bluuebunny/crossref_metadata_2025_split huggingface dataset:
Osteosarcoma prognostic nomograms for predicting the 10-year probability of mortality and recurrence.
Authors: Wang Haotong , Miao Ruoyu , Jacobson Alex , Goldberg Saveli , Harmon David C. , Cote Gregory , Hornicek Francis J , Raskin Kevin , Nielsen Gunnlaugur , DeLaney Thomas F. , Choy Edward , Chen Yen-Lin 
Published: September 2018

11020 Background: The multidisciplinary approach in treatment of osteosarcoma has been well established and well adopted nationwide. This study combined the clinical prognostic factors at initial presentation into a nomogram to predict local control (LC), metastasis free survival (MFS), and overall survival (OS) for patients with non-metastatic bone osteosarcoma. Methods: We reviewed 397 osteosarcoma patients treated from 1995 to 2014. Patients with metastatic disease at diagnosis or limited follow up were excluded, resulting in 283 cases for analysis. Clinical and pathologic variables were recorded. Predictive variables included age at diagnosis, gender, previous radiation history, site, tumor size, histologic subtype, histologic grade, extra-osseous extension (EOE), lymphovascular invasion (LVI), necrosis rate and margin. The multivariate Cox proportional hazards regression was used to analyze survival outcomes and risk variables. Results: At 10 years, LC was 70.4% (95% confidence interval, CI: 64.0%-76.7%), MFS was 64.7% (95% CI: 58.1%-71.3%), and OS was 61.5% (95% CI: 54.9%-68.1%). Multivariate Cox model identified age (p = 0.033), site (p = 0.020), EOE (p = 0.017), LVI (p = 0.011), and margin (p = 0.039) were correlated with LC; age (p = 0.028), tumor size (p < 0.001), histologic grade (p = 0.039), and LVI (p = 0.014) were correlated with MFS; whereas age (p < 0.001), prior radiation history (p = 0.010), tumor size (p = 0.002), histologic subtype (p = 0.012), EOE (p = 0.002), and LVI (p = 0.001) were associated with OS. The nomograms were drawn on the basis of the Cox regression model and were internally validated using bootstrapping, with predictive accuracy of ±7.2% for 10-year LC, ±7.4% for 10-year MFS, and ±7.5% for 10-year OS. Conclusions: Nomograms have been developed to predict the 10-year local-control failure, recurrence and death. We suggest that this tool at presentation may be useful for individualized risk evaluation, patient counseling, and making clinical decisions.
Inhibition of autophagy sensitizes gastrointestinal stromal tumor cells to TKI/Bcl-2 inhibitors-induced apoptosis.
Authors: Zhang Shuchao , HU Guozhi , Paz-Mejia Ana Cristina , Li Luyuan , Trent Jonathan C. 
Published: September 2018

11036 Background: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor of the GI tract. Most GISTs are driven by mutations in KIT or platelet-derived growth factor receptor-α (PDGFRA), which responds well to imatinib, a tyrosine kinase inhibitor (TKI) that blocks KIT and PDGFR-α signaling. Bcl-2 family plays a critical role in the regulation of cell apoptosis in GISTs. ABT-737 as an inhibitor of Bcl-2/Bcl-xL can result in a time and dose-dependent activation of apoptosis. Autophagy is a key mechanism to promote tumor cells survival, inhibition of which can induce the cell death in GISTs. Chloroquine, an antimalarial drug, has been also identified as an autophagy inhibitor. In this study, we assessed the combinational effects of imatinib, ABT-737 and chloroquine in GIST cells. Methods: Human GIST cell lines, GIST-T1 and GIST-882, were employed in our study. Cells were treated with imatinib, ABT-737 and chloroquine either separately or in different combinations. Cell viability was tested by means of MTS and synergistic effects were analyzed by isobologram software. The levels of related proteins of apoptosis (PARP, Caspase-3) and autophagy (LC3-II, beclin-1) were measured by western blot. Cell apoptosis and cell cycle were tested by flow cytometry. Results: Cell viability assay indicated cell survival percentage of double or triple drug combinations ( < 5%) dramatically decreased compared to single drug treatments (42%, 36% or 12%) ( P< 0.05). Isobologram analysis revealed triple drugs combination had stronger synergistic effects than double drugs combinations (CI = 0.204 vs 0.309 or 0.356, P< 0.05). Cell apoptosis percentage of double (32.9% or 36.6%) or triple drugs combinations (66.5%) significantly increased compared to single treatments (6.1%, 6.1% or 13.1%) ( P< 0.05). Western blot showed drugs combinations increased cleavage of PARP and Caspase-3 levels, but inhibited autophagy. Conclusions: The combination of imatinib, ABT-737 and chloroquine has collaborative effects on the treatment of GISTs in vitro. The combined strategy may enhance the clinical efficacy, which provides a rationale for the clinical evaluation of these drug combinations in GISTs treatment.
