bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immunoprofiling in alveolar soft part sarcoma.
Authors: Salah Samer , Lewin Jeremy Howard , Davidson Scott , Anderson Nathaniel , Periera Sergio L , Lau Beatrice , Shlien Adam , Dickson Brendan , Ferguson Peter , Wunder Jay , Abdul Razak Albiruni Ryan 
Published: September 2018

11059 Background: Alveolar Soft Part Sarcoma (ASPS) is a distinctive tumor characterized by a canonical ASPL-TFE3 fusion. Treatment options are limited. We assessed tumor immune cell infiltrates, and correlated this with patients receiving PD-1 blockade. Methods: A retrospective institutional review was performed for 18 cases of ASPS. Immunohistochemistry was performed on paraffin-embedded tissue (PET) for T-lymphocyte markers (CD3/CD4/CD8), and PD-1/PD-L1 (Ventana). Expression was quantified by standard methods: (total cells per high power field: score; 0:0; 1-10:1; 11-50:2; 50-99:3; 100:4). Select cases underwent DNA sequencing analysis using whole exome (WES, > 80X, n = 4) and genome (WGS, > 30X, n = 1) sequencing. Indel analysis was conducted via mutect2 ( > 5% variant allele frequency) and mutational signature was performed using deconstructSigs. Results: The median age was 27 (15-54). Disease status at diagnosis was: 44% localized; 56% metastatic. The median overall survival was 17 yrs (2.9-31). Four patients (pts) received immunotherapy with PD-1 blockade with 1 complete response (CR), 2 durable partial responses (PR) and 1 stable disease (SD). PET was available in 12 cases. PD-1/PD-L1 expression (≥1) was seen in 50% and 17%, respectively. Composite CD3, CD4 and CD8 infiltration were 2, 1, and 1, respectively. Patients with CR/PR to PD-1 blockade (n = 3) had no clear correlation with PD-1, PD-L1 or lymphocyte markers. Exomic characterization (n = 4) demonstrated no clear excess mutation burden compared to Ewing sarcoma (5.7 vs 6.4 mut/MB). Mutational signatures via COSMIC were identified in the mismatch repair (MMR) pathway in 2 of 4 cases (Pt A: Signature (S) 26; pt B: S6 and S15). Pt B also underwent WGS which confirmed a COSMIC signature in the MMR pathway. Indel analysis did not confirm aberrations in standard MMR or polymerase genes. Conclusions: Preliminary findings suggest activity with PD-1 blockade in ASPS; however, this does not appear to correlate with tumour-infiltrating T lymphocytes. Genomic analysis suggests an MMR signature may account for these responses, but standard MMR aberrations were not identified. Further validation is underway.
Trabectedin for advanced soft tissue sarcoma: Ten-year real-life perspective.
Authors: Shamai Sivan , Merimsky Ofer 
Published: September 2018

11060 Background: Trabectedin is a marine - derived chemotherapy, which lately received FDA approval for use in anthracycline resistant advanced soft tissue sarcoma (STS), especially liposarcoma and leiomyosarcoma (L-sarcomas). Methods: We report our ten-year real-life experience with trabectedin, 1.5mg/m2/d c.i.v. q3w till progression, regarding safety and efficacy in a cohort of 86 patients (24-83y). Liposarcoma was the diagnosis in 46% , leiomyosarcoma in 43%. Results: A total of 703 cycles of Trabectedin were given, with a median of five cycles per patient (range 1-59). Median overall survival (mOS) was 11 months for liposarcoma patients (range 1-63), and 15 months for leiomyosarcoma patients (range 1-35). There was no statistically significant difference in progression free survival (PFS), when stratified according to previous treatment lines given. Trabectedin exhibited a favorable safety profile, with only 22% requiring dose reductions. Grade 3 and more toxicity were noted in 25% of the patients, mostly myelosuppression. There was no treatment related death. Conclusions: In contrast to former trials, our retrospective data represents real life experience with Trabectedin, and includes patients with diverse age, histology, performane status, prior treatments and tumor burden. The group includes 10 patients (11.6%) who received Trabectedin as first line (Either due to congestive heart failure or to rapid progression following adjuvant Doxorubicin and Ifosfamide), 10 patients (11.6%) were above age 70, nine (10.5%) had histologies other than liposarcoma or leiomyosarcoma, and 23 (26.7%) had ECOG PS of 2 or higher. Trabectedin is a safe and effective drug in advanced high grade STS. Further research is needed to identify which patients will benefit most.
