bluuebunny/crossref_metadata_2025_split huggingface dataset:
Anthracycline, gemcitabine, and pazopanib in epithelioid sarcoma: Results of a retrospective multi-institutional case series.
Authors: Frezza Anna Maria , Asano Naofumi , Jones Robin , Ratan Ravin , Teterycz Pawel , Gelderblom Hans , Boye Kjetil , Brahmi Mehdi , Palmerini Emanuela , Hindi Nadia , Brunello Antonella , Desar Ingrid , Grignani Giovanni , Fedenko Alexander A. , Vincenzi Bruno , Papai Zsuzsanna , Kawai Akira , Lo Vullo Salvatore , Casali Paolo Giovanni , Stacchiotti Silvia 
Published: September 2018

11065 Background: To report on a multi-institution retrospective study on the activity of anthracycline-based (Ab) and gemcitabine-based (Gb) regimens as well as pazopanib (P) in patients with advanced epithelioid sarcoma (ES) treated within 16 sarcoma reference centres in Europe, US and Japan. Methods: Patients with a histologically confirmed diagnosis of locally advanced/metastatic ES were selected. Classic and distal subtypes were defined based on morphology (WHO 2014). INI1 expression is under evaluation.Response was evaluated by RECIST.Progression-free survival (PFS) and overall survival (OS) were computed by Kaplan-Meier method. Results: Ninety ES patients were identified (Table 1). They were treated with Ab (72), Gb (30) and P (20); 25 pts received more than one treatment. The median follow-up for Ab, Gb and P groups was 32, 24 and 22 months, respectively. The response rate (RR) for Ab was 25% (95% CI 16%-37%), with a median PFS and OS of 6 and 17 months. The RR for Gb was 23% (95% CI 10% - 42%), with 1 complete response and a median PFS and OS of 5 and 20 months. In the P group, no objective responses were reported, and median PFS and OS were 3 and 9 months. A non-statistically significant trend towards a greater RR in proximal than classic subtype was seen in both Ab (27% vs 22%) and Gb (30% vs 13%) groups. Conclusions: This retrospective series, the largest currently available, confirms the activity of Ab and Gb in ES, with a similar RR and PFS in both groups. In this population, the value of P seems limited. These data may serve as a benchmark for trials of novel agents in ES. [Table: see text]
Expression and prognostic significance of PDGF ligands (A, B, C, and D) and PDGFR (A, B, and L) in soft-tissue sarcomas and GIST.
Authors: Lesluyes Tom , Blay Jean-Yves , Schoffski Patrick , Italiano Antoine , Le Cesne Axel , Debiec-Rychter Maria , Mir Olivier , Sciot Raf , Toulmonde Maud , Ray-Coquard Isabelle Laure , Rios Maria , Brahmi Mehdi , Chevreau Christine , Isambert Nicolas , Bonvalot Sylvie , Piperno-Neumann Sophie , Coindre Jean-Michel , Chibon Frederic 
Published: September 2018

11067 Background: Sarcomas are a variety of rare connective tissue cancers. Doxorubicin and olaratumab (Ab against PDGFRA) improved survival in a recent Phase 1/2 study. Besides PDGFRA mutated gastrointestinal stroma tumor (GIST) and dermatofibrosarcoma protuberans, the role of PDGFR and the according ligands in the biology of sarcoma remain unclear. Methods: The expression levels of PDGF (A,B,C,D) and PDGFRs (A,B,L) were studied in a series of 255 sarcoma pts in localized phase using the Agilent 014850 platform. Data are available online (http://atg-sarc.sarcomabcb.org). Histologies were GIST (n = 60), myxoid liposarcoma (MLPS, n = 50), synovial sarcoma (SyS, n = 58), and sarcoma with complex genomics (SCG, n = 87). Expression levels were analyzed and tested for prognostic values for metastasis free survival (MFS) in uni- and multivariate analysis using SPSS 19.0. Results: Expression levels (ELs) of PDGFs and PDGFRs varied across histotypes: PDGFA levels were highest in SyS and lowest in MLPS (p < 0.0001). PDGFB and C levels were lower in GIST (p < 0.0001), while PDGFD ELs were similar across histological subtypes. PDGFRA ELs were highest in MLPS, while PDGFRB & L ELs were lowest in GIST and SyS (p < 0.0001 all). Complex patterns of correlation of expression between ligands and receptors were observed in each individual subtypes. PDGFA ELs above median were associated with a marginally higher risk of metastasis . Conversely, PDGFD ELs above median was associated with a reduced risk of metastasis in the whole cohort (p = 0.02). The ELs of the 3 receptors were not correlated to MFS. In multivariate analysis using Cox model on the non-GIST sarcoma cohort (histology, grade, depth, with size, PDGFA, PDGFD as continuous variables): histology, size, grade and PDGFA ELs were independent adverse prognostic factors (PF), while PDGFD ELs was a favorable PF for MFS. In the GIST cohort, testing AFIP score, PDGFA & D ELs as continuous variable, PDGFD ELs was also an independent favorable PF for MFS, in addition to AFIP score. Conclusions: The expression of PDGFs and the according receptors varies across sarcoma histological subtypes. PDGFA and D expression levels correlate independently to the risk of metastatic relapse.
Predictive role of FAS for trabectedin in second lines of advanced soft tissue sarcoma (ASTS): A Spanish group for research on sarcoma (GEIS) study.
Authors: Martin Broto Javier , Marcilla David , Ramos Rafael , Moura David Silva , Alvarez Ramiro , Hernandez Nieves , Agra Pujol Carolina , Mayordomo Empar , Romagosa Cleofe , Bague Silvia , Reguero Eugenia , Cruz Julia , Martin Francisco Javier , Gutierrez Antonio , Cruz Josefina , Alvarez Alvarez Rosa Maria , Diaz Beveridge Robert , Valverde Morales Claudia Maria , Lopez-Pousa Antonio , Martinez-Trufero Javier 
Published: September 2018

