bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of bone marrow plasma cell infiltration pre-auto transplant with adverse outcomes in multiple myeloma.
Authors: Bashir Qaiser , Parmar Simrit , Dinh Yvonne , Qureshi Sofia , Rondon Gabriela , Popat Uday R. , Nieto Yago , Jones Roy B. , Champlin Richard E. , Qazilbash Muzaffar , Shah Nina 
Published: March 2020

8102 Background: Auto-stem cell transplantation (SCT) has become the standard of care for eligible patients (pts) with multiple myeloma (MM). However, the impact of bone marrow (BM) plasma cell (PC) percentage before SCT is not yet known. Methods: Retrospective review of 1489 MM pts who underwent auto-SCT from 7/8/98 – 12/31/2010 with post-induction, pre-SCT BM biopsy information available. Pts were divided into 2 groups: <10% PC infiltration (“PC low”) and >10% PC infiltration (“PC high”). Progression-free (PFS) and overall (OS) survivals were estimated by the Kaplan-Meier method. Log-rank test was performed to test differences in survival. Results: 1489 pts were studied. 1174 pts had <10% involvement of BM by PCs and 315 had > 10% involvement. For pts in the PC low group, 32% had a CR, 20% had a VGPR, 31% had a PR, 13% had <PR and 3% had progressive disease (PD) after SCT. For pts in the PC high group, 11% had a CR, 14% had a VGPR, 48% had a PR, 21% had <PR and 5% had PD after SCT. Median PFS was significantly shorter for the PC high group vs the PC low group (24.8 vs 29.5 months, p=0.05), as was median OS (52.5 vs 79.4 months respectively, p<0.001). When only pts who had a PR to induction were examined, there was a significant difference in both PFS (24.4 vs 33.2 months, p=0.04) and OS (58.3 vs 81.2 months, p =0.002) for the PC high vs PC low groups, respectively. For the 1299 (87%) pts treated in the era of novel therapeutics (after 2000), the differences between the PC high and PC low groups were maintained for both PFS (24.4 vs 29.5 months respectively (p=0.029)) and OS (54.8 vs 88.4 months respectively, p<0.001). Chemo-mobilization before SCT did not improve PFS or OS but this was done in only 44 (14%) of PC high pts. Conclusions: PC BM infiltration before auto-SCT is associated with a worse outcome. This finding persists in pts with a PR before SCT. Thus BM disease burden may further stratify pts with a PR. Though additional therapy did not significantly change the outcome for pts with high PC burden, this was done only in a minority of pts. Additionally, differences between PC high and PC low groups are maintained despite new salvage agents over the last 10 years. Further prospective study is warranted to determine the true impact of BM PC infiltration.
Use of whole genome sequencing to identify highly recurrent somatic mutations in Waldenström’s macroglobulinemia.
Authors: Hunter Zachary R , Xu Lian , Yang Guang , Zhou Yangsheng , Liu Xia , Cao Yang , Tripsas Christina , Manning Robert J , Patterson Christopher J , Sheehy Patricia S , Treon Steven P. 
Published: March 2020

8107 Background: Waldenstrom’s Macroglobulinemia (WM) is an IgM secreting lymphoplasmacytic lymphoma. The genetic basis for this disease remains to be clarified. Methods: We performed whole genome sequencing (WGS) using CD19+ selected bone marrow lymphoplasmacytic cells (LPC) from 30 WM patients. For 10 of these patients, paired CD19+ depleted peripheral blood samples were used for WGS as normal controls. Results: The most common somatic variants identified and validated by Sanger sequencing included MYD88 L265P, an activating mutation for IRAK/TRAF6/NFKB and MAPK signaling, which was observed in 27/30 (90%) patients; the N-terminal domain of CXCR4, which included mutations associated with WHIM syndrome and confer constitutive CXCR4 signaling resulting from dysfunctional receptor endocytosis, a finding observed in 8/30 (27%) patients, and ARID1A (5/30; 17%), a tumor suppressor gene. Less common somatic variants were also identified in MUC16 (4/30; 13%), TRAF2 (3/30; 10%), TRRAP (3/30; 10%) and MYBBP1A (2/30; 7%). Conclusions: Using WGS and confirmatory Sanger sequencing, we have identified several somatic variants with oncogenic function, the most common of which include MYD88 L265P, the N-terminal domain of CXCR4, and ARID1A.
Analysis of molecular mechanisms of response and resistance to vemurafenib (vem) in BRAFV600E melanoma.
Authors: Sosman Jeffrey Alan , Pavlick Anna C. , Schuchter Lynn Mara , Lewis Karl D , McArthur Grant A. , Cowey Charles Lance , Moschos Stergios J , Flaherty Keith T. , Kim Kevin B. , Weber Jeffrey , Hersey Peter , Long Georgina V. , Lawrence Donald P. , Kockx Mark , Spleiss Olivia , Koehler Astrid , Bollag Gideon , Joe Andrew K. , Trunzer Kerstin , Ribas Antoni 
Published: March 2020