Influence of chemotherapy combined with radiotherapy on the time-to-development of radiation-induced sarcomas: A multicenter, retrospective analysis.
Authors: Zhang Alison Yan , Judson Ian Robert , Benson Charlotte , Wunder Jay , Ray-Coquard Isabelle Laure , Grimer Robert , Quek Richard Hong Hui , Wong Eva , Miah Aisha , Ferguson Peter Charles , Dufresne Armelle , Teh Jonathan Yi Hui , Stockler Martin R. , Tattersall Martin HN 
Published: September 2018

11046 Background: An increasing number and proportion of cancer patients with apparently localised disease are treated with chemotherapy and radiation therapy in contemporary oncology practice. In a pilot study of radiation-induced sarcoma (RIS) patients, we demonstrated that chemotherapy was associated with a reduced time to development of RIS. We now present an international multi-centre collaborative study to validate this association. Methods: This was a retrospective cohort study of RIS cases across five large international sarcoma centres between the 1st January, 2000 to 31st December, 2014. The primary endpoint was time to development of RIS, defined as the date of diagnosis of the first malignancy to date of the RIS diagnosis. We also assessed the relationship between chemotherapy, patient and cancer characteristics, and time to RIS. Results: We identified 419 patients with RIS, who were predominantly diagnosed with their first malignancy at adulthood. The median interval from the index cancer to development of RIS for the entire cohort was 11 years (range 1-64). Chemotherapy for the first malignancy was associated with a shorter time to RIS development (HR 1·37; 95% CI: 1·08-1·72; P = 0·009). In the multi-variable model, older age (HR 2·11; CI 1·83-2·43; P < 0·001) and chemotherapy for the first malignancy (HR 1·61; CI 1·26-2·05; P < 0·001) were independently associated with a shorter time to RIS. Anthracyclines and alkylating agents significantly contribute to the effect. Conclusions: This study confirms an association between chemotherapy given for the first malignancy and a shorter time to development of a RIS. Our data highlights the importance of vigilance in surveillance for RIS after chemotherapy and radiation therapy, particularly in younger patients who also have a longer potential time to develop a second malignancy.
Trabectedin and radiotherapy in soft-tissue sarcoma (TRASTS) study: An international, prospective, phase I/II trial—A collaborative Spanish (GEIS), Italian (ISG), and French (FSG) groups study.
