bluuebunny/crossref_metadata_2025 huggingface dataset:
Specificity of methylated BCAT1 and IKZF1 for colorectal cancer.
Authors: Symonds Erin L. , Yao Beibei , Pedersen Susanne Kartin , Murray David , Young Graeme P
Published: January 2019

580

Background: Methylated BCAT1 and IKZF1 are useful circulating tumor DNA (ctDNA) biomarkers for detection and following the course of colorectal cancer (CRC). This study aimed to determine the specificity of methylated BCAT1/ IKZF1 for CRC detection by assaying specimens from patients with other adenocarcinomas. Methods: Blood was collected from patients with invasive adenocarcinoma of the prostate (n = 32), breast (16), oesophagus (15) or colon/rectum (212), prior to any treatment or resection, and from 245 clinically assessed controls with no known prior or current adenocarcinoma. Biopsies were collected from cancer tissue and adjacent non-neoplastic tissue either prior to treatment or at surgery from 9 prostate, 26 breast, 6 oesophagus, 15 CRC cases. All specimens were assayed for methylated BCAT1 and IKZF1 DNA. Calculation of positivity rates: tissue, the proportion of tissue cases with ≥ 5% methylation; blood, the proportion of cases with any detectable signal of either marker. Results: ctDNA positivity rates were significantly higher in CRC (126/212, 59.4%, 95% CI: 52.5 - 66.1) and oesophageal cancer (6/16, 33.3%, 11.0 - 58.7) cases only compared to controls (16/245, 6.5%, 3.8 - 10.4; p < 0.01). ctDNA was more likely to be positive in late stage cancers, although only significant for CRC, Table. Cancer tissue positivity rates were: CRC, 15/15, 100% (96.4 - 100); oesophageal, 5/6, 83.3% (35.9 - 99.6); prostate, 4/9, 44.4% (13.7 - 78.8); breast, 5/26, 19.2% (6.6 - 39.4). All cancer tissues had significantly higher methylation levels than the adjacent tissue (Chi2 test, p >0.05). Conclusions: Only colorectal and oesophageal cancer patients had significantly higher ctDNA positivity rates (using methylated BCAT1/IKZF1) compared to controls. This was also reflected in a higher proportion of cases showing methylation in the cancer tissue. The methylated BCAT1/IKZF1 blood test should be investigated further as a screening and surveillance tool for oesophageal cancer. [Table: see text]
Molecular subtype assay to reveal anti-EGFR response sub-clones in colorectal cancer (CRC).
Authors: Fontana Elisa , Nyamundanda Gift , Cunningham David , Ragulan Chanthirika , Sclafani Francesco , Eason Katherine , Bali Maria Antonietta , Vendrell Ines , Patil Yatish , Hulkki Wilson Sanna , Moorcraft Jenkev Samantha Sing Yu , Begum Ruwaida , Chau Ian , Starling Naureen , Sadanandam Anguraj
Published: January 2019

658

Background: We previously stratified CRC into five intrinsic gene expression subtypes (CRCAssigner) and four consensus molecular subtypes (CMS1-4) using expensive and time-consuming microarray/RNAseq platforms. Recently, we developed a low-cost (NanoCRC) assay using nCounter platform (NanoString Technology) and robust gene signatures to classify individual samples into both CRCAssigner and CMS subtypes. Here, we tested the assays using formalin-fixed paraffin-embedded (FFPE) patient samples from Royal Marsden Hospital. Given increased sensitivity to cetuximab in one of our CRCAssigner subtypes transit-amplifying (TA) that represents partly CMS2 subtype, we associated anti-EGFR response to the presence of TA sub-clones. Methods: FFPE from resected and biopsy CRC samples were profiled for our NanoCRC assay. Along with our single-sample subtyping method, we developed a tool to identify sub-clones of TA within individual samples. RAS/BRAF wild-type patients treated with single agent anti-EGFR therapy were statistically associated with sub-clonal molecular profiles, sidedness and single gene expression. Results: NanoCRC assay was highly reproducible with > 0.9 correlation coefficient. Among 76 samples (from 64 patients), all the five CRCAssigner, four CMS subtypes (including the mixed samples) and their associations with RAS/BRAF mutations were successfully identified. Subtype-mutational associations were similar to our previous publications. Among 15 KRAS/BRAF wild-type (wt) patients with single agent anti-EGFR therapy response data, TA sub-clone was identified in 7/9 with clinical benefit and 1/6 with no benefit (p < 0.05). The other sub-clones, sidedness and individual genes within the panels were not significantly associated. This TA sub-clone association was further confirmed using a publicly available cetuximab response data (39 KRAS wt; Khambata-Ford data; p=0.02). Conclusions: Overall, we developed a robust NanoCRC assay to classify CRC FFPE samples in to molecular subtypes. With caveat of small numbers, the presence of TA sub-clones is significantly associated with cetuximab response. Extensive validation is warranted.
Prevalence of RAS and BRAF mutations in metastatic colorectal cancer (mCRC) patients by tumor location.
Authors: Bylsma Lauren C , Gillezeau Christina , Garawin Tamer , Kelsh Michael Anthony , Fryzek Jon , Sangaré Laura , Lowe Kimberly
Published: January 2019