11071 Background: There are currently several second-line options for the treatment of ASTS as gemcitabine combinations, trabectedin, pazopanib, eribulin or olaratumab plus doxorubicin in cases where anthracyclins are still possible. There is an unmet need for predictive biomarkers which hinders the rational selection of the best sequence in second line. We already published the prognostic value of FAS in first line of ASTS while this study analyzes its predictive role in different second line schemes. Methods: Most relevant selection criteria for this study were having received trabectedin in 2nd line or beyond for ASTS, progressive disease after at least one previous line for ASTS and signed CI. A TMA was set up for FAS staining (Cell Signaling) with blocks from diagnostic time. Two expert blinded pathologists reviewed and classified the cases as negative, weak or strong. Kaplan–Meier estimations were used for time-to-event variables and the log-rank test was used to compare groups. Results: A series of 198 patients accomplished selection criteria. Metastases at diagnosis occurred in 46 (24%) and median time to metastases was 18.8 months (CI 16,3; 21.3). Previous line to trabectedin consisted of gemcitabine combination 83 (42%), Doxorubicin-based 65 (33%) and others 50 (25%). Median PFS for previous and trabectedin lines were 3.5 (2.8-4.2) and 3.4 (2.8-4) months respectively. FAS positive entailed significantly better PFS for the previous trabectedin line: 4.1 (1.5-6.7) vs 3.0 (2.5-3.5) months, p = 0.01 whereas FAS positive was related with worse PFS for the trabectedin line 2.5 (2.2-2.8) vs 3.7 (2.7-4.8) months, p = 0.028. These results were more notorious for L-sarcoma cases: 7.0 (3.6-10.5) vs 4.3 (1.9-6.6) months, p = 0.017 in previous line and 2.4 (2.2-2.6) vs 6.5 (3.8-9.3) months, p < 0.001 in trabectedin. From trabectedin administration, FAS+ had significantly worse OS especially in L-sarcomas: 11.9 (5.2-18.7) vs 21.7 (12.7-30.8) months, p = 0.002. Conclusions: FAS showed predictive value in PFS and OS for trabectedin administration in ASTS. The different prognostic role of FAS across distinct lines and its relevance in L-sarcomas deserve further attention.
NY-ESO-1 antigen expression as a prognostic factor for soft tissue sarcomas.
Authors: Komarov Yuriy , Barchuk Anton , Semenova Anna Igorevna , Semiglazova Tatiana , Imianitov Evgenii , Iyevleva Aglaya , Baldueva Irina , Novik Alexey Viktorovich , Nehaeva Tatyana Leonidovna , Pipia Nino , Huhtala Heini , Ivantsov Alexander , Artemyeva Anna , Moore Malcolm , Protsenko Svetlana ,   NII
Published: September 2018