Circulating cell free tumor DNA detection as novel biomarkers to monitor desmoid tumors evolution.
Authors: Salas S Bastien , Macagno Nicolas , Penel Nicolas , Duffaud Florence , Nanni Isabelle , Bouvier Corinne , Rouah Raquel , Ouafik L'houcine , Bouhadiba Toufik , Bonvalot Sylvie , Fina Frederic 
Published: September 2018

11063 Background: Since desmoid tumors (DT) exhibit an unpredictable clinical course, with stabilization and/or spontaneous regression, an initial “wait-and-see” policy is the new standard of care to select best indications of active treatments in case of significant evolution. Therefore, translational research is crucial to identify predictive factors of progression. Most DT are characterized by CTNNB1 mutation (CM) in exon 3 (T41A, S45F, S45P). Circulating cell-free tumoral DNA (ctDNA), named "liquid biopsy", has emerged as a new promising non-invasive tool to detect biomarker in several cancers. Methods: We present a method of detection of DT-specific CM using a targeted strategy digital droplet PCR (ddPCR) on cell-free DNA (cfDNA) extracted from blood samples of 31 DT patients (pts). T41A, S45P, S45F and their respective CTNNB1 wild-type probe were designed for ddPCR. Furthermore, we analyzed the correlation of cfDNA levels (CTNNB1 wt/ml plasma) and evolution of the tumor. Results: Initial DT CM statuswas known for 28 pts and unknown for 3 pts. 24 pts presented a CM (17 pts T41A, 6 pts S45F and 1 pt S45P), 2 pts a mutation of APC, 2 pts were wild-type, and 3 pts were undetermined. Among pts with a CM, CTNNB1 mutants were detected in the cfDNA of 6 patients (19.4%). CM detection was not correlated with the quantity of cfDNA analyzed (p = 0,7263–Mann-Whitney (MW)). Absolute quantification of cfDNA (CTNNB1 wt) normalized by mL of plasma displayed higher levels for patients with progressive DT (p = 0,0009 - MW), this difference of cfDNA quantity was also present between progressive, stable and self-regressive DT (p = 0,0012 - MW). A threshold of 875 CTNNB1 copies/mL predicted DT progression with a sensibility of 100% (CI95%: 59-100) and a specificity of 76.5% (CI95%: 50.1-93.2). Absolute cfDNA quantity was also higher in patients harboring multiple desmoids (p = 0.0292 - MW). Conclusions: The absolute quantification of normalized cfDNA is correlated with evolution of the disease, independently of the initial tumor type of CM. This study opens the perspective of using cfDNA as a genomic biomarker to assess the tumor dynamics at initial diagnosis, and to monitor treatment strategy in case of tumor evolution.
Potential therapeutic genomic alterations in desmoplastic small round blue cell tumor.