681

Background: There is evidence to suggest that tumor biology and pathology differ for right- and left-sided colon tumors which may affect treatment efficacy and clinical outcomes. Therefore, we conducted a systematic review and meta-analysis of the available scientific literature to summarize the prevalence of RAS and BRAF mutations by primary tumor location and to identify potential sources of heterogeneity in mutation prevalence. Methods: This study was conducted in accordance with PRISMA guidelines. Using comprehensive search strings, several medical research databases were queried and relevant variables abstracted including tumor mutation prevalence, study country, metastasis site, tissue source, study design, study dates, median age of the cohort, mutation assessment method, and length of follow-up. Results: Final abstraction was performed on 40 articles, 36 observational studies and 4 randomized trials. Most studies were from Europe (n = 16), followed by Asia (n = 11), USA, (n = 7), Australia (n = 3), and the remaining 3 were conducted in multiple countries. The proportion of males in each study ranged from 37% to 72%, and the mean age ranged from 55 to 76 years. The prevalence of all RAS mutations was significantly higher among right-sided colon tumors than left-sided colon tumors (44%, 95% Confidence Interval [CI]: 38 – 50% vs 34%, 95% CI: 29 – 38%; p = 0.009). BRAF mutation prevalence was also higher in right-sided tumors (16.1%, 95% CI: 13.1 – 19.6% vs 4.4%, 95% CI: 3.4 – 5.8%; p < 0.0001). Conclusions: This systematic review and meta-analysis found that mutation prevalence varied by primary tumor right- or left-sided location among mCRC patients. Some of this variation may be explained by study characteristics such as mutation assessment method, country and length of follow-up. Further research will help to better understand treatment and outcome implications of tumor sidedness and mutation prevalence.
Prognostic and predictive factors in metastasic colorectal cancer.
Authors: Garcia Alfonso Pilar , Garcia Gonzalo , Gallego Iria , Peligros Isabel , Corcuera Ana , Puente Beatriz , Lobo De Mena Miriam , Ruperez Ana , Aguado Gema , Sandoval Carmen , Blanco-Codesido Montserrat , Calvo Aitana , Muñoz Martín Andres J. , Martin Miguel
Published: January 2019

690

Background: In recent years, prognostic and predictive factors in mCRC are becoming more important, outstanding the tumor and metastasic location, the primary tumor and/or metastasis resections as well as molecular biomarkers (KRAS, NRAS, BRAF and PIK3CA). Methods: We conducted a retrospective study of 334 patients with mCRC diagnosticated between January 2010 and June 2015 in the Oncology Service from HGUGM. The objective of our study was to evaluate the overall survival (OS) relating to each of these settings. We also evaluated OS considering the biological treatment received in first line. Multivariant analysis was performed with independence of tumor and metastasic location, metastasectomies, no primary tumor resection, biological treatment used in first line, age, sex and moleculars biomarkers. Results: Median OS was 24,34m. The advantageous prognostic factors which statistically significant impact on the median OS have been triple (RAS and BRAF) (n = 86) and quadruple (RAS, BRAF and PIK3CA) (n = 76) wild-type (wt 36,6m vs mut 23m, p = 0,02; wt 37,6m vs mut 23,38m, p = 0.02, respectively), left tumor location with rectum (left 25,55m vs right 19,44m, p = 0,001) and isolated hepatic and pulmonary metastasic location (30,32 vs 23 m, p = 0,03; 45,32m vs 23,38 m, p = 0,004, respectively). The main disadvantageous prognostic factor has been the no primary tumor resection (13,75m vs 31,61m, p = 0,00001) with independence of synchronous presentation of the disease as well as biomarkers mutational status. Median OS in first line was 30.13 m with bevacizumab (n = 54) vs 16,18m with antiEGFR (n = 28) (p = 0.02) in extended RAS wild-type patients (n = 101). Considering the multivariate analysis, the independent prognostic factors have been the isolated pulmonary metastasis (HR = 0,46; CI 95% 0,30-0,73;p = 0,001), quadruple wild-type (HR = 0,69;CI 95% 0,49-0,97; p = 0,031), metastasectomies (HR = 0,29; CI 95% 0,21-0,4; p = 0,000), right location (HR = 1,43; CI 95% 1,08-1,9;p = 0,014) and no primary tumor resection (HR = 2,06; CI 95% 1,49-2,86; p = 0,000). Conclusions: Isolated pulmonary metastasis, quadruple wild-type, metastasectomies, left location and primary tumor resection have independent positive prognostic value, according to our retrospective study.
Reproducibility of pretreatment lymphocyte-to-monocyte ratio (LMR) in rectal cancer.
Authors: Gawiński Cieszymierz , Winiarek Mariola , Rybski Sebastian , Temnyk Maciej , Kokoszyńska Katarzyna , Wyrwicz Lucjan
Published: January 2019