Authors: Gronchi Alessandro , Hindi Nadia , Cruz Josefina , Blay Jean-Yves , Sanfilippo Roberta , Morosi Carlo , Romero Jesus , Peinado Javier , Lopez-Pousa Antonio , Alvarez Alvarez Rosa Maria , Italiano Antoine , Perez Jose Luis , Sangalli Claudia , Sunyach Marie Pierre , Romagosa Cleofe , Ranchère-Vince Dominique , Collini Paola , Martin Broto Javier 
Published: September 2018

11061 Background: Myxoid liposarcoma/round cell liposarcoma (ML) exhibits especial sensitivity to trabectedin (T). In prospective series, long-lasting T treatment showed responses in 44% of patients (pts) with ML. ML is also sensitive to radiation therapy (RT) and preclinical data suggested radiosensitizing properties of T. Preoperative short-course of T with concurrent low-dose RT was conducted in a multicenter, European, phase I/II trial. We present here data from the phase I part in pts with centralized diagnosis of locally advanced, resectable ML. Methods: Pts received 3 cycles (C) of T in combination with RT (45 Gy) in 25 fractions (1.8Gy/fraction). The phase I had the classic 3+3 design. Dose Levels for T were: -1 (1.1 mg/m2), 1 (1.3 mg/m2) and 2 (1.5 mg/m2). Dose-limiting toxicity (DLT) were defined as grade ≥3 events excluding G3/4 neutropenia lasting < 5 days and G3-4 nausea/vomiting due to inadequate prophylaxis. RECIST responses were evaluated preoperatively at week 10. Surgical specimens were processed for histologic changes and residual tumor. Results: From February 2015 to May 2016,14 pts (M/F 7/7) with median age 36y (24-71) and median tumor size 12.5 cm were enrolled. 7 pts received T at dose Level 1 and 7 pts at Level 2. One DLT (G3 transaminitis) occurred at Level 1 and another (sepsis due to catheter infection) at Level 2. Overall, grade G 3/4 AEs were: ALT elevation (n = 6, 43%), and GGT elevation, neutropenia, anemia, epithelitis and sepsis (n = 1, 7% each). There were no deaths. One pt developed metastasis after C3 and did not undergo surgery; another one had a sepsis after C1 and received definitive RT. All pts completed RT. 13 pts were evaluable for response: 5 achieved PR (38%), 7 SD (53%), 1 distant PD (8%). 12 pts underwent surgery (7 R0/5 R1). Median viable residual tumor was 5% (0-60) with 9/12 pts (75%) with ≤ 10% viable remaining tumor, 3/12 (25%) complete responses. Conclusions: T in combination with RT was feasible and well tolerated in the preoperative setting. T dose of 1.5 mg/m2 is the recommended phase II dose. A high proportion of patients achieved a good pathological response, with 3/12 (25%) complete responses. Clinical trial information: 2014-001549-26.
Rhabdomyosarcoma (RMS) in adults: Histologic subtypes and overall survival with actinomycin-based chemotherapy vs doxorubicin-based chemotherapy.
Authors: Vang Alia , Robinson Steven Ian , Okuno Scott H. 
Published: September 2018

11073 Background: RMS typically occurs in children. Vincristine, Actinomycin and Cyclophosphamide (VAC) based chemotherapy is the current standard. Limited data exist on the frequency of the histologic subtypes and optimal chemotherapy regimen for the treatment of adult patients with RMS. Methods: We retrospectively identified patients ≥18 years with RMS seen at our institution from 2000-2015. The analysis was performed with JMP statistical software. Results: We identified 73 patients, with a median age of 51 (range 18-85 years). The majority of patients were male (40 of 73) and presented with localized disease (59 of 73). Histologic subtypes were as follows: 32% embryonal (E), 27% alveolar (A), 36% pleomorphic (P), and 6% variants (V) (botryoid and spindle cell/sclerosing). The median overall survival (OS) for patients with localized disease was 16.2 months and metastatic disease 9 months. The median OS for patients with localized disease treated with VAC was 20.3 months (4A, 7E, 3P) and VDC (vincristine doxorubicin cyclophosphamide) was 14.1 months (3A, 3E, 2P). For those with localized disease treated with a VAC/actinomycin-based chemotherapy had a median OS of 19.5 months (4A, 9E, 3P) and with a VDC/doxorubicin-based chemotherapy had a median OS of 15.9 months (8A, 5E, 13P, 2V). Conclusions: Adult patients with RMS have an even distribution among the histologic subtypes. Given the small, unbalanced number of patients in each histologic subtype treated with VAC/actinomycin-based or VDC/Doxorubicin-based regimens, the overall survival benefit favoring the use of VAC/actinomycin-based is hypothesis generating and confirmatory studies are needed to truly determine the optional regimen for adult patients with RMS.
RAS mutations concordance in circulating tumor DNA (ctDNA) and tissue in metastatic colorectal cancer (mCRC): RASANC, an AGEO prospective multicenter study.
