bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of the multikinase inhibitor regorafenib in neuroblastoma.
Authors: Zage Peter E. , Subramonian Divya , Mo Qianxing , Huang Shixia 
Published: September 2018

10553 Background: Neuroblastoma (NB) is the most common extracranial solid pediatric tumor, and children with high-risk NB have poor survival rates and need novel treatment strategies. Regorafenib, a multi-receptor tyrosine kinase (RTK) inhibitor approved for treating adult solid tumors such as advanced metastatic colorectal cancer and gastrointestinal stromal tumors, inhibits many RTKs, including PDGFR-β, VEGFR1-3, RET, c-Kit and FGFR family members. Based on the potential roles for these targets in neuroblastoma pathogenesis, we explored the therapeutic potential of Regorafenib alone and in combination with 13-cis-retinoic acid against neuroblastoma cells. Methods: We treated NB cell lines with increasing concentrations of Regorafenib and measured cell viability using MTT assays. We further measured the occupied percent confluence over time using continuous live cell imaging. We performed Western blots for caspase cleavage to measure apoptosis and flow cytometry to determine cell cycle expression. We performed Reverse Phase Protein Array (RPPA) analysis of neuroblastoma cells before and after treatment with regorafenib combined with 13- cis-retinoic acid. Results: IC50values for the tested cell lines ranged between 2.5mcM and 12.5mcM after 72 hours of exposure to Regorafenib, and decreased viability was due to a combination of apoptosis and cell cycle arrest. RPPA analysis identified alterations in multiple proteins and pathways after Regorafenib with retinoic acid treatment, including the PI3K/Akt/mTOR and Jak/Stat pathways. Phosphorylation of Erk1/2, S6, Akt, and c-Jun were decreased, while protein expression of GATA3 was increased in a dose-dependent manner. Conclusions: Regorafenib treatment results in reduced neuroblastoma cell viability and increased apoptosis via effects on several signaling pathways. Effects on intracellular signaling pathways associated with responses to the combination of regorafenib plus retinoic acid represent opportunities to develop novel combination therapies, representing potential new therapeutic strategies for children with neuroblastoma.
Risk factors associated with metastatic site failure in patients with high-risk neuroblastoma.
Authors: Lucas John Thomas , Wakefield Daniel Victor , Doubrovin Michael , Li Yimei , Cooper David , Manole Bogdan-Alexandru , Santiago Teresa , Federico Sara Michele , Merchant Thomas E. , Davidoff Andrew M. , Krasin Matthew J. , Shulkin Barry L. , Santana Victor M. , Furman Wayne Lee 
Published: September 2018

10557 Background: This retrospective study sought to identify predictors of metastatic site failure (MSF) in patients with high-risk (HR) neuroblastoma (NB). Methods: Seventy-six patients with HR NB treated on prospective trials at from 1997 to 2014 were eligible for inclusion. All patients were treated with induction chemotherapy (chemo) with surgery followed by myeloablative chemo & stem cell rescue. Primary & metastatic site (MS) RT were applied according to institutional protocol. CT & I-123 MIBG scans were used to assess Curie scores at diagnosis, post-induction, post-transplant & failure. Overall (OS), & progression-free survival (PFS) were described using the Kaplan-Meier estimator. Cox proportional hazards frailty (cphfR) & CPH regression (CPHr) were used to identify covariates predictive of MSF & new site MSF. Results: Forty-two (55%) patients had documented MSFs. Consolidative MS RT was applied to 30 MSs in 10 patients. Original site MSF occurred in 146 of 383 (38%) & 18 of 30 (60%) non-irradiated & radiated MSs respectively. Original site MSF occurred in post-induction MIBG avid lesions in 68 of 81 (84%) & 12 of 14 (85%) non-irradiated & radiated MSs respectively. The median OS & PFS were 61 mo (95% CI 42.6-NR) & 24.1 mo (95% CI 16.5-38.7). Univariate cphfR identified an increased hazard for original MSF when MIBG avid following induction chemo (HR 4.9, 95%CI 1.1-20.9, p = 0.03) & transplant (HR 7.3 95%CI 1.8-30.2, p = 0.006) relative to lesions that cleared after induction. Notably, MS RT nor site location did not modify the hazard for MSF. Multivariate CPHr identified inability to undergo transplant (HR 32.4 95%CI 9.3-96.8, p < 0.001) &/or maintenance chemo (HR 5.2, 95%CI 1.7-16.2, p = 0.005) & the presence of lung metastases (HR 4.4 95%CI 1.7-11.1, p = 0.002) at diagnosis as predictors of new site MSF. The new MSF free survival at 3 years was 25% vs. 87% in patients with high-risk factors relative to those without the risk factors suggesting limited benefit of consolidative MS RT in this population. Conclusions: Metastatic lesions that remained MIBG avid following induction chemo & post-transplant had an increased hazard for MSF. Consolidative site RT likely has limited benefit in patients with HR features.
Is incomplete estradiol suppression during aromatase inhibitor treatment in post-menopausal patients with breast cancer due to insufficient systemic drug concentrations?
Authors: Hertz Daniel Louis , Kidwell Kelley M. , Speth Kelly A , Gersch Christina L , Desta Zeruesenay , Storniolo Anna Maria , Stearns Vered , Skaar Todd C , Hayes Daniel F. , Henry Norah Lynn , Rae James M. 
Published: September 2018