715

Background: Lymphocyte-to-monocyte ratio (LMR) is a strong prognostic factor in many cancers. Recently, in Polish-2 study it was demonstrated to have a predictive value for hypofractionated neoadjuvant radiotherapy in rectal cancer (WCGIC 2017). LMR > 2.6 was associated with significant improvement of overall survival after short-course radiotherapy (5x5 Gy) and consolidating chemotherapy when compared to chemoradiotherapy (HR 0.36). To our knowledge this is the first observation on use of a predictive biomarker for hypofractionated radiotherapy. In this study we assessed the intra-patient variability of pre-treatment LMR in order to evaluate its reproducibility. Methods: Patients with rectal cancer treated in Maria Sklodowska-Curie Memorial Cancer Center, Warsaw, Poland between January 2013 and August 2017 were identified. In order to test reproducibility of the biomarker, only the patients with minimum two peripheral blood morphology tests within 5 weeks prior to any anti-cancer therapy were selected. Other inclusion criteria were locally advanced rectal cancer with no distant metastasis; no prior radiotherapy or chemotherapy. Patients with LMR > 2.6 were identified as “LMR high”. Results: After pre-screening of 719 rectal cancer patients, 50 patients met the inclusion criteria. LMRs calculated at two time-points were correlated with the coefficient of 0.588 (p < 0.05). 40% of assessments were “LMR high”. In 18% of patients the second test has not confirmed initial assignment to LMR class (95% CI 8.6%-31.4%). If LMR at the first time-point was in the range of 2.2-3.0 (+/- 0.4 from cut off), the chance for misclassification rose to 40% (95% CI 12.2%-73.8%), while outside of this range it dropped to 7.5% (95% CI 1.6%-20.4%). Conclusions: In our study LMR demonstrated significant intra-patient variability, espetially in patients with LMR outside of the indicated range (2.2-3.0). Further translational research is needed to identify the exact biological context of this biomarker in order to identify the molecular subtype of rectal cancer responding to hypofractionated radiotherapy.
SAPPHIRE: A randomized phase II study of mFOLFOX6 + panitumumab versus 5-FU/LV + panitumumab after 6 cycles of frontline mFOLFOX6 + panitumumab in patients with colorectal cancer.
Authors: Nakamura Masato , Munemoto Yoshinori , Takahashi Masazumi , Kotaka Masahito , Kuroda Hiroaki , Kato Takeshi , Minagawa Noritaka , Noura Shingo , Fukunaga Mutsumi , Kuramochi Hidekazu , Touyama Tetsuo , Takahashi Takao , Akagi Yoshito , Satake Hironaga , Kurosawa Shuichi , Miura Tomoko , Mishima Hideyuki , Sakamoto Junichi , Oba Koji , Nagata Naoki
Published: January 2019

729

Background: FOLFOX therapy, an infusion of 5-fluorouracil (5-FU) with leucovorin in combination with oxaliplatin (OXA), is a common first-line chemotherapy regimen for unresectable, advanced or recurrent colorectal carcinoma (CRC). However, long-term administration of OXA is associated with peripheral neuropathy (PN); decreasing treatment length of OXA may be beneficial without reducing its efficacy. Methods: Chemotherapy-naïve pts aged ≥20 yrs with RAS wild-type advanced/recurrent CRC were enrolled to receive 6 cycles of panitumumab (Pmab) + mFOLFOX6 once every 2 wks. Pts who completed 6 cycles of Pmab + mFOLFOX6 and confirmed no progressive disease were subsequently randomized 1:1 to continue to receive Pmab + mFOLFOX6 (arm 1) or Pmab + 5-FU/LV (arm 2). The primary endpoint was progression-free survival (PFS) rate at 9 mos after randomization. The threshold PFS rate was defined as 30%, and the expected rate was set at 50%, with a 90% power and a 1-sided alpha value of 0.10. In the primary analysis, a binomial test was conducted separately for each arm. This study was designed as a phase II randomized screening comparison study which does not use direct comparison for the primary analysis. Results: Of 164 enrolled pts who received initial Pmab + mFOLFOX6 treatment, 56 were randomized to arm 1 and 57 to arm 2. PFS rates at 9 mos after randomization were significantly higher than the defined threshold at 44.6% (80% CI, 36.4–53.2) in arm 1 and 47.4% (39.1–55.8) in arm 2. Median PFS after randomization was 9.1 (8.6–11.2) and 9.3 (6.0–13.0) mos, respectively. Grade ≥2 PNs occurred in 6 (10.7%) and 1 (1.8%) pts in arms 1 and 2, respectively. Serious AEs occurred in 14 (25.0%) pts in arm 1 and in 9 (16.7%) pts in arm 2. Conclusions: The results of this trial suggest that Pmab + 5-FU/LV after 6 fixed-cycles of Pmab + mFOLFOX6 may be a treatment option in pts with RAS wild type chemotherapy-naïve advanced/recurrent CRC. Pts treated with Pmab + 5-FU/LV had a lower occurrence of grade ≥2 PNs compared with Pmab + mFOLFOX6. Clinical trial information: NCT02337946.
Impact of primary tumor sidedness on erlotinib efficacy in patients with metastatic colorectal cancer treated with bevacizumab maintenance: Results from the DREAM phase III trial.
Authors: Chibaudel Benoist , Andre Thierry , Samson Benoit , Garcia-Larnicol Marie-Line , Dauba Jérôme , Lledo Gerard , Dupuis Olivier Jean Marie , Rinaldi Yves , Mabro May , Aucoin Nathalie , Viret Frédéric , Tubiana-Mathieu Nicole , Khalil Ahmed , Baba Hamed Ghaouti Nabil , Scheithauer Werner , Carola Elisabeth , Vernerey Dewi , Louvet Christophe , De Gramont Aimery , Tournigand Christophe ,   GERCOR
Published: January 2019