11075 Background: While a number of antigens are known to be expressed in soft tissue sarcomas, little is known about the prognosis of patients with such tumors. Recent data have demonstrated immunologic activity in sarcoma patients expressing the NY-ESO antigen, found positive in 20-80% cases. MAGE A3 has also recently attracted attention with regard to soft tissue sarcomas. In our study we aimed to assess any association between antigen expression and prognosis. Methods: In a case-control study we retrospectively collected data from a prospective database of all 137 patients with sarcomas receiving first line therapy in the Petrov Research Institute of Oncology in Saint-Petersburg. All cases were morphologically verified, with mRNA expression of NY-ESO-1, MAGE A3, PDGFR A, PDGFR B, beta-tubullin and top2alpha additionally being tested by quantitative real-time PCR in a subset of patients. The log-rank test was applied to compare Kaplan-Mayer estimates of progression-free (PFS) and overall survival (OS) by univariate analysis. Hazard ratios were derived after adjustment for age, gender, several covariates for type of chemotherapy and disease stage with two-sided probability at a significance level of 0.05. Results: The positive rate for expression of NY-ESO was 20% (11/43).Only NY-ESO was significantly associated with PFS (p < 0,001), with a median durations of 10, 4 and 7 months for positive, negative and not tested for NY-ESO expression, respectively. The adjusted hazard ratio (HR) for NY-ESO positive patients was 2.2 (95%CI, 1.2;4.2) compared with their negative counterparts, The HR for patients not tested for NY-ESO was 2.0 (95%CI, 1.3;3.0). Among other covariates, only a combination of drugs was associated with a lower risk of progression (HR, 0.7 95%CI, 0.4;0.98) , as compared to those receiving a single chemotherapy agent. Conclusions: This first report showing prognostic significance of NY-ESO expression in soft tissue sarcoma patients, suggests that research should be focused on targeting this antigen. Participation in clinical trials for patients with positive NY-ESO expression is highly recommended, because of poor survival regardless of the type of standard treatment.
Effect of mast cells on efficacy of anti-angiogenic therapy by secreting matrix-degrading granzyme b.
Authors: Wroblewski Mark , Velthaus Janna-Lisa , Bauer Raimund , Müller Volkmar , Schem Christian , Fasching Peter A. , Karn Thomas , Fehm Tanja N. , Kühn Thorsten , Rack Brigitte Kathrin , Denkert Carsten , Untch Michael , Kittel Kornelia , Janning Melanie , Minner Sarah , Sauter Guido , Bokemeyer Carsten , Von Minckwitz Gunter , Loibl Sibylle , Loges Sonja 
Published: September 2018

11522 Background: Resistance towards anti-angiogenic therapy (AAT) still represents a substantial clinical challenge. As mast cell (MC) density is known to correlate with tumor angiogenesis, we analyzed if inhibition of MC holds potential to increase efficacy of AAT in mice and cancer patients. Methods: C57BL/6J (WT), NSG or MC-deficient KitW-sh(Wsh) mice were subcutaneously injected with Panc02, EL4 or BxPC3 cells with or without bone marrow-derived MC. Tumors were treated with 20 mg/kg of anti-VEGFR2 antibodies (DC101) or 25 mg/kg cromoglicic acid. Tissue microarrays from n = 299 breast cancer patients from the GeparQuinto Phase 3 clinical trial were stained for MC and MC numbers were correlated with clinical data. Results: We observed that absence of MC reduced tumor growth and increased the efficacy of AAT in different tumor models. Intriguingly, AAT only initially reduced microvessel proliferation but this was abrogated over time as a result of MC-mediated resistance. We show that MC secrete increased amounts of granzyme b upon therapy, which mobilizes alternative pro-angiogenic factors from the tumor matrix. These factors act beside the targeted VEGFA-VEGFR2-axis and reinduce angiogenesis despite the presence of AAT. Importantly, MC-mediated resistance could be overcome using the FDA-approved MC inhibitor cromoglicic acid. In line with our preclinical data, high intratumoral MC density correlated with disease progression in HR+ breast cancer patients when Bevacizumab was added to standard neodjuvant chemotherapy (HR 8.45, p = 0.006). Accordingly, Kaplan-Meier curves indicated that disease free survival of patients with high tumoral MC density was numerically shorter in the whole cohort and significantly shorter in the HR+ cohort upon addition of AAT to chemotherapy (p = 0.168 and p = 0.004, respectively). Conclusions: Here we unravel a novel resistance mechanism, by which MC hamper efficacy of AAT in mice and cancer patients. In preclinical models this effect could be overcome by combining AAT with an FDA-approved MC inhibitor indicating high clinical relevance. Thus, combination of FDA-approved MC inhibitors with AAT might be a suitable approach to increase efficacy of AAT in the clinic.
Circulating tumor DNA profiling to reveal heterogeneity of EGFR-TKI resistance mechanisms in lung adenocarcinoma patients.
Authors: Chen Rongrong , Zhao Jun , Hu Xingsheng , Dai Pingping , Yi Yuting , Zhou Zhenzhen , Guan Yanfang , Zhao Meiru , Liu Tao , Yang Ling , Yi Xin , Xia Xuefeng 
Published: September 2018