1063 Background: Aromatase inhibitors (AI) suppress estrogen biosynthesis and are effective treatments for estrogen receptor (ER)-positive breast cancer. In a prospectively enrolled cohort we observed a subset of post-menopausal women who exhibit high plasma estradiol (E2) concentrations during AI treatment, which could potentially contribute to treatment failure. We tested the hypothesis that incomplete E2 suppression is due to insufficient systemic AI concentrations. Methods: Five hundred post-menopausal women with ER-positive breast cancer were randomized to daily exemestane (Exe) 25 mg or letrozole (Let) 2.5 mg. Plasma E2 was measured using GC/MS/MS (lower limit of quantification (LLOQ) = 1.25 pg/mL) at baseline and after 3 months. Let and Exe plasma concentrations measured after 1 or 3 months were compared with the magnitude of E2 depletion using four complementary statistical procedures to assess associations of drug concentrations with: 1) a binary outcome of E2 suppression below LLOQ (logistic regression), 2) 3-month E2 concentrations (linear regression), 3) absolute change from baseline in E2 concentrations (Spearman correlation), and 4) an ordinal outcome defined by E2: decreased to below LLOQ, decreased but not to LLOQ, stayed the same, or increased from baseline (cumulative logistic regression). Results: 397 patients with E2 and AI concentration measurements were evaluable (Exe n = 199, Let n = 198). Thirty (7.6%) patients (Exe n = 13, Let n = 17) had E2 concentrations above the LLOQ at 3 months (range: 1.42-63.8 pg/mL). Exe and Let concentrations were not associated with achievement of unmeasurable E2 concentrations, on-treatment E2 concentrations, E2 change from baseline, or ordinal groupings of E2 change (all p > 0.05). In a parallel analysis there was no association of estrone-sulfate and drug concentrations (data not shown). Conclusions: Our results suggest that circulating drug concentrations do not explain incomplete E2 suppression in women receiving AI therapy. Additional studies are underway to determine whether age, body mass and genetic variation in the aromatase enzyme influence AI treatment response.
Primary surgery versus no surgery in synchronous metastastic breast cancer: Patient-reported outcomes of the ABCSG 28 Posytive trial.
Authors: Bjelic-Radisic Vesna , Fitzal Florian , Steger Guenther G. , Marth Christian , Balic Marija , Knauer Michael , Singer Christian F. , Hubalek Michael , Schrenk Peter , Haid Anton , Wette Viktor , Swoboda Ursula , Fuegger Reinhold , Greil Richard , Soelkner Lidija , Gnant Michael ,   ABCSG
Published: September 2018