737

Background: Primary tumor sidedness (PTS) could be a predictive maker for treatment efficacy of EGFR inhibitors monoclonal antibodies in patients with wild-type (WT) RAS metastatic colorectal cancer (MCRC), cetuximab having limited efficacy in patients with WT-RAS right-sided tumors. DREAM study demonstrated that adding erlotinib, an oral EGFR tyrosine kinase inhibitor (TKI) to bevacizumab during maintenance therapy improved clinical outcomes (RR, PFS, OS) in patients with MCRC, whatever KRAS status. The aim of this post-hoc analysis is to evaluate the clinical outcomes according to KRAS mutational status and PTS when adding erlotinib to bevacizumab maintenance therapy. Methods: PTS was retrospectively collected in patients from the DREAM phase III trial treated with bevacizumab with or without erlotinib as maintenance therapy for MCRC who have been controlled by induction therapy. The limit for the definition of PTS was splenic flexure, and rectal tumors were considered as left-sided tumors. The primary endpoint was overall survival (OS). Results: Among 452 patients who received maintenance therapy, PTS ascertainment was 84.7% (n = 383) with 265 (71.0%) patients having left-sided primary tumor and 108 (28.9%) having right-sided primary tumors (3 patients had both and tumor location was unknown in 7 patients). Median OS and treatment effect are presented in table 1. Conclusions: The greatest OS benefit of adding erlotinib to bevacizumab maintenance therapy was observed in patients with WT-KRAS and right-sided MCRC, suggesting a clinical impact of the different mechanism of action between EGFR TKI and monoclonal antibodies. Clinical trial information: NCT00265824. [Table: see text]
Influence of timing of surgery on perioperative morbidity after neoadjuvant therapy for locally advanced rectal cancer.
Authors: Roxburgh Campbell SD , Strombom Paul , Lynn Patricio B , Paty Philip , Guillem Jose G. , Nash Garrett Michael , Smith Jesse Joshua , Wei Iris H , Garcia-Aguilar Julio , Weiser Martin R.
Published: January 2019

754

Background: Timing of surgery following completion of neoadjuvant therapy (NT) for locally advanced rectal cancer (LARC) has important implications for treatment response. However, it was recently reported in the GRECCAR 6 trial that delayed surgery beyond 8 weeks from completion of NT is associated with increased complications. Within a cohort of LARC patients treated with NT (CRT alone, Total NT (TNT) and chemotherapy alone) we examine perioperative complications based on time from NT to surgery. Methods: Patients with Stage II/III LARC ≤15cm from the anal verge who received NT from 06/01/09 – 03/01/15 were identified and preoperative morbidity collected on those undergoing rectal resection. Patients were grouped according to time of surgery from completion of NT (5-8 weeks – early surgery / 8-12 weeks – late surgery). Results: 798 patients were identified and 547 underwent rectal resection within 12 weeks of completing NT (440 LAR and 107 APR). Surgery was performed 5-8 following NT in 252 pts and 8-12 weeks following NT in 246 pts. 204 patients (41%) had a post-op complication: 53 (10%) Grade 3-5 complication and 83 (17%) SSI. There were no statistically significant differences in rates of all complications (44% vs 38%), grade 3-5 complications (9% vs 11%), SSI (17% vs 17%), and LOS (median 6 days vs 6 days) between the early and late surgery groups. Similar results were obtained when evaluating the subgroups by type of NT (CRT alone, chemo alone or TNT), surgical approach (open vs minimally invasive and sphincter preservation vs colostomy), post-treatment TNM stage and year of treatment (all NS). In addition, we did not observe differences in rates of downstaging responses: T downstaging (63% vs 64%), N downstaging (61% vs 54%), > 95% regression (34% vs 34%) or pCR rates (18% vs 18%) between the early and later surgery groups. Conclusions: In patients undergoing radical surgery for LARC post NT, we do not observe an effect of timing of surgery on surgical complications. Although timing of surgery is reported to influence response rates, we did not reproduce these findings, likely as a consequence of the high rate of deferral of surgery/ non-operative management in this cohort.
The impact of pre-operative chemotherapy in patients with peritoneal lavage cytology positive or localized peritoneum metastasis for gastric cancer: A multicenter retrospective study.
Authors: Makuuchi Rie , Yamaguchi Toshifumi , Takashima Atsuo , Nagashima Kengo , Yamada Tatsuya , Kinoshita Takahiro , Hata Hiroaki , Kawachi Yasuyuki , Kawabata Ryohei , Tsuji Toshikatsu , Hirabayashi Naoki , Sakamoto Takeshi , Inada Takao , Ishiyama Koshiro , Fukagawa Takeo , Boku Narikazu , Katai Hitoshi
Published: January 2019

95

Background: Peritoneal lavage cytology of positive and localized peritoneum metastasis of gastric cancer (GC) are defined as CY1 and P1 in the 14th edition of the Japanese Classification of GC. Patients (pts) with CY1 and/or P1 have poor prognosis after removing all macroscopically visible disease by standard gastrectomy followed by S1. The aim of this study was to investigate the efficacy of pre-operative chemotherapy (Pre-Cx) in patients with CY1 and/or P1. Methods: We retrospectively reviewed the GC pts who were diagnosed to have CY1 and/or P1 at 34 institutions participating in the Stomach Cancer Group of Japan Clinical Oncology Group between 2007 and 2012. Inclusion criteria were: no distant metastasis other than CY1 or P1, no prior treatment for GC. The subjects were divided to two groups according to treatment strategy with/without Pre-Cx before surgery. In the Pre-Cx group, status of CY and P was diagnosed by laparoscopy before and after Pre-Cx, and indication of surgical resection was decided by each physician. Results: A total of 824 pts were collected from 34 institutions. Of the 713 eligible pts, 150 pts received Pre-Cx (Pre-Cx group) and 563 pts underwent surgery followed by Cx (Post-Cx group). Proportions of P0CY1/P1CY0/P1CY1 were 69/12/19% and 69/17/14% in the Pre- and Post-Cx. Cx regimen for Pre-Cx were S1 plus cisplatin/ docetaxel and cisplatin plus S1/others (n=90/37/23). In the Pre-Cx, 57 (38%) pts who achieved P0CY0 after Pre-Cx showed better survival than the remaining 92 pts (overall survival (OS), 31.0 vs. 19.9 months (M), HR=1.99, 95% CI 1.32-2.93, p=0.001). OS was 24.8 and 24.0 M in the Pre- and Post-Cx (HR 1.07; 95% CI 0.87-1.32, p=0.502). In multivariate analysis, P1CY1, over 65 years old and clinical N3 lymph node metastasis were identified as the independent prognostic factor for OS (p<0.05). Conclusions: Although Pre-Cx showed favorable survival in case of achieving P0 and CY0, Pre-Cx did not show a survival benefit for GC pts with CY1 and /or P1.
CheckMate 648: A randomized phase 3 study of nivolumab plus ipilimumab or nivolumab combined with fluorouracil plus cisplatin versus fluorouracil plus cisplatin in patients with unresectable advanced, recurrent, or metastatic previously untreated esophageal squamous cell carcinoma.
Authors: Ajani Jaffer A. , Kato Ken , Doki Yuichiro , Chau Ian , Xynos Ioannis , Balogh Agnes , Kitagawa Yuko
Published: January 2019