8503^ Background: Vem induces frequent clinical responses (RR >50%) and improved survival in patients (pts) with BRAF-mutated metastatic melanoma. Multiple mechanisms of escape from vem have been proposed. We performed a centralized analysis of pretreatment, cycle 1, day 15 (D15), and progression (DP) tumor samples collected during the phase II BRIM-2 trial (Sosman et al, NEJM 2012). Methods: Of 132 pts enrolled, archival tumor samples, biopsies taken at baseline (BL), D15, and DP were obtained from 84, 38, 26, and 22 pts, respectively, and analyzed by immunohistochemistry (IHC) for signaling molecules in the MAPK, PI3K/AKT, and cell cycle pathways. Genetic analyses of signaling genes were performed using Sequenom MASSarray and direct DNA sequencing. Results: High levels of ERK phosphorylation were seen at BL indicating constitutive MAPK signaling due to the BRAF mutation. In 19/22 paired samples, pERK levels were reduced following vem (BL vs D15). Mean absolute pERK reduction in pts with clinical response (RECIST criteria) to vem (n=14) was significantly greater than in non-responders (n=8; p=0.013). Baseline cytoplasmic PTEN H-score was higher in responders vs non-responders (H-score=88 vs 68; p=0.042). At progression, upregulation of pERK (H-score=181) was frequently, but not uniformly found vs D15 tumors (H-score=48.5). At progression, increases in Cyclin D1 and Ki67 were seen, without obvious changes in PTEN or pAKT. NRAS mutations occurred in 3/13 DP; 2 had paired BL samples without NRAS mutations. Only 1/82 pts had a concomitant NRAS and BRAF mutation at BL, and did not respond to vem. MAP2K1 (MEK1) codon 124 mutations occurred in 7/92 BL and 1/20 DP samples. 2 pts with BL MEK1 mutations had partial responses. Conclusions: MAPK signaling was effectively inhibited by vem early in treatment, and in the subset of patients with matched tumor samples the degree of pathway inhibition correlated with clinical response. MAPK signaling is upregulated in many lesions at progression. NRAS mutations appear to be a mechanism of acquired resistance in a few tumors (3/13), while the role of MEK1 mutations in resistance is less clear.
Safety and efficacy of MET inhibitor tivantinib (ARQ 197) combined with sorafenib in patients (pts) with NRAS wild-type or mutant melanoma from a phase I study.
Authors: Means-Powell Julie Ann , Adjei Alex A. , Puzanov Igor , Dy Grace K. , Goff Laura Williams , Ma Wen Wee , Fetterly Gerald J. , Michael Shaunita A. , Chai Feng , Lamar Maria , Schwartz Brian E. , Sosman Jeffrey Alan 
Published: March 2020