1074 Background: The ABCSG 28 Posytive trial compared primary surgery versus primary systemic therapy without surgery in synchronous metastatic breast cancer. The primary aim of the study was to investigate whether immediate resection of the primary tumor followed by standard systemic therapy improves median survival compared with no surgical resection (NCT01015625). This report describes quality-of-life (QoL) results. Methods: Patients were randomized between 2011 and 2015. Patients completed the EORTC QLQ-C30 and EORTC QLQ-BR 23 before treatment and every 6 months during follow-up. Results: 90 patients (45 with surgery, 45 with primary systemic therapy without surgery) from 15 centers were included in the QoL analysis. At 6 months patients after surgery reported more insomnia, breast symptoms and arm symptoms than patients without surgery, but these differences were no longer present at later follow-up visits. In the univariate and multivariate analysis the global health status and physical functioning scales of EORTC QLQ C30 were statistically significant predictors for OS and TTP (p < 0.05). Over a 24-month follow-up, patients > 60 years showed more QoL impairments than those < 60 years, independent of treatment. Patients < 60 years had better physical functioning and less fatigue, appetite loss, constipation and breast symptoms than older patients. There were no differences in QoL between patients with bone metastases vs those with visceral ± bone metastases. Conclusions: In patients with primary metastatic breast cancer primary surgery does not appear to improve QoL. Global health status and physical functioning scales of EORTC QLQ-C30 appears to be a predictive factor for OS and TTP. Clinical trial information: NCT01015625.
A phase I trial of mifepristone (M), carboplatin (C), and gemcitabine (G) in advanced breast and ovarian cancer.
Authors: Stringer Erica Michelle , Saha Poornima , Swoboda April , Kocherginsky Masha , Baker Gabrielle , Olberkyte Simona , Owusu Nana , Dyer Brittany , Olalde Lauren , Olszewski Elizabeth , Hahn Olwen Mary , Hoffman Philip C. , Phillips Brooke Elizabeth , Suh Grace K. , Conzen Suzanne D. , Fleming Gini F. , Nanda Rita 
Published: September 2018

1083 Background: Glucocorticoid receptor (GR) activity inhibits chemotherapy-induced apoptosis, and GR antagonism with m enhances chemotherapy sensitivity in GR+ breast (B) and ovarian cancer (OC) cells. C+G is a commonly used regimen for B and OC. We report the results of a phase I trial of the GR antagonist m plus C+G in patients with advanced B and OC. Methods: A standard “3+3” dose escalation phase I study was performed. Objectives were to assess the safety and tolerability of the regimen, and to determine the recommended phase 2 (RP2D) dose of M+C+G. C+G was administered on days 1 and 8 of a 21 day cycle, and m was administered the day prior to and the day of chemotherapy. The starting dose level (DL) was 1, with additional DLs as follows in the table. Results: 31 patients (pts) with a median age of 54 years (range 32-76) were enrolled. 18 pts had BC (3 ER+, 15 triple-negative), and 13 had high grade serous OC (11 platinum-sensitive, 2 platinum-resistant). The median number of prior therapies for advanced BC was 1 (range 0-5) and for OC was 2 (range 1-3). Dose de-escalation was necessary due to the DLT of neutropenia. After DL -3, prophylactic G-CSF (PGF) was instituted. The RP2D was C AUC 2, G 600 mg/m2, m 300 mg with PGF administered on day 9. Of the BC pts, 2 had a complete response (CR), 2 had a partial response (PR), 8 had stable disease (SD), 4 had progressive disease (PD). Of the OC pts, there was 1 CR (CR2 lasted > 27 mos; CR1 lasted only 8 mos), 1 PR, 6 SD, and 3 PD. 4 pts were inevaluable for response. Conclusions: These data suggest that M+C+G is safe and tolerable, and the most common DLT is neutropenia. This was easily managed with the institution of PGF. Studies correlating tumor GR expression with response are ongoing, and may help identify patients who are most likely to benefit from this combination. Clinical trial information: NCT02046421. [Table: see text]
Weekly paclitaxel (WP) +/- bevacizumab (B) in angiosarcoma (AS) patients (pts): Analysis of prognostic/predictive factors from a randomized phase 2 trial.
Authors: Lebellec Loic , Bertucci Francois , Tresch-Bruneel Emmanuelle , Ray-Coquard Isabelle Laure , Le Cesne Axel , Bompas Emmanuelle , Piperno-Neumann Sophie , Italiano Antoine , Chevreau Christine , Cupissol Didier , Bay Jacques-Olivier , Collard Olivier , Saada-Bouzid Esma , Isambert Nicolas , Delcambre Corinne , Blay Jean-Yves , Goncalves Anthony , Penel Nicolas 
Published: September 2018