Authors: Bachet Jean-Baptiste , Bouche Olivier , Taïeb Julien , Dubreuil Olivier , Garcia Marie-Line , Meurisse Aurelia , Gornet Jean-Marc , Artru Pascal , Louafi Samy , Soularue Emilie , Baumgaertner Isabelle , Coriat Romain , Tougeron David , Lecomte Thierry , Mary Florence , Marthey Lysiane , Blons Helene , Taly Valerie , Bonnetain Franck , Laurent-Puig Pierre 
Published: September 2018

11509 Background: RAS mutational status is required to prescribe anti-EGFR antibodies in mCRC. In comparison to molecular testing from tumor tissue, the characterization of RAS mutations in ctDNA is a promising and credible way to shorten the workflow. This study reports for the first time the performance of plasma testing in a large prospective series. Methods: Blood samples were prospectively collected before 1st line chemotherapy in mCRC patients. ctDNA was centrally assessed by NGS using the colon lung cancer V2 Ampliseq panel and by methylation digital PCR assay (WIF or NPY). Tumor tissue testing was done according to routine practice in each center. We expect a minimal kappa coefficient of 0.7 to reflect concordance. In order to have a precision of ± 0.07 with an estimated 5% of non-exploitable data 425 pts had to be included. Results were analyzed separately in the whole study population and in the subgroup of pts with ctDNA evidenced either by the presence of at least 1 mutation or by the presence of 1 methylated biomarker. Results: From 07/2015 to 12/2016, 425 patients were included, and 406 plasma samples were available for analysis. A RAS mutation was detected in 183 plasma samples (45.1%) As compared to tumor mutational status the kappa coefficient was 0.68 (95%CI: 0.61-0.75) with a concordance of 83.7%. Primary tumor removal, metachronous status, absence of liver metastases and peritoneal carcinomatosis were significantly associated with mutant RAS tumor and negative plasma status. In the subgroup of 324 samples for which ctDNA was evidenced, kappa coefficient was 0.85 (95%CI: 0.80-0.91) with a concordance of 92.9%. 23 pts had discordant results: RAS mutation in tumor tissue and not in ctDNA (15 pts, 4.6%), RAS mutation detected in ctDNA but not in tumor tissue (8 pts, 2.5%). Rectal tumor, absence of liver metastases, peritoneal carcinomatosis and tumor tissue cellularity < 10% were associated with discordant cases. Conclusions: We confirm, in this large prospective multicenter study, the high concordance rate for RAS status assessment between blood and tumor samples. This result argues for the use of blood testing in daily practice for pts with detectable ctDNA. Clinical trial information: NCT02502656.
Changes in computer extracted features of vessel tortuosity on CT scans post-treatment in responders compared to non-responders for non-small cell lung cancer on immunotherapy.
Authors: Velcheti Vamsidhar , Alilou Mehdi , Khunger Monica , Thawani Rajat , Madabhushi Anant 
Published: September 2018

11518 Background: Immune-checkpoint blockade treatments demonstrate promising clinical efficacy in patients with non-small cell lung cancer (NSCLC). Nivolumab is a PD-1 inhibitor that is FDA approved for treatment of patients with chemotherapy refractory advanced NSCLC. The current standard clinical approach to evaluating tumor response is sub-optimal in defining clinical benefit from immunotherapy drugs. We sought to evaluate whether computer extracted measurements of vessel tortuosity significantly and differentially change post treatment between NSCLC patients who do and do not respond to immunotherapy. Methods: A total of 50 NSCLC patients including pre- and post- treatment CT scans were included in this study. The patients were either responders or non-responders to Nivolumab. Patients who did not receive Nivolumab after 2 cycles due to lack of response or progression as per RECIST were classified as ‘non-responders’. A total of 35 tortuosity features of the vessels around the lung nodules were investigated. In the training cohort (N = 25), the features were ranked based on the degree of change between pre- and post- treatment CT. The top 4 features were used for training a Support Vector Machine (SVM) classifier to identify which patients did and did not respond to immunotherapy on a validation cohort of N = 25 patients. Results: The top features identified were the ones associated with the curvature of the vessel branches. The AUC for the SVM classifier was 0.75 for the training and 0.79 for the test set. Conclusions: Changes in specific vessel tortuosity features between baseline and post-treatment CT scans following nivolumab were different between NSCLC patients who did and did not respond. Multi-site validation of the vessel tortuosity features is needed to establish it as a predictive biomarker for NSCLC patients treated with immunotherapy.