11527 Background: EGFR-TKI therapy has significantly improved prognosis of NSCLC patients with EGFR sensitive mutation. However, almost all patients ultimately develop PD while receiving TKI treatment. Circulating tumor DNA (ctDNA) is promising as a minimally-invasive liquid biopsy for comprehensive analysis of molecular abnormalities. Methods: A total of 254 advanced lung adenocarcinoma patients with signs of EGFR-TKI resistance were enrolled in the study. ctDNA was analyzed using next-generation sequencing based ER-Seq method, which enables simultaneously assess single-nucleotide variants, insertions/deletions, rearrangements, and somatic copy-number alterations across 59 genes. Results: ctDNA profiling was possible for all patients, 172 patients had ≥ 1 ctDNA alteration(s). Median number of plasma somatic mutations was 2, predominantly located in EGFR and TP53, with MET, ERBB2 and PIK3CA followed. Of that, 30.6% of mutations detected in ctDNA were at a frequency below 1%. In exploring the mechanisms of TKI-resistance, we found TKI-sensitizing mutations were not detected in plasma of 138 patients (54.3%). Known mechanisms such as EGFR T790M/C797S mutation, activating mutations of PI3K- AKT- mTOR signaling, amplification of MET, activating mutation / amplification of ERBB2, activating mutation of KRAS, BRAF or mutations in EGFR EX20 other than T790M/C797S were identified in 59, 16, 8, 7, 3, 2, and 2 patients respectively. T790M/C797S was detected in 50.8% of patients with plasma positive for TKI-sensitizing mutations. Of note, C797S was only detected in patients treated with AZD9291. EGFR amplification were identified in 15 patients, though whether it would result in TKI-resistance was still controversial. Co-occurrence of resistance mechanisms were observed in 22 patients including 13 patients without TKI-sensitizing mutations. Conclusions: There was a high frequency of inter and intra-patient heterogeneity of resistance mechanisms after EGFR TKI therapy. ctDNA can be used as a ‘liquid biopsy’ to facilitate the broad exploration of potential resistance mechanisms.
Bim and soluble PD-L1 (sPD-L1) as predictive biomarkers of response to anti-PD-1 therapy in patients with melanoma and lung carcinoma.
Authors: Dronca Roxana Stefania , Mansfield Aaron Scott , Liu Xin , Harrington Susan , Enninga Elizabeth Ann , Kottschade Lisa A. , Koo Chi Wan , McWilliams Robert R. , Block Matthew Stephen , Nevala Wendy Kay , Markovic Svetomir , Dong Haidong 
Published: September 2018

11534 Background: To date, there are no validated blood-based biomarkers of predicting response to PD-1 blockade. We previously reported that Bim is a downstream signaling molecule of the PD-1 pathway, and that measurement of Bim levels in circulating T-cells may predict and monitor responses to anti–PD-1 therapy in melanoma. We have identified the existence of sPD-L1 in cancer patients and showed that the sPD-L1 is biologically active and capable of triggering apoptosis in activated T-cells. Here we evaluated T cell Bim and sPD-L1 in the peripheral blood (PB) as biomarkers of response in a cohort of patients with metastatic melanoma and lung cancer undergoing anti-PD1 therapy. Methods: 60 pts treated with anti-PD-1 had PB collected at baseline and at radiographic tumor evaluation. Frequencies of Bim+ T cells and Bim median fluorescence intensity (MFI) were measured by flow cytometry in gated tumor-reactive CD11ahighPD1+ CD8+ T cells. We also measured levels of sPD-L1 at baseline and serially during treatment with sPD-L1 ELISA. Baseline Bim and sPD-L1 levels and percent change in Bim levels in patients (pts) who had a radiographic response (CR/PR) were compared to those who had progressive disease (PD) at 12 wks. Results: Similarly to previously reported preliminary data, pts with objective response (CR/PR, 15/60) after 4 cycles of anti-PD1 therapy had higher frequency of Bim T cells at baseline compared to pts with PD (16/60) (mean 43% vs. 30%, P = 0.0484). The frequencies of Bim+ T cells decreased significantly after the first 3 months of treatment in responders compared with progressors (mean -16% vs. + 40% P = 0.0111). High baseline sPD-L1 were associated with progression on anti-PD1 therapy (mean 2.8 ng/mL vs. 0.7 ng/mL, p = 0.07, n = 13) and the levels increased by the first tumor assessment in patients resistant to anti-PD-1. Conclusions: Measurements of Bim and sPD-L1 levels may help to select patients who are likely to benefit from anti-PD1 monotherapy versus combinatorial strategies, and provide a new non-invasive way to monitor response to anti-PD-1 blockade. A larger validation study is underway.
Association of circulating tumor DNA (ctDNA) tumor mutational burden (TMB) with DNA repair mutations and response to anti-PD-1/PD-L1 therapy in non-small cell lung cancer (NSCLC).
Authors: Davis Andrew A. , Chae Young Kwang , Agte Sarita , Pan Alan , Iams Wade Thomas , Cruz Marcelo Rocha De Sousa , Mohindra Nisha Anjali , Villaflor Victoria Meucci , Giles Francis J. 
Published: September 2018