TPS193

Background: Esophageal cancer (EC) is the sixth most common cause of cancer-related death worldwide, with a 5-y survival rate of 5%–8% in pts with metastatic disease. First–line platinum-based doublet chemotherapy (CTX) provides a modest survival benefit in pts with metastatic squamous cell EC (mESCC), with a median OS of 7.6 months. Over 40% of pts with EC have PD-L1+ tumors, which are associated with worse OS outcomes. Nivolumab (NIVO), an anti–PD-1 mAb, demonstrated efficacy and a manageable safety profile in pts with ESCC. In the phase 2 ATTRACTION-1 trial, NIVO 3 mg/kg produced an ORR of 17% and median OS of 10.8 months in heavily pretreated pts with ESCC (Kudo T et al Lancet Oncol 2017). NIVO + ipilimumab (IPI) yielded enhanced responses with a manageable safety profile in multiple tumor types. Similarly, NIVO + platinum-based CTX resulted in encouraging clinical activity and an acceptable safety profile in pts with metastatic gastric cancer and SCC NSCLC. This randomized phase 3 study will evaluate the efficacy and safety of NIVO + IPI or NIVO + fluorouracil (5-FU)/cisplatin (Cis) vs 5-FU/Cis as first-line treatment (Tx) in pts with advanced (adv) or mESCC (CheckMate 648; NCT03143153). Methods: 939 pts aged ≥ 18 y with histologically confirmed unresectable advanced, recurrent or mESCC, not amenable to curative approaches, and no prior systemic therapy for advanced/metastatic disease, with adequate organ function and ECOG PS 0 or 1 will be randomized 1:1:1 to NIVO + IPI, NIVO + 5-FU/Cis or 5-FU/Cis. Pts with autoimmune diseases, serious or uncontrolled medical disorders; active infections or positive for HIV, AIDS, or hepatitis B/C, indicating acute or chronic infection and/or detectable virus; and previous Tx with other therapy targeting T-cell co-stimulation or immune checkpoint pathways are excluded. Primary endpoints are OS and PFS by central assessment in pts with a PD-L1+ tumor (defined as PD-L1 expression on ≥ 1% of tumor cells). Secondary endpoints include ORR, PFS, and OS in all pts, as well as ORR in pts with PD-L1+ tumors. Clinical trial information: NCT03143153.
Phase II study of copanlisib (BAY 80-6946) in combination with gemcitabine and cisplatin in advanced cholangiocarcinoma.
Authors: Mehta Rutika Jitesh , Kim Dae Won , Soares Heloisa P. , Kim Jongphil , Kim Richard D.
Published: January 2019

TPS525

Background: The current standard of treatment for cholangiocarcinoma (CCA) is gemcitabine and cisplatin that favored both overall survival (OS) and progression free survival (PFS) when compared to gemcitabine alone. The survival however remains less than than 1 year. Predominant activation of PI3K/AKT signaling pathway is seen in cell line and human tumors of CCA promoting tumorigenesis and increased resistance to radiation and chemotherapy. Inhibition of this pathway sensitizes CCA cells to therapies. Copanlisib is a selective and reversible pan-class I PI3K inhibitor. In preclinical studies, copanlisib demonstrated anti-tumor activity in PIK3CA mutated cells particularly in BC. In a Phase I study, 4 treatment naïve patients with CCA showed response, including 1 complete response. The maximum tolerated dose of copanlisib was determined to be 0.8 mg/kg in this study. We hypothesize that the addition of copanlisib to gemcitabine + cisplatin will enhance the efficacy of the current standard regimen in advanced CCA. Tumor tissue will be collected on every patient for PTEN immunohistochemical staining and NGS analysis using a 26-genes panel. Methods: This is a single institution phase II single arm two-stage design trial using copanlisib in combination with gemcitabine and cisplatin in patients with advanced CCA. Eligible patients include those diagnosed with advanced, unresectable CCA that are treatment naïve or should have received adjuvant treatment more than 6 months prior to initiating the trial. Patients will be treated with Cisplatin (25 mg/m2) plus Gemcitabine (1000 mg/m2) and Copanlisib (60 mg) on days 1 and 8 on a 21 days cycle. Primary objective of the study is PFS at 6 months with secondary objectives being response rate, median PFS, OS, safety and tolerability. Accrual began on June 28, 2016, with planned enrollment for 25 patients. 14 eligible patients will be enrolled in the first stage. If 8 or more patients (≥57%) are alive and progression free at 6 months, an additional 11 patients will be enrolled in the second stage. 11 patients have been enrolled until now. After 3 cycles, response and progression will be evaluated using RECIST v1.1. Clinical trial information: NCT02631590.
ACELARATE: A phase III, open label, multicentre randomised clinical study comparing Acelarin (NUC-1031) with gemcitabine in patients with metastatic pancreatic carcinoma.
Authors: Palmer Daniel H. , Ross Paul J. , Silcocks Paul , Greenhalf William , Faluyi Olusola Olusesan , Ma Yuk Ting , Wadsley Jonathan , Rawcliffe Charlotte Louise , Valle Juan W. , Neoptolemos John P.
Published: January 2019