Cell-free DNA (cfDNA) mutations from clonal hematopoiesis: Implications for interpretation of liquid biopsy tests.
Authors: Razavi Pedram , Li Bob T. , Hou Chenlu , Shen Ronglai , Venn Oliver , Lim Raymond S. , Hubbell Earl , De Bruijn Ino , Liu Qinwen , Vijaya Satya Ravi , Xu Hui , Shen Ling , Sehnert Amy , Maddala Tara , Berger Michael F. , Aravanis Alex , Reis-Filho Jorge S. , Lee Mark , Solit David B. , Baselga Jose 
Published: September 2018

11526 Background: A large fraction of cfDNA fragments are derived from hematopoietic sources. Somatic alterations in cfDNA can be tumor-derived but also could represent somatic changes associated with clonal hematopoiesis. We performed deep sequencing of both plasma cfDNA and matched white blood cell (WBC) genomic DNA (gDNA) to determine the contribution of clonal hematopoiesis to the variants observed in cfDNA. Four cohorts were investigated: metastatic breast (BC), non-small cell lung (NSCLC), castration-resistant prostate cancer (CRPC), and non-cancer participants (pts). Methods: Metastatic cancer pts with de novo or progressive disease were prospectively enrolled. Non-cancer pts were blood bank donors. Plasma cfDNA and matched WBC gDNA were sequenced using a targeted 508-gene panel (2 Mb) to > 60,000X raw depth. Variant calling used a novel pipeline that employed molecular barcoding for error suppression followed by de novo assembly and graph-based variant calling. Results: Of 151 metastatic cancer pts (48 BC, 49 NSCLC, 54 CRPC), median age was 64 (30-87) with 53% female and 33% treatment naive. Of 47 non-cancer pts, median age was 61 (20-78) with 51% female. Analysis of cfDNA identified 1072 variants (AF > 0.1%, > 2 mutant reads, passing bioinformatic quality filters) which were also detected in WBC gDNA as non-germline ( < 35% allele frequency [AF]) non-synonymous variants. For these cfDNA variants, AF ranged from 0.1-14.4% and correlated with AF in WBC gDNA (r2 = 0.47, p < 0.001). Mutated genes were consistent with clonal hematopoiesis, with the most frequently mutated genes being DNMT3A, TET2, PPM1D, and TP53 (215, 77, 45, and 36 variants, respectively). For both cancer and non-cancer pts (age > 45), median number of overlapping variants was 5 per pt (range 0-22). The number of WBC gDNA and cfDNA variants per individual was positively associated with age (p < 0.001) in both cancer and non-cancer pts (interaction p = 0.08). Conclusions: Somatic cfDNA variants are frequently derived from clonal hematopoiesis and increase with age. Accurate assessment of somatic alterations in cfDNA should account for this phenomenon to distinguish between tumor-derived and WBC-derived variants.
Dynamics of soluble programmed death-ligand 1 (soluble PDL1) during chemotherapy and its prognostic implication in cancer patients.