8519 Background: The MET receptor tyrosine kinase is implicated in tumor cell proliferation, invasion, and metastasis, and is activated in NRAS mutant melanoma. Tivantinib is an oral, selective MET inhibitor currently in phase II/III clinical trials. Tivantinib plus sorafenib exhibited synergistic antitumor activity vs single-agent activity in several tumor models. This phase I dose-escalation study assessed the safety of tivantinib plus sorafenib in pts with advanced solid tumors. Methods: Endpoints were safety, the recommended phase II dose (RP2D) of tivantinib plus sorafenib, and antitumor activity. Dose escalation previously established the RP2D as tivantinib 360 mg twice daily (BID) plus sorafenib 400 mg BID. Extension cohorts enrolled ≤ 20 pts each with melanoma or other tumors. Pts were treated until disease progression or unacceptable toxicity. Results: 16 pts with melanoma (median age, 66 yr) received treatment at the RP2D, and 3 pts are still on study. 12 pts received ≥ 1 previous systemic anticancer treatment (median, 1.2; range, 0-5) including ipilimumab (2 pts) or MEK inhibitor (1 pt). Common adverse events (≥ 25%) were rash (50%), diarrhea and fatigue (44% each), anorexia (38%), stomatitis and nausea (31% each), and anemia, weight decrease, and hypophosphatemia (25% each). Best responses were complete response (CR) in 1 pt, partial response (PR) in 3 pts, and stable disease (SD) in 3 pts. 4 pts had progressive disease and 5 pts were not evaluable (3 pts had not reached first assessment time, 1 pt withdrew consent, and 1 pt had unacceptable toxicity). The overall response rate and disease control rate were 25% and 44%, respectively. Median progression-free survival (mPFS) was 5.3 mo (95% CI, 1.6-12.9 mo). Among 8 pts with NRAS mutations, mPFS was 9.2 mo (95% CI, 5.3-12.9 mo) and responses were 1 CR, 1 PR, and 2 SD. Conclusions: Tivantinib plus sorafenib combination therapy was well tolerated and exhibited preliminary anticancer activity in pts with melanoma. Dual inhibition of MET and angiogenesis may be an effective treatment strategy in NRAS-mutant melanoma.
Clinical significance of genomic alterations of the CDK4-pathway and sensitivity to the CDK4 inhibitor PD 0332991 in melanoma.
Authors: McArthur Grant A. , Young Richard J. , Sheppard Karen E , Mar Victoria , Waldeck Kelly , Fox Stephen B. , Kelleher Fergal C , Liu Wendy , Dobrovic Alexander , Pearson Richard , Kelly John , Christensen James G. , Randolph Sophia 
Published: March 2020

8520 Background: Activation of CDK4 by amplification, increased expression of Cyclin D1 (CCND1) or reduced expression of the CDK inhibitor p16 (CDKN2A) can contribute to transformation of melanocytes indicating that CDK4 can act as an oncogene in melanoma.To explore if CDK4 may be a viable target for the treatment of human melanoma we have analyzed the frequency and clinico-pathological associations of genomic alterations of the CDK4 pathway in primary human melanoma and examined the genomic predictors of sensitivity to the highly selective CDK4/6 inhibitor PD 0332991 (991) in a panel of melanoma cell lines. Methods: A series of 167 primary melanomas with clinical, molecular and pathological annotation, including median follow up of 6.6 years, were analyzed for copy number variation (CNV)- gain of CDK4 or CCND1 (average gene copy >2.4) or loss of CDKN2A (average gene copy <1.4), by fluorescence in situ hybridization. A panel of 39 cell lines were treated with 991 in vitro and GI50s calculated. The mean GI50 of the melanoma cell lines was used to define sensitivity. Gene expression profiling and mutation or CNV in CDKN2A were used to identify predictors of sensitivity. Results: 75% of primary melanomas had at least one CNV (75%, 70% and 82% for BRAF, NRAS or wild-type BRAF/NRAS mutation status respectively). 55% showed loss of CDKN2A. 28% of melanomas had two or more CNVs. Melanomas with two or more CNVs involving CCND1 had worse overall survival (HR 5.56, p=0.02). Low CDKN2A mRNA expression or mutation or loss of CDKN2A predicted sensitivity to 991 with 30/33 mutant/loss lines being sensitive compared to only 2/6 wild type lines (p<0.006). Expression of CDK4, CCND1 or other cyclins or CDK-inhibitors did not predict sensitivity to 991. Conclusions: Genomic alterations in the CDK4 pathway are frequent in melanoma and are associated with worse survival, particularly when melanomas harbor two or more CNVs involving CCND1. Mutation, loss or low expression of CDKN2A in melanoma cell lines predicted sensitivity to the CDK4 inhibitor 991. Taken together these data support evaluation of CDK4 inhibitors in melanoma and suggest that CDKN2A maybe a genomic predictor of sensitivity to these agents.
A Cancer Research UK two-stage multicenter phase II study of imatinib in the treatment of patients with c-kit positive metastatic uveal melanoma (ITEM).
Authors: Nathan Paul D. , Marshall Ernest , Smith Catrin Tudur , Bickerstaff Matthew , Escriu Carles , Marples Maria , Damato Bertil , Kalirai Helen , Coupland Sarah 
Published: March 2020