Authors: Xiu Joanne , Bulbul Ajaz , Rashad Sadaf 
Published: September 2018

11066 Background: Desmoplastic Small Round Blue Cell Tumor (DSRCT) originates from a cell with multilineage potential. A molecular hallmark of DSCRT is the EWS-WT1 reciprocal translocation. Ewing’s and DSRCT are treated similarly due to similar oncogene activation pathways and DSRCT has been represented in very limited numbers in sarcoma studies. Methods: Thirty-five DSRCT tumors were tested with a multiplatform profiling service (Caris Life Sciences, Phoenix, AZ). Specific tests performed included sequencing (NextGen), protein expression (IHC) and gene amplification (CISH or FISH). Tumor mutational load (TML) was calculated as somatic nonsynonymous missense mutations sequenced with a 592-gene panel. Molecular alterations were compared to 88 Ewing sarcomas (ES). Chi-square tests were used for comparison and statistical significance was determined as p < 0.05. Results: In the 35 DSRCT tumors, high expression of TOP2A were seen in 63%, TOPO1 in 63%, PTEN in 62%, androgen receptor (AR) in 59%, EGFR in 42% of tumors; low expression of TUBB3 was seen in 44%, MGMT in 45%, TS in 48%, RRM1 in 57% and ERCC1 in 76% of tumors. When compared to ES, no significant difference was seen in protein expressions with the exception of a significantly higher overexpressson of AR in DSRCT (59% vs. 3%, p = 1.7E-10) and TUBB3 (56% vs. 29%, p = 0.03). Tumor expression of PD-L1 (Ab: SP142) was not seen in the 4 DSRCT and 10 ES tested. NextGen revealed a TP53 mutation (7%) and a FOXO3 mutation (L382fs) in DSCRT, while 6 TP53 mutations (13%), 2 APC mutations (L1129S and I1307K), 1 BRCA1(c.301+1G > A) and 1 CTNNB1 (T41A) mutation were identified in ES. Tumor mutational load evaluated in the 3 DSRCT and 11 ES tumors averaged 6 and 5 mutations per megabase, respectively. Conclusions: Molecular profiling on 35 DSRCT tumors and comparison with Ewing’s sarcoma revealed low immunogenicity ( < 10 Mutations/MB) and low frequency of actionable mutations including PD-L1 in both tumor types. High AR expression could present as a potential therapeutic target for DSRCT while taxanes may be more effective in Ewing’s sarcoma compared to DSCRT based on TUBB3 expression. Genomic and Molecular assessment may help determine the ideal regimen that will help achieve maximal tumor debulking.
When to treat Kaposi’s Sarcoma? Paclitaxel survival benefit on classic versus AIDS/HIV-related subtypes.
Authors: Eyzaguirre Eduardo , Enriquez Daniel , De la Cruz Ku Gabriel Antonio , Castro Victor , Morante Zaida , Valdiviezo Natalia , Portillo Diana , Cuellar Ponce de León Luis Ernesto , Mas Luis , Gomez Henry Leonidas 
Published: September 2018

11077 Background: Kaposi’s Sarcoma (KS) is a angioproliferative disease related to AIDS/HIV (AIDS-KS) or not (Classic, CKS). Treatment options are limited in low-income countries where taxanes represent a cost-effective alternative. Our aim was to compare overall response (ORR) of paclitaxel and progression free survival (PFS) and overall survival (OS) between KS subtypes. Methods: We reviewed 203 medical records from pts diagnosed between 2002-2014 at the Instituto Nacional de Enfermedades Neoplasicas (Peru). Survival differences were calculated by log-rank test in the univariate analysis and Cox regression analysis for prognostic factors. Results: From 203 pts, 85 had CKS and 118 AIDS-CK. Mean age was 67 and 36years in CKS and AIDS-KS, respectively. Most pts were males (84.7%), coinfections as tuberculosis (11.9%) were more frequent in AIDS-CK. In CKS pts, 80% debuted with localized elevated lesions at lower limbs, 16% were resected, 48% received RT and 29% paclitaxel. Among AIDS-KS, 37% had poor risk, 22% were diagnosed concurrently to HIV infection. 76.9% had generalized lesions with origin at lower limbs, 50.5% had +ve nodes and 19% visceral disease. 25.8% had Zubrod > 2 and mean neutrophil to lymphocyte ratio (NLR) was 3.5, CD4 count was lower in pts with recently diagnosis of AIDS/HIV (166 vs 268, p = 0.039) and no differences were noted on viral load (mean 233 411). 77.1% of AIDS-KS pts received ART and 56.8% paclitaxel. In AIDS-KS ORR was 77%(CR:52%, PR:22%) versus 86% in CKS (CR:43%, PR:43%). At 4.3year median follow-up, 3-year PFS and OS was 71% and 75% in AIDS-CK, while CKS had 78% and 79%, respectively. Paclitaxel was associated with better survival among AIDS-KS patients (PFS HR:0.41, 95%CI:0.2-0.7, p = 0.004 and OS HR: 0.37, 95%CI:0.1-0.7, p = 0.007), patients with Zubrod≤2 had more survival benefit. There was not survival benefit in CKS pts. At multivariate analysis, ART and paclitaxel were associated with favorable PFS and OS, while higher NLR and poorer status performance to worse outcomes in AIDS-KS pts. Conclusions: Paclitaxel is an effective alternative treatment for AIDS-KS, there was not survival benefit in CKS patients. Poorer status performance and higher NLR were associated to worse prognosis.