11024 Background: WP is an active regimen for treatment of AS pts (Ray-Coquard JCO 2015). We report here the correlative analysis conducted during a phase 2 trial assessing WP +/- B. Methods: Circulating pro/anti-angiogenic factors (FGF, PlGF, SCF, Selectin, thrombospondin, VEGF, VEGF-C) were collected at D1 and D8. Prognostic value for PFS was assessed using Cox model (biomarkers as continuous variables). We attempt to identify subgroups of pts benefiting from adding B using interaction tests (predictive factors). Results: Among the 51 pts enrolled in this trial, 45 were analyzable: 20 in Arm A (WP without B) and 25 in Arm B (with B). Median PFS was 5.5 and 6.1 months, respectively (p = 0.84). Samples were collected in 45 pts at D1 and 42 pts at D1 and 8. Baseline biomarkers were similar in both arms (excluding Selectin, significantly lower in arm A: median of 25 vs. 35 ng/mL, p = 0.03). In arm A, there was no significant difference between values at D1 and D8. In arm B, there were a significant decrease in VEGF (from a median of 0.49 to 0.08 ng/mL; p < 0.01) and selectin (from a median of 35.3 to 31.7 ng/mL; p < 0.01), and a significant increase in PlGF (from a median of 16.1 to 30.0 pg/mL; p < 0.01). In univariate analysis, factors associated with PFS were: de novo vs. radiation-induced AS (HR = 2.39 (p < 0.01), visceral vs. superficial AS (HR = 2.04; p < 0.03), VEGF-C at D1 (HR = 0.77; p < 0.03), FGF at D8 (HR = 1.17; p < 0.01), difference in FGF D8-D1 (HR = 1.24; p < 0.01), and PlGF value at D1 (HR = 1.02; p < 0.05). In multivariate analysis, factors associated with PFS were: de novo AS (HR = 2.39; p = 0.03), VEGF-C at D1 (HR = 0.73; p < 0.02) and FGF difference between D8 and D1 (HR = 1.16; p < 0.02). None of these factors were associated with benefit of adding B. Conclusions: Baseline VEGF-C levels and change in FGF were independent prognostic factors in pts with or without B. Addition of B significantly decreased the level of circulating VEGF and selectin and increased the level of circulating PlGF in AS patients. We did not identify subgroup of pts benefiting from adding of B to WP. Clinical trial information: NCT01303497.
The genomic and evolutionary landscape of osteosarcoma progression and lung metastasis.
Authors: Wang Jin , Bao Hua , Xu Huaiyuan , Shek Tony WH , Wu Xue , Tang Qinglian , Zhang Huizhong , Han Anjia , Yin Junqiang , Zou Changye , Wang Yongqian , Huang Gang , Batalha Sellma , Xie Xianbiao , Lu Jinchang , Song Guohui , Kang Yao , Shao Yang , Lam YingLee , Shen Jingnan ,   Bioinformaticians from Nanjing Geneseeq Technology Inc. and Pathologists from Queen Mary Hospital, Hong Kong
Published: September 2018

11029 Background: Osteosarcoma (OS) is a primary malignant bone tumor that has a high potential to metastasize to lungs. Recent studies have characterized somatic mutations of primary OS tumors. Nevertheless, lung metastases of OS are poorly studied, and whether they harbor distinct genetic alterations beyond those observed in primary tumors is largely unknown. Methods: We performed whole-exome sequencing (WES) of matched primary tumors and lung metastases in a cohort of 15 OS patients. Somatic single nucleotide variations (SNV) and copy number alterations (CNA) were analyzed to characterize the genomic and evolutionary landscape of metastatic OS. Results: Compared to matched primary tumors, lung metastases exhibited higher transversion rate for base substitution, and poor overlap ( < 10%) of genetic alterations was observed between primary and metastasis tumors. Multiple novel significantly mutated genes were identified, including ZNF717 in lung metastases, SPDYE1 in primary tumors, and CRIPAK in both. Copy number analysis indicated recurrent CNAs, including NEURL1B deletion and FLG amplifications in lung metastases, GSTT1 deletion in primary tumors, and CEACAM gene family deletion in both. Furthermore, phylogenetic analyses revealed that paired primary tumors and metastases underwent parallel evolution with few ubiquitous clonal mutations, suggesting that OS metastases are likely to be derived from primary tumors at a very early stage of their evolution. Conclusions: This study for the first time provides important evidence that OS metastases harbor distinct genetic alterations compared with primary tumors. Our findings strongly support a parallel evolution model of primary and metastatic tumors. Moreover, several novel CNAs and significantly mutated genes that are specifically associated with lung metastases may provide future therapeutic insight for OS.
Analysis of tumor-infiltrating immune cells in gastrointestinal stromal tumors (GIST) after tyrosine kinase inhibitor therapy.
Authors: Hohenberger Peter , Zhao Wenyi , Deligianni Maria , Simon-Keller Katia , Cao Hui , Marx Alexander 
Published: September 2018