8523 Background: The median overall survival (OS) for metastatic uveal melanoma is less than 6 months with a median progression free survival(PFS) of 3 months. No systemic or regional therapy has shown a survival advantage over best supportive care. Despite pre-clinical evidence suggesting anti-tumour activity for the KIT tyrosine kinase inhibitor imatinib, there are several negative phase II trials in unselected patients. Our primary aim was to test the efficacy of imatinib in patients with prospectively-tested c-kit immunopositive metastatic uveal melanoma. Secondary aims included assessment of toxicity and patient recruitment. Methods: A phase II UK multicentre single-arm, two-stage Gehan design recruited 25 evaluable patients receiving imatinib 400mg OD until progression/unacceptable toxicity. Primary efficacy outcome was PFS at 3 months. Secondary outcomes were OS, overall PFS, disease response (RECIST) and toxicity. Prospective sample collection for putative biomarkers was included. Results: After 16.6 months 37 patients were screened, with 25 were registered and included in final efficacy analyses. The sample included PS 0-1 patients with a median age of 63 yrs and a median 9.3 months from diagnosis of metastatic disease. 82% had high LDH levels (>460IU/L), 65% had no previous treatment for metastatic disease and 8% did not have liver involvement by metastasis. Preliminary final results indicate the estimated proportion of patients progression free at 3 months is 0.24 (95% CI, 0.09 to 0.45). Median PFS and OS were 12.0 weeks (95% CI,11.6 to 14.3) and 29.6 weeks (95% CI, 19.3 to 61.0) respectively. Two patients had confirmed PR with response duration of 93 and 112 weeks, respectively, despite the absence of mutations in exons 11, 13, and 17 of the c-KIT gene. Conclusions: The trial successfully recruited to target in this rare disease area failing to convincingly show improved PFS in a selected cohort of c-kit immunopositive patients. Both patients with PR experienced long periods of disease control. Response was not dependent upon the presence of activating mutations in KIT. Further translational studies are ongoing to determine putative biomarkers of response.
Activity of cabozantinib (XL184) in metastatic melanoma: Results from a phase II randomized discontinuation trial (RDT).
Authors: Gordon Michael S. , Kluger Harriet M. , Shapiro Geoffrey , Kurzrock Razelle , Edelman Gerald , Samuel Thomas A. , Moussa Ali H. , Ramies David A. , Laird A. Douglas , Schimmoller Frauke , Shen Xiaodong , Daud Adil 
Published: March 2020

8531 Background: MET and VEGF signaling are implicated in angiogenesis, invasion, and metastasis. Cabozantinib (cabo) is an oral, potent inhibitor of MET and VEGFR2. A RDT evaluated activity and safety in 9 tumor types. Here we report on the metastatic melanoma cohort, including the ocular subtype. Methods: Eligible patients (pts) were required to have progressive measurable disease per RECIST. Pts received cabo at 100 mg qd over a 12 wk Lead-in stage. Tumor response (mRECIST) was assessed q6 wks. Treatment ≥ wk 12 was based on response: pts with PR continued open-label cabo, pts with SD were randomized to cabo vs placebo, and pts with PD discontinued. Primary endpoint in the randomized phase was progression free survival (PFS). Results: Enrollment to this cohort is complete (n = 77); all pts are unblinded. Baseline characteristics: median age 66 years; melanoma subtype: cutaneous/mucosal 70% and ocular 30%; known BRAF mutation 32%; LDH ≥ 1.1 x upper limit normal 35%; bone metastases 19%; median prior lines of therapy 1 (range 0-5). Median follow-up was 2.8 months (range 0.3 - 25). 35 pts (45%) completed the open-label Lead-in stage with 25 pts randomized to continue cabo (n=12) or to placebo (n=13). Median PFS from randomization was 5.7 months for cabo vs. 3 months for placebo (HR=0.3, p =0.055). Median PFS from Study Day 1 was 4.4 months. The estimate of PFS at month 6 (PFS6) is 44%. Evidence of objective tumor regression was observed in 39/65 pts (60%) with ≥ 1 post-baseline tumor assessment including 11/23 pts (48%) with ocular melanoma. Two bone scan evaluable pts demonstrated partial resolution of bone lesions at wk 6 accompanied by pain relief. Most common Grade 3/4 AEs were fatigue (14%), HTN (9%), constipation (4%), and diarrhea (3%); one related Grade 5 AE of diverticular perforation and peritonitis reported during Lead-in stage. Conclusions: Cabo demonstrates activity in metastatic melanoma pts, regardless of subtypes or BRAF mutation status, with improvement in PFS relative to placebo, and high rates of PFS6 and objective tumor regression. The safety profile of cabo was comparable to that of other VEGFR TKIs.
Randomized phase III trial of intravenous (IV) versus hepatic intra-arterial (HIA) fotemustine in patients with liver metastases from uveal melanoma: Final results of the EORTC 18021 study.
Authors: Leyvraz Serge , Suciu Stefan , Piperno-Neumann Sophie , Baurain Jean-Francois , Zdzienicki Marcin , Testori Alessandro , Marshall Ernest , Scheulen Max E. , Jouary Thomas , Negrier Sylvie , Vermorken Jan Baptist , Kaempgen Eckhart , Durando Xavier , Schadendorf Dirk , Karra Gurunath Ravichandra , Polders Larissa , De Schaetzen Gaetan , Vanderschaeghe Simon , Gauthier Marie-Pierre , Keilholz Ulrich 
Published: March 2020