TPS537

Background: Single agent gemcitabine still remains an appropriate choice for patients with metastatic pancreatic adenocarcinoma who are not suitable for combination therapy. Known resistance factors, such as low hENT1 and dCK, and CDA overexpression limit gemcitabine’s efficacy. NUC-1031 (Acelarin), is designed to overcome this resistance and deliver significantly higher intracellular levels of the active agent, dFdCTP, than gemcitabine. In Phase I studies Acelarin has shown activity in a range of metastatic cancers, including pancreatic, biliary and ovarian cancers. This Phase III study is designed to show superiority of Acelarin over gemcitabine in patients unsuitable for combination chemotherapy. Methods: To date, 85 patients have been randomised in this multicentre, Phase III study comparing Acelarin with gemcitabine first-line in patients with metastatic pancreatic adenocarcinoma. Patients must have a Performance Status of 0-2 and be unsuitable for combination chemotherapy. To detect a hazard ratio of 0.705 between the two arms, 270 events must be obtained from 328 patients, assuming a median survival of 6 months in the control arm. Currently, pts are being recruited at 27 centres. Patients receive either 825mg/m2 Acelarin or 1000mg/m2 gemcitabine on Day 1, 8 and 15 of a 28-day cycle until disease progression. The primary outcome measure is Overall Survival. Secondary outcome measures include Progression Free Survival, Response Rate, Disease Control Rate and Toxicity. Translational research will explore the use of biomarkers for predictive benefit of Acelarin over gemcitabine. Clinical trial information: ISRCTN16765355.
An open-label, phase II study of intravenous anetumab ravtansine, an anti-mesothelin antibody drug conjugate, in pretreated mesothelin-expressing advanced pancreatic cancer.
Authors: Chokshi Saurin , Hochster Howard S.
Published: January 2019

TPS540

Background: Advanced pancreatic cancer remains one of the deadliest malignancies with median OS of 11 months with the most aggressive therapy regimen. Hence, a need exists for more effective, durable, and targeted therapies. Mesothelin is a membrane associated antigen overexpressed in most pancreatic adenocarcinomas. The biological function of mesothelin remains unknown but it is an internalizing antigen. Given its limited expression in normal tissue and high expression in malignant cells, mesothelin is an excellent target for antibody directed cytotoxic drug delivery. Anetumab ravtansine (AR) is an ADC consisting of a fully human IgG1 antibody directed at mesothelin and conjugated to tubulin-binding toxophore, DM4 (maytansine derivative). Preclinical efforts have shown antiproliferative activity in mesothelin positive cancer cell lines and 75% tumor regression in pancreatic xenograft models (Golfier S, et al. Mol Cancer Ther 13(6):1537-48, 2014). Methods: This is a multicenter, non-randomized, Phase II study evaluating the efficacy of AR in pretreated mesothelin-expressing advanced pancreatic cancer. The study utilizes minimax, Simon 2-stage design testing 5% null hypothesis versus 21% alternative. If no response among the first 20, trial will terminate early. If at least one response among the first 20, trial will accrue additional 10 patients for maximum of 30. Four or more responses out of 30 will reject the null hypothesis. Significance level (alpha) is 0.1 and power is 90%. Probability of stopping early is 36% if the response rate is 5% or lower. Patients will receive AR infusion at 6.5 mg/kg on Day 1 of 21-day cycle. Primary objective: response rate per RECIST 1.1. Secondary objectives: time to progression; toxicity. Eligibility: measurable disease per RECIST 1.1; no more than two prior chemotherapy regimens; 30% of cells with 2+/3+ mesothelin staining per IHC; no history of keratitis or corneal disease. Correlative studies: serum soluble mesothelin levels and apoptotic factors (CK18, caspase-cleaved fragments) at baseline and throughout the study to predict treatment response/outcome. Enrollment is on-going. Clinical trial information: NCT03023722.
ClarIDHy: A phase 3 multicenter randomized double-blind study of AG-120 versus placebo in patients with non-resectable or metastatic cholangiocarcinoma with an IDH1 mutation.
Authors: Abou-Alfa Ghassan K. , Valle Juan W. , Kelley Robin Kate , Goyal Lipika , Shroff Rachna T. , Javle Milind M. , Borad Mitesh J. , Cleary James M. , El-Khoueiry Anthony B. , Bendell Johanna C. , Macarulla Teresa Mercade , Vogel Arndt , Korth Christopher , Jiang Liewen , Gliser Camelia , Wu Bin , Agresta Samuel V. , Pandya Shuchi Sumant , Zhu Andrew X.
Published: January 2019