Authors: Ha Hyerim , Bang Ju-Hee , Nam Ah-Rong , Park Ji Eun , Kim Mei Hua , Bang Yung-Jue , Oh Do-Youn 
Published: September 2018

11542 Background: The soluble form Programmed Death-Ligand 1(sPDL1) is suggested to have immunosuppressive activity and under investigation as candidate biomarker for immuno-oncology drug development. In this study, we measured the serum sPDL1 at pre-and post-chemotherapy and evaluated its prognostic implication and dynamics during chemotherapy in biliary tract cancer (BTC) patients. Methods: From 90 advanced BTC patients (training cohort 42 patients, validation cohort 48 patients) who were candidates for palliative 1st-line chemotherapy, blood was collected at pre-and post-chemotherapy. sPDL1 was measured using an enzyme-linked immunosorbent assay. Response to chemotherapy, overall survival (OS) and other prognostic factors including neutrophil-lymphocyte ratio (NLR) were also obtained. Results: OS of all patients was 11.5 months (95% CI; 9.7-16.2). The best response was CR in 7 patients (7.8%), PR 20 patients (22.2%), SD 52 patients (57.8%) and PD 11 patients (12.2%). Median sPDL1 at pre-chemotherapy was 0.97 ng/mL (range 0.6-1.9). Patients with high pre-chemo sPDL1 (≥ 1.30 ng/mL) showed worse OS than patients with low pre-chemo sPDL1 (9.1 vs. 12.5 months, p =0.003). In multivariate analysis, high pre-chemo sPDL1 (HR 1.96, 95% CI; 1.2-3.9, p = 0.011) and pre-chemo NLR (HR 1.82, 95% CI; 1.1-3.0, p = 0.020) were independent poor prognostic factors for OS. Post-chemotherapy sPDL1 and its changes compared with pre-chemotherapy were not significantly different across tumor response groups. However, at the time of disease progression, sPDL1 was increased significantly compared with pre-chemo sPDL1 (1.59 ng/mL vs 0.72 ng/mL, p = 0.003). In PR group, sPDL1 at pre-chemo, post-chemo, and PD was 1.19, 0.98, and 2.77 ng/mL, respectively. In SD group, sPDL1 at pre-chemo, post-chemo, and PD was 1.16, 1.19, and 1.83 ng/mL, respectively. In PD group, sPDL1 at pre-chemo and PD was 0.62, and 1.04 ng/mL. Conclusions: sPDL1 at pre-chemotherapy confers the prognostic value for OS in BTC patients under palliative chemotherapy. The dynamics of sPDL1 during chemotherapy correlates with disease progression.
Cell surface GRP78 expression on T and NK cell sub-populations of breast cancer patients.
Authors: Yerushalmi Rinat , Lubin Ido , Lipovettzky Julia , Hardy Britta , Raiter Annat 
Published: September 2018

11561 Background: The targeting of unfolded protein response (UPR) in tumor cells has received much attention. However, data are sparse on the impact of UPR on T and NK cells. The master regulator of UPR is the glucose-regulated protein 78 (GRP78) that is expressed in some tumor cells or normal stressed cells. There are few studies concerning GRP78 expression on T and NK cells in cancer and its relationship to stress induction by chemotherapy. We aimed to reveal the effect of UPR activation on the peripheral T and NK cells of breast cancer patients by the evaluation of cell surface GRP78 expression on T and NK cells before and after neoadjuvant chemotherapy. Methods: Forty-seven patients with triple negative, ER positive/Her2 negative and Her2 positive breast cancer were included. FACS analysis of their blood specimens before and after neoadjuvant treatment was performed. For multicolor FACS analysis, anti-CD3, CD4, CD8, CD56, CD16, NKG2D, CD45RA, CD45RO, CCR7 CD62L and anti-GRP78 antibody (AF488) were added to one of the tubes. A second tube was incubated with IgG-AF488 as isotype control. Analysis of the different T and NK subpopulations that expressed cell surface GRP78 were analyzed with the Gallios Flow cytometer and Kaluza Flow Analysis Software (Beckman Coulter, Inc.). Results: The percentage of cell surface GRP78 baseline expression in CD3 (1.8±0.9), CD8 (2.9±1.5), NKG2D (4.8±2) and CD45RO/CD62L/CCR7 active T memory cells (2.1±0.5) in Her2 positive patients were significantly higher than in triple negative and ER positive/Her2 negative patients. GRP78 expression on CD56, CD16 and NKG2D cells measured after neoadjuvant treatment was significantly higher in patients with complete response (CR) compared to patients without CR. 89% of the CR patients presented with Her2+ subtype. The non-CR patients include triple negative and Her2 negative subtypes. Conclusions: GRP78 was found to be expressed in the different T and NK sub-populations. The level of expression changed with each breast cancer subtype and response to chemotherapy. These novel findings suggest that GRP78 may be used as a new predictive biomarker. It sets the stage for understanding the mechanism of UPR activation on the immune system in breast cancer.