8532 Background: HIA fotemustine has shown promising results in Phase II studies that led to the EORTC randomized phase III trial (18021) in unpretreated patients (pts) with liver metastases from uveal melanoma. Methods: The treatment consisted in an induction cycle of either HIA (fotemustine 100 mg/m² over 4 hours, day 1, 8, 15, 22) vs IV control arm (fotemustine 100 mg/m² over 1 hour, day 1, 8, 15). After a 5-week break, maintenance cycles were given every 3 weeks. Randomization was stratified by PS (0 vs 1), LDH (normal vs abnormal) and center. Main endpoint was overall survival (OS). Required accrual per protocol was set to 262 pts, with final analysis planned after 220 deaths (hazard ratio (HR) =0.67, power=85%, 1-sided α=2.5%). Due to poor accrual an interim analysis was done after 134 deaths, in order to test futility (power=79%). Results: Between Feb-2005- Feb-2011, 171 pts were randomized (HIA: 86, IV: 85). Characteristics: PS 1: 20%, abnormal LDH: 42%, male: 50%, median age: 59 y.; balanced between arms. In the HIA arm 20 (23%) pts never started treatment mainly due to catheter problems and 2 pts in the IV arm. In those who started the treatment, leucopenia grade 3-4 was 18% and thrombopenia grade 3-4: 21% in the HIA arm compared to 32% and 42% in the IV arm. Non-hematological grade 3-4 toxicities were minimal (GI toxicity, catheter complications). In May 2011, as the OS HR=1.097 was > critical value 0.87, the IDMC recommended stopping accrual for futility. The final results from Jan-2012 are presented in the table below. Treatment comparison adjusted by PS and LDH provided similar results. Conclusions: Even if HIA fotemustine administration could not start in 23% of pts, it led to a higher ORR and longer PFS compared to IV administration. HIA did not translate into an improvement in OS. [Table: see text]
Role of cytokine-induced plasticity in melanoma on invasive, therapy-resistant cells that express EMT-related genes and pathways.
Authors: Cebon Jonathan S. , Anaka Matthew , Hudson Christopher , Lo Pu-Han , Davis Ian D. , Vella Laura J , Jayachandran Aparna , Behren Andreas 
Published: March 2020

8542 Background: The acquisition of new mutations can explain resistance to targeted therapies; however resistance also develops without demonstrable new mutations. To better understand potential mechanisms for treatment failure we studied subpopulations of chemo-resistant cells that can be identified in early passage cell lines and the cellular plasticity that yields these. Methods: Melanoma subpopulations were identified and sorted on the basis of functional assays. Gene expression was evaluated with Illumina HT12 arrays and qPCR to identify potential mechanisms and targets. Sorted cells were evaluated in vitro for the induction of phenotype switching and effects of target inhibition. Results: A subset of slow proliferating label-retaining cells (LRC) was identified using a membrane dye. Direct isolation of LRC from a pt showed these were not an in vitro artefact. LRC isolated from multiple cell lines comprised the majority of cells that resisted cytotoxic drugs and could invade through an artificial extracellular membrane. Gene expression profiling identified a network of over-expressed genes related to epithelial-to-mesenchymal transition (EMT) notable for the expression of Thrombospondin-1 (TSP-1), Transforming-Growth Factor, Beta Induced, (TGFBI) and other extracellular matrix molecules. Initial studies show that LRC shared gene expression characteristics with PLX4032-resistant cells. Although interrogating LRC by qPCR showed up-regulation of the putative melanoma stem cell marker ABCB5 and the lysine specific demethylase Jarid1B, cell sorting and serial re-labelling experiments revealed a dynamic and interchangeable phenotype for these cells, challenging the hierarchical stem cell model for melanoma. The observed slow-cycling and chemo-resistant phenotype could be induced in vitro through TGF beta-mediated phenotype switching and cellular invasion was blocked using an antibody against TSP-1. Conclusions: Cytokine-induced plasticity in melanoma yields invasive, therapy-resistant cells which express EMT-related genes and pathways. We hypothesize that these cells are a source of treatment resistance in vivo and blocking their emergence may prevent treatment failure.