Cancer-associated macrophage-like cells as prognostic indicators of overall survival in a variety of solid malignancies.
Authors: Adams Daniel , Adams Diane K , Lin Steven H. , Cristofanilli Massimo , Bergan Raymond C. , Marks Jeffrey R , Martin Stuart S , Chumsri Saranya , Ho Thai Huu , Lapidus Rena G. , Tsai Susan , Tang Cha-Mei , Alpaugh R. Katherine 
Published: September 2018

11503 Background: Cancer Associated Macrophage-Like cells (CAMLs) are a recently described circulating stromal cell subtype commonly found in the peripheral blood of patients in all stages of solid malignancies and in a variety of cancer subtypes. However, while their biological association to cancer is being studied, their clinical utilization as it relates to cancer prognosis has not been evaluated. Methods: A two year prospective study was undertaken to evaluate the relationship of CAMLs and overall survival (OS) in 6 solid tumor types. The single blind multi-institutional study consisted of 269 stage I-IV patients; breast (n = 57), esophageal (n = 21), prostate (n = 43), pancreatic (n = 59), lung (n = 54), and renal cell (n = 35), in treatment (n = 134) and untreated baseline (n = 135). 7.5mL of whole blood was filtered by CellSieve microfiltration assay and CAMLs enumerated, as previously described. Patients were grouped by CAML number ( < 6 or ≥6) and by size ( < 49 or ≥50 µm) to evaluate hazard ratios (HR) by censored univariate & multivariate analysis. Results: CAMLs were identified in 93% of samples, averaging 8.2 CAMLs/7.5mL blood sample, and found in all 6 cancers at baseline and during treatment. Average CAML number was associated with disease stage and CAML positivity was 4.4 & 80% (Stage I), 4.7 & 93% (Stage II), 9.3 & 98% (Stage 3), 12.1 & 97% (Stage IV). Univariate analysis of patients (n = 269) stratified by ≥6 CAMLs had reduced OS (HR = 1.8, 95%CI 1.1-2.9, p = 0.03). Further, CAML size also had reduced OS in patients with ≥50 µm CAMLs (HR = 2.7, 95%CI 1.8-4.0, p < 0.0001). Conclusions: Our data suggests that in solid malignancies, CAML number and size appear to clinically correlate with OS in early and late stage disease. Given these results relating CAMLs with OS, further analysis is warranted to determine if CAMLs can serve as a clinically-relevant blood-based marker.
VEGFR2 cytoplasmic expression (VEGFR2ce) in relation to survival in metastatic breast cancer (MBC) patients (pts) treated with bevacizumab (Bev).