TPS545

Background: Advanced cholangiocarcinoma (CC) is a life-threatening disease with limited effective chemotherapy options. Mutations in isocitrate dehydrogenase 1 (mIDH1) occur in 13–15% of CC cases, and up to 25% of intrahepatic CC cases, leading to epigenetic and genetic changes that promote oncogenesis via production of the oncometabolite 2-hydroxyglutarate (2-HG). AG-120 (ivosidenib), a first-in-class oral mIDH1 inhibitor, displayed a favorable safety profile and clinical activity in a phase 1 study enrolling 73 mIDH1 CC patients who had received ≥1 prior systemic regimen. As of 10 Mar 2017, 4/73 (5%) had a partial response and 41/73 (56%) stable disease. Progression free survival (PFS) rates at 6 months and 12 months were 38.5% and 20.7%, respectively. The 500 mg once daily dose level of AG-120 was selected for further development in mIDH1 CC. Methods: ClarIDHy is a global, phase 3, multicenter, double-blind, randomized (2:1) study of AG-120 (500 mg once daily) vs. matched placebo in 186 mIDH1 CC patients (ClinicalTrials.gov NCT02989857). Key eligibility criteria: non-resectable or metastatic CC, documented mIDH1 by central laboratory testing, ECOG performance status 0–1, measurable disease (RECIST v1.1), documented disease progression after ≤2 prior systemic therapies in the advanced setting including at least 1 gemcitabine- or 5-fluorouracil-containing regimen, and no prior mIDH inhibitor therapy. Crossover from placebo to AG-120 will be allowed at time of radiographic disease progression. Primary endpoint: PFS assessed by independent radiologists. Secondary endpoints: safety, tolerability, overall response rate (RECIST 1.1), overall survival, pharmacokinetic/pharmacodynamic analyses, and quality of life (EORTC QLQ-C30 and QLQ-BIL21 scales). An independent data monitoring committee will monitor the data during study conduct. The ClarIDHy study is currently activated at participating sites in the US, UK, EU, and S. Korea. R eused with permission from the American Society of Clinical Oncology (ASCO). This abstract was accepted and previously presented at the 2017 ASCO Annual Meeting. All rights reserved. Clinical trial information: NCT02989857.
An interview with Edith Heard
Authors: Brown Katherine
Published: January 2019

A geneticist by training, Edith Heard's research interests centre on the epigenetic events underlying X chromosome inactivation during mammalian development. In January 2019, Edith takes over as the Director General of the European Molecular Biology Laboratory (EMBL), with responsibility for six research sites across Europe. Before her move to EMBL, she was the Director of the Genetics and Developmental Biology Unit at the Institut Curie in Paris, and she continues to hold a chair in epigenetics and cellular memory at the Collège de France. We met with Edith to discuss her research interests, her future plans for EMBL and the extent to which she considers herself a role model for women in science.
How Do Patents Affect Follow-On Innovation? Evidence from the Human Genome
Authors: Sampat Bhaven , Williams Heidi L.
Published: January 2019

We investigate whether patents on human genes have affected follow-on scientific research and product development. Using administrative data on successful and unsuccessful patent applications submitted to the US Patent and Trademark Office, we link the exact gene sequences claimed in each application with data measuring follow-on scientific research and commercial investments. Using these data, we document novel evidence of selection into patenting: patented genes appear more valuable—prior to being patented— than non-patented genes. This evidence of selection motivates two quasi-experimental approaches, both of which suggest that on average gene patents have had no quantitatively important effect on follow-on innovation. (JEL I10, O31, O34)
An Economic Analysis of Privacy Protection and Statistical Accuracy as Social Choices
Authors: Abowd John M. , Schmutte Ian M.
Published: January 2019

Statistical agencies face a dual mandate to publish accurate statistics while protecting respondent privacy. Increasing privacy protection requires decreased accuracy. Recognizing this as a resource allocation problem, we propose an economic solution: operate where the marginal cost of increasing privacy equals the marginal benefit. Our model of production, from computer science, assumes data are published using an efficient differentially private algorithm. Optimal choice weighs the demand for accurate statistics against the demand for privacy. Examples from US statistical programs show how our framework can guide decision-making. Further progress requires a better understanding of willingness-to-pay for privacy and statistical accuracy. (JEL C38, C81, D83)
Job Search Periods for Welfare Applicants: Evidence from a Randomized Experiment
Authors: Bolhaar Jonneke , Ketel Nadine , van der Klaauw Bas
Published: January 2019

We combine a randomized experiment with administrative data to study the effects of mandatory job search periods in the Dutch welfare system. Job search periods postpone the first welfare benefits payment and encourage applicants to start searching for jobs actively. Job search periods substantially reduce benefits take up. The decline in benefits receipt is permanent, but fully compensated by increased earnings because of higher reemployment rates. We do not find detectable effects on health and crime outcomes, nor do we observe income declines for more vulnerable applicants. Our results suggest that job search periods are an effective instrument for targeting benefits to welfare applicants. (JEL C93, I38, J31, J64)
Severe Air Pollution and Labor Productivity: Evidence from Industrial Towns in China
Authors: He Jiaxiu , Liu Haoming , Salvo Alberto
Published: January 2019

We examine day-to-day fluctuations in worker-level output at two manufacturing sites in China. Ambient fine-particle (PM2.5) pollution is severe but significantly variable, largely due to exogenous atmospheric ventilation. We obtain an insignificant immediate output response from concurrent (same-shift) variation in particle pollution. We then allow worker outcomes to respond to day-to-day variation in pollution with up to 30 days of delay. We uncover statistically significant adverse output effects from more prolonged exposure, but effects are not large. A substantial + 10 μg/m3 PM2.5 variation sustained over 25 days reduces daily output by 1 percent. (JEL J24, O13, P23, P25, P28, Q51, Q53)
Understanding the Average Impact of Microcredit Expansions: A Bayesian Hierarchical Analysis of Seven Randomized Experiments
Authors: Meager Rachael
Published: January 2019