11042 Background: There is initial evidence that immune-infiltrates of tumor may correlate with the clinical course of patients with GIST beyond the response to tyrosine kinase inhibitors (TKI) according to the mutational status. We were interested to analyze the composition of tumor-infiltrating immune cells in GIST tumor tissues after different TKI regimens vs untreated controls. Methods: From 40 GIST patients who were treated with imatinib alone (neoadjuvant group) and other TKIs (M1 HEP group, progressing on more than ≥2 TKI inhibitors) prior to tumor removal, surgical specimens were available at ten 10 cases each,. They were compared with 20 untreated primary tumors graded for malignant behaviour (low vs high risk ) acc. to Miettinen&Lasota 2006. 2-μm sections of formalin-fixed, paraffin-embedded tissue samples were used for IHC-staining anti-CD68 (Dako); anti-CD11c, anti-CD11b, anti-FOXP3 (all Abcam); anti-CD163, anti-CD4 , anti-CD8 (all Leica). Evaluation was performed with Dako REAL EnVision Detection System (K5007). The phenotypes of immune cells were compared in the defined GIST groups. In the neoadjuvant group we used recurrence-free survival (RFS) for correlation, and overall survival (OS) after TKI failure in the M1 HEP group. Results: Foxp3+ Tregs, CD163+ M2 macrophages and CD11b+ myeloid cells are significantly higher in TKI resistance or neoadjuvant (viable cells > 30%) tissues compared with neoadjuvant (viable cells < 10%) cases. The rate of CD11c+ M1 macrophages is higher in low-risk GISTs compared to high risk GISTs, but CD11b+ myeloid cells are exactly the opposite. Kaplan-Meier curves show high CD163+ M2 macrophages or CD11b+ myeloid cells to correlate significantly with worse RFS in after neoadjuvant IM (p 0.01). In the TKI resistant condition, patients with high CD11c+ M1 macrophages show better median OS (p = 0.07, ns). Conclusions: Our study reveals dynamic changes of tumor-infiltrating immune cell protagonists in GISTs after different TKI therapeutic regimen and after neoadjuvant treatment. We could not detect a different immune infiltrate in untreated primary tumors of different risk categories.
Prognostic factors of recurrence and survival of gastrointestinal stromal tumors: First multicentric study of Mexico.
Authors: Medrano Guzman Rafael 
Published: September 2018

11045 Background: Gastrointestinal stromal tumors are mesenchymal lesions arising from the interstitial cells of Cajal. In GIST the location, size, number of mitosis and risk group are accepted as prognostic factors; some factors in which there are still controversies about their value as prognostic factors include male gender, tumor cellularity, the margins of resection, the presence or absence of p16 or intraperitoneal tumor breakdown. Methods: Observational, retrospective and longitudinal study. Patients admitted to the Oncology Hospital, CMN Siglo XXI of January 1, 1991 to April 30, 2012. Results: We identified 384 patients, the mean follow-up time was 55.86 months, the mean age was 58 years, 80.3% had symptoms and only 4.54% the finding was incidental. The most common site was the stomach (66.6%), followed by small intestine (28.7%) and colon (1.54%). The 7.57% had metastases at diagnosis, 4.54% in liver and 3.03% in the peritoneum. Were expressed by abdominal pain (39.39%) and gastrointestinal bleeding (30.30%), intestinal obstruction in 1.5%. The most common site was the stomach (66.6%), followed by small intestine (28.7%) and colon (1.54%). The 7.57% had metastases at diagnosis. The average tumor size was 10.84 cm (2.2 to 38 cm). Immunohistochemical markers were studied: 94.28% positive for CD117, CD34 74.28%, 11.42% S100 protein, desmin 5.71% and 51.72% for smooth muscle actin (AML). Overall rate at 5 years and 82% rate of recurrence-free survival at 5 years and 61% survival. The location of the tumor (p = 0.0002), size (p = 0.03145), the number of mitosis (p = 0.008), risk group (p = 0.020) and adjuvant treatment with Imatinib showed a statistically significant difference for Survival Recurrence-free. For overall survival, lesion location was the only factor that showed statistical significance with p = 0.0054. Conclusions: The tumor location, size, number of mitosis, the risk group and adjuvant treatment with Imatinib were statistically significant prognostic factors for disease recurrence. The location of the lesion was the only factor that showed statistical significance as a predictor of overall survival.