Authors: Borba Roseana Melo , Felismino Tiago Cordeiro , Da Costa Alexandre Andre B. A. , Lima Vladmir C. , Corassa Marcelo , Bezerra Stephania , Osorio Cynthia Bueno de Toledo , Paiva Tadeu Ferreira 
Published: September 2018

11523 Background: Bev is a monoclonal antibody that binds to VEGFA that demonstrated improved progression free survival (PFS) in MBC clinical trials. VEGFR2, NOTCH1, Integrin a1b2 and ILK are angiogenesis-related proteins possibly related with Bev efficacy. The correlation of these proteins expression and Bev survival variables was evaluated. Methods: We retrospectively analyzed 1st line chemotherapy in two HER2 negative MBC cohorts. Pts were treated between May-07 and July-14. Cohort 1 (C1) was treated with paclitaxel and Cohort 2 (C2) with paclitaxel and Bev. Expression of biomarkers was determined by immunohistochemistry. Tumor samples were arranged on a tissue microarray. Survival curves were calculated by Kaplan-Meier method and log-rank test. Cox model was used in multivariate analysis. Results: C1 had 42 pts. Median age was 63y. Tumor subtypes were divided in luminal (92.9%) and triple negative (TN) (7.1%). Visceral metastasis (mets) were present in 71.4%. Median follow-up (mFUP) time was 32.1m. mPFS was 8.0m and mOS was 33.5m. C2 had 29 pts. Median age was 57y. Luminal 79.3%; TN 20.7%; Visceral mets 79.3%; mFUP 38m. mPFS was 10.5m and mOS was 47m. In C2, high VEGFR2ce was correlated with improved PFS (high VEGFR2 16.5m x low VEGFR2 6.8m, p = 0.025). Breast cancer subtype, metastasis pattern and VEGFR2 expression were included in the multivariate analysis for PFS. VEGFR2 remained as independent factor (HR 0.35; IC95% 0.14 – 0.85, p = 0.021). In C1, VEGFR2 was not correlated with improved PFS (high VEGFR2 8.6m x low VEGFR2 8.0m, p = 0.24). Other markers were not associated with PFS. Conclusions: High VEGFR2ce was associated with increased PFS in patients treated with Bev. In MBC VEGFR2 may have a role as a predictive tool on benefit of antiangiogenic therapy.
Circulating tumor cell status and benefit of radiotherapy in stage I breast cancer.
Authors: Goodman Chelain Rae , Seagle Brandon-Luke L , Donnelly Eric Donald , Strauss Jonathan Blake , Shahabi Shohreh 
Published: September 2018

11524 Background: Circulating tumor cell (CTC) status has been shown to be prognostic of decreased survival in non-metastatic breast cancer. While up to 20-30% of patients with early breast cancer have detectable CTCs, less is known regarding the role of CTC-status in guiding clinical management. Methods: An observational cohort study was performed on women with stage I breast cancer evaluated for CTCs from the 2004-2014 National Cancer Database. Logistic regression was used to explore clinicopathological associations with CTC-status. Kaplan-Meier and multivariable Cox proportional-hazards survival analyses were used to estimate associations of CTC-status with overall survival using a propensity score-adjusted and inverse probability-weighted matched cohort. Results: Of the stage I breast cancer women evaluated for CTCs, 23.1% (325/1,407) were CTC-positive. Age, histology, receptor status, and nodal stage were associated with CTC-status. CTC-status was an effect modifier of the radiotherapy-survival association: CTC-positive women who did not receive radiotherapy had an increased hazard of death compared to CTC-negative women who also did not receive radiotherapy (four-year survival: 85.7% vs. 93.3%, HR = 2.92, CI = 1.43-5.98, P = 0.003). CTC-positive patients treated with radiotherapy did not have decreased survival compared to CTC-negative patients not treated with radiotherapy (HR = 0.67, CI = 0.28-1.65, P = 0.40). From the matched cohort analysis, CTC-positive women who did not receive radiation had a 4.82-fold increased hazard of death compared to CTC-positive women treated with radiotherapy (four-year survival: 83.2% vs. 96.6%; CI = 2.62-8.85, P < 0.001). Conclusions: Treatment with adjuvant radiotherapy was associated with improved survival in CTC-positive women with stage I breast cancer. If prospectively validated, CTC-status may be valuable as a predictor of benefit of radiotherapy in early stage breast cancer.
Association of circulating tumor DNA clearance during treatment with improved progression-free survival in advanced non-small cell lung cancer patients.
