was generally well tolerated. 1 patient withdrew because of interstitial pneumonitis (reversible) and 1 patient had a fatal MI, possibly bevacizumab-related. Grade 3 mucositis occurred in 13%; other grade 3 toxicities occurred in < 10% of patients. Conclusions: The combination of bevacizumab and everolimus was well tolerated and has activity in patients with metastatic melanoma. Updated results in all 56 patients will be presented. [Table: see text]
Phase I/II study of arginine deiminase (ADI-PEG 20) in patients with advanced malignant melanoma (MM)
Authors: Ott P. A. , Carvajal R. D. , Pandit-Taskar N. , Jungbluth A. A. , Hoffman E. , Venhaus R. , Pan L. , Old L. , Pavlick A. C. , Wolchok J. D. 
Published: August 2020

9030 Background: ADI-PEG 20 is an enzyme that degrades arginine, a crucial amino acid central to metabolism and biosynthesis of growth and development of normal and neoplastic cells. Melanoma is auxotrophic for arginine because it lacks argininosuccinate synthetase (ASS), a key enzyme required for synthesis of arginine from citrulline via the urea cycle. This study evaluates the safety and clinical efficacy of ADI-PEG 20 in patients with MM. Methods: Patients with histologically confirmed stage III (unresectable)/ IV cutaneous, uveal or mucosal MM were treated with 40, 80 or 160 IU/m2 ADI-PEG 20 i.m. weekly for 9 weeks in a phase I setting. In a phase II component, 16–25 pts receiving 160 IU/m2 will be evaluated for tumor response (TR) by RECIST. Secondary endpoints for all patients included metabolic response by 18FDG-PET, pharmacodynamics (PD), immunogenicity and ASS tumor expression by immunohistochemistry. Results: As of Nov. 2008, 24 pts were enrolled (40 IU/m2, n=6, 80 IU/m2, n=6, 160 IU/m2, n=12): 14 males, 10 females. Median age: 66 yrs (range 29- 83 yrs). Toxicity consisted primarily of Grade 1/2 adverse events (AE) (injection site pain, myalgia, arthralgia, fatigue, flushing, rash/itch, nausea, diarrhea, hyperuricemia, taste alteration). One dose limiting toxicity (DLT) of G3 arthralgia was observed at 80 IU/m2. Two DLTs (G3 seizure and G3 lymphedema) were reported, at 160 IU/m2. No grade 4 or 5 AEs were observed. Of 22 patients evaluable for TR, 8 had stable disease (SD) with 2 of these durable for ≥ 6 months. Notably, 3 SD were uveal melanoma. 14 patients had progressive disease. PD analysis showed plasma arginine depletion during study weeks 1–6 regardless of dose. Immunohistochemical ASS expression analysis in tumor tissue: negative= 13 pts, < 5% cells positive= 5 pts. Conclusions: ADI-PEG 20 as a single agent is well tolerated in advanced MM leading to consistent arginine depletion. The extent of clinical activity has yet to be shown. Combination therapy of ADI-PEG20 with other treatments such as pro-apoptotic reagents during the first 6 weeks of ADI-PEG 20 treatment while arginine is depleted could lead to synergistic anti-cancer activity. No significant financial relationships to disclose.