11537 Background: Identifying optimal biomarkers for response to anti-PD-1/PD-L1 therapies in NSCLC is critical. TMB is a potential biomarker of genomic instability and neoantigen binding sites to activated effector T cells. The goal of this study was to derive a measure of ctDNA TMB and to examine the association between TMB and clinical variables, DNA repair mutations, and response to checkpoint blockade. Methods: We retrospectively examined 136 patients with NSCLC who had undergone ctDNA next-generation sequencing (NGS) in our institution. The ctDNA testing, performed by Guardant360, is not currently clinically indicated for TMB. We derived ctDNA TMB using coding base substitutions and indel alterations both including and excluding potentially functional variants, but excluded rearrangements, fusions, and copy number variants. In addition, survival data were obtained for 17 patients who were treated with anti-PD-1/PD-L1 therapy and had ctDNA before first line therapy or within 90 days of therapy initiation. Results: ctDNA TMB was associated with the number of direct and indirect DNA repair gene mutations (t-test, p < 0.05). Smoking was also associated with higher TMB when including functional variants (chi-square test, p = 0.034). Driver mutations (EGFR, KRAS) and prior radiation therapy were not correlated with TMB. Lower ctDNA TMB (below the median, 15 mutations/MBp) was associated with longer PFS and OS (Kaplan-Meier log-rank test, p < 0.05). Conclusions: ctDNA TMB was derived and was significantly associated with greater number of DNA repair mutations. Smoking predicted higher TMB score. However, in a small subset of patients, lower ctDNA TMB predicted response to checkpoint blockade. Potential reasons include the small sample size, the possibility of ctDNA reflecting tumor burden, and the limited length of DNA sequenced (~78,000-138,000 bp). Larger, prospective studies are necessary to validate these findings.
Progastrin: A new specific early cancer screening biomarker.
Authors: Prieur Alexandre , Mazard Thibault , Assenat Eric , Ychou Marc , Gourgou Sophie , Mariani Odette , Bronzini Thierry , Salomon Anne Vincent- , Joubert Dominique 
Published: September 2018

11545 Background: One in two people will be diagnosed with cancer during his/her lifetime. Because we are lacking effective screening tests, most cancers are detected in late stages, when survival rates are very low. Here, we show the development of the first early cancer screening test for multiple cancers using progastrin (PG) as biomarker. The gene coding for PG is a target gene of the Wnt oncogenic pathway that is activated in almost all type of cancers, at the earliest stages of development. We showed that the neutralization of PG by a specific humanized antibody could be used for colorectal cancer treatment. Moreover, as PG is secreted by cancer cells, we can specifically detect it in the blood of persons having a cancer at early stage. Methods: Antibodies directed against PG were produced and selected for target specificity and affinity. ELISA is the most reliable assay to detect biomarker on the blood. Hence, selected antibodies were used to set up an ELISA sandwich to detect PG in the blood of patients with various types of cancers and at various stages. Results: We first set up a prototype ELISA using polyclonal antibodies. We validated our test using 223 blood samples from patients with polyps and colorectal cancers at various stages for which we observed an increased levels of PG. Then, we showed the presence of PG in the blood of 212 patients with other types of cancer, including liver, pancreatic and breast cancers, confirming that PG could be used as a biomarker for multiple types of cancers. Next, we set up our industrial ELISA using polyclonal and monoclonal antibodies called DECODE Lab and tested 245 new blood samples from patients with various types of cancer including early stages. Strikingly, using our test we were able to detect breast (AUC = 0.9638; sensitivity 70%), colorectal (AUC = 0.9635; sensitivity 73%), melanoma (AUC = 0.9882; sensitivity 87%) and cervix utery (AUC = 0.9827; sensitivity 84%) all stages combined with a high specificity of 97.5%. Finally, for early stage patients with melanoma and breast cancer, we had a sensitivity of 68% and 81% respectively. Conclusions: Taken together, the results presented here show that PG is a reliable biomarker for early cancer screening. The ELISA test that we developed is very efficient and now available for the clinic.