Authors: Lu Shun , Song Yong , Xie Zhanhong , Li Min , Zhu Zhengfei , LIU LI , Dong Xiaorong , Chen Yuan , Zheng Di , Zhao Weixin , Chang Jian Hua , Jin Meiling , Hu Jie , Tong Gangling , Rao Chuangzhou , Xu Haiyan , Zhang Lu , Mao Xinru , Han-Zhang Han , Liu Hao 
Published: September 2018

11528 Background: Currently, response assessment of patients with non-small cell lung cancer (NSCLC) primarily relies on imaging scans, which do not reflect biological processes at the molecular level. We utilized circulating tumor DNA (ctDNA) coupled with capture-based ultra deep next generation sequencing to conduct dynamic monitoring of treatment response, thus evaluating the ability of ctDNA as a tumor clonal response biomarker. Methods: We performed capture-based sequencing on longitudinal plasma samples, including baseline and a minimum of 2 evaluation points, obtained from 88 patients with advanced NSCLC using a ctDNA panel, spanning 160KB of human genome and consisting of critical exons and introns from 168 genes. This real world study comprises a highly heterogeneous cohort with a mixture of prior treatment exposure. Results: At baseline, treatment-naïve patients often harbor solo driver mutation; in contrast, patients with prior treatments are more likely to harbor concurrent driver mutations. Patients who received molecular targeted therapy according to the baseline sequencing results have a longer progression-free survival (PFS) (p = 0.0001), demonstrating the value of ctDNA in directing treatment. During subsequent evaluations, we observed 74% concordance rate between molecular and radiographic responses. Furthermore, our data revealed that during follow-up, patients with at least one time of undetectable ctDNA are associated with a longer PFS (p = 5.52e-6), regardless the type of treatment commenced. Among 44 patients who had at least one time of undetectable ctDNA, 39 achieved partial response or stable disease as their best response. Collectively, this phenomenon reflects clonal response, thus demonstrating the biological nature underlying the clinical response assessed by imaging modalities. Conclusions: This real world study demonstrates that patients with at least one time of ctDNA clearance during subsequent evaluation are associated with a longer PFS. Our study warrants further investigations to explore the value of ctDNA clearance as a surrogate endpoint of efficacy and as a risk stratification factor.
Prevalence and heterogeneity of androgen receptor splice variants and intra-AR structural variation in patient with castration-resistant prostate cancer.
Authors: Dirix Luc Yves , De Laere Bram , van Dam Pieter-Jan , Whitington Tom , Mayrhofer Markus , Henao Diaz Emanuela , Van den Eynden Gert , Vandebroek Jean , Del-Favero Jurgen , Van Laere Steven J , Gronberg Henrik , Lindberg Johan 
Published: September 2018

11530 Background: Androgen receptor splice variant 7 (AR-V7) is linked to a priori resistance to abiraterone acetate and enzalutamide. However, AR-V7 negativity does not necessarily indicate responsiveness and up to 20% of AR-V7 positive patients do demonstrate moderate response to these second-line endocrine therapies. Methods: Peripheral blood samples from patients with CRPC (n = 30) starting a new line of systemic therapy were subjected to comprehensive profiling of AR. AR splice variant (ARV) profiling for eight isoforms was performed by targeted RNA-Seq on CellSearch-enriched circulating tumour cells. Low-pass whole-genome and targeted sequencing of the entire AR gene in plasma-derived circulating cell-free DNA allowed the assessment of copy number status and structural rearrangements, respectively. ARV expression, structural variation, copy number alterations and ligand-binding domain mutations were combined and correlated to clinicopathologic parameters. Results: Twenty-five out of 30 patients (83%) demonstrated an aberration in AR. Twenty out of 30 patients (66.7%) demonstrated AR amplifications. Interestingly, 15/30 patients had intra-AR structural variants, of whom 14 expressed ARVs. In the context of endocrine treatment, 15/26 (57.7%) patients were ARV-positive with 13/15 patients having less than 6 months benefit from their therapy (Fisher’s exact test, p = 0.0115). ARV expression was heterogeneous with 10/15 ARV-positive patients expressing several ARV. Notably, AR-V7 was most frequently detected, however AR-V3 was 3.5x more abundant (Wilcox signed rank, p = 0.0029). In 17 patients, a baseline AR profile was available and demonstrated how having any ARV was associated with progression-free survival (HR: 4.53, 95%CI: 1.424–14.41; p = 0.0105). In the poor response group, 6/17 (35.2%) were AR-V7 negative, of whom 4 carried other AR aberrations. Conclusions: Comprehensive AR profiling on liquid biopsies is feasible and provides new insights into the mechanisms driving endocrine resistance. Clinical validation, by means of a non-interventional, prospective and multicentric study, is essential and currently ongoing.