Despite evidence from multiple randomized evaluations of microcredit, questions about external validity have impeded consensus on the results. I jointly estimate the average effect and the heterogeneity in effects across seven studies using Bayesian hierarchical models. I  find the impact on household business and consumption variables is unlikely to be transformative and may be negligible. I find reasonable external validity: true heterogeneity in effects is moderate, and approximately 60 percent of observed heterogeneity is sampling variation. Households with previous business experience have larger but more heterogeneous effects. Economic features of microcredit interventions predict variation in effects better than studies’ evaluation protocols. (JEL D14, G21, I38, O12, O16, P34, P36)
When Is Foreign Exchange Intervention Effective? Evidence from 33 Countries
Authors: Fratzscher Marcel , Gloede Oliver , Menkhoff Lukas , Sarno Lucio , Stöhr Tobias
Published: January 2019

This paper examines foreign exchange intervention based on novel daily data covering 33 countries from 1995 to 2011. We find that intervention is widely used and an effective policy tool, with a success rate in excess of 80 percent under some criteria. The policy works well in terms of smoothing the path of exchange rates, and in stabilizing the exchange rate in countries with narrow band regimes. Moving the level of the exchange rate in flexible regimes requires that some conditions are met, including the use of large volumes and that intervention is made public and supported via communication. (JEL E52, E58, F31, F33, O19, O24)
Demographic Structure and Macroeconomic Trends
Authors: Aksoy Yunus , Basso Henrique S. , Smith Ron P. , Grasl Tobias
Published: January 2019

We estimate the effect of changes in demographic structure on long-term trends of key macroeconomic variables using a panel VAR for 21 OECD economies from 1970 –2014. The panel data variation assists the identification of demographic effects, while the dynamic structure, incorporating multiple channels of influence, uncovers long-term effects. We propose a theoretical model, relating demographics, innovation, and growth, whose simulations match our empirical findings. The current trend of population aging and low fertility is projected to reduce output growth, investment, and real interest rates across OECD countries. (JEL E22, E23, E32, E43, J11, J13)
Extremal tricyclic, tetracyclic, and pentacyclic graphs with respect to the Narumi–Katayama index
Authors: Ashrafi Ali Reza , Eliasi Mehdi , Ghalavand Ali , Ori Ottorino
Published: January 2019

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Changes in leisure-time physical activity levels and perceived barriers among Estonian adults over a two-year period
Authors: Lusmägi Peeter , Mooses Kerli , Roosmaa Eve-Liis , Kull Merike
Published: January 2019

The aim of this study is to describe the changes in leisure-time physical activity (LTPA) levels among the Estonian adult population in the years 2013–2015 in order to examine the relationships between LTPA level and socioeconomic status (SES) and health indicators, and also to explore perceived barriers to LTPA. Data from the National Physical Activity Survey were used. The sample consisted of 1009 participants aged 15–69 in 2013 and 1004 respondents in 2015. The proportion of Estonian adults exercising regularly at least four times per week increased from 39% in 2013 to 45% in 2015. Being in the older age groups increased the odds for physical inactivity 2.07–4.74 times compared to the youngest age group (15–24) (p<0.01). Having primary, basic, or secondary education increased the odds of being inactive 2.33–3.14 times compared to respondents with higher education (p < 0.01). The most prevalent barriers to physical activity reported by inactive adults were: 1) the absence of interest or unwillingness to make an effort, 2) tiredness at work, and 3) lack of time. In conclusion, despite a slight positive trend, LTPA levels are low. As the perceived barriers depend on age, public health strategies should involve age-specific solutions, especially for older adults.
The effect of peers’ autonomy-supportive behaviour on adolescents’ psychological need satisfaction, intrinsic motivation and objectively measured physical activity
Authors: Tilga Henri , Kalajas-Tilga Hanna , Hein Vello , Raudsepp Lennart , Koka Andre
Published: January 2019

Based on self-determination theory, adolescents’ leisure-time (LT) physical activity (PA) behaviour may depend on the extent by which they perceive an environment as autonomy-supportive. The present study aimed to investigate whether adolescents’ perception of autonomy-supportive behaviour from their peers is related to adolescents’ objectively measured LT moderate-to-vigorous physical activity (MVPA) through perceived psychological needs satisfaction and intrinsic motivation towards PA. School students (n=215) aged between 12 to 15 years old (age: 13.20±0.96 yrs) completed self-reported measures of perceived peers’ autonomy support, psychological needs satisfaction, and intrinsic motivation in the context of LT PA. In addition, study participants wore an accelerometer (Acti-Graph GT3X) to monitor their MVPA. Results of the structural equation modelling revealed that perceived autonomy support from peers had a significant and positive effect on perceptions of all three psychological need satisfaction in LT, which, in turn, had a significant and positive effect on adolescents’ intrinsic motivation. Adolescents’ LT PA was significantly predicted by their intrinsic motivation towards PA. Only one pathway through autonomy need satisfaction was revealed by which adolescents’ perception of their peers’ autonomy-supportive behaviour is related to intrinsic motivation and MVPA. The findings of the current study highlight the role of peers’ autonomy-supportive behaviour on adolescents objectively measured PA through motivational processes in the context of LT.
The effect of isometric handgrip training on blood pressure
Authors: Piikmann Silvia , Reisberg Kirkke
Published: January 2019

The aim of this study was to determine the effect of single-bout isometric handgrip training on systolic (BPS) and diastolic blood pressure (BPD). Healthy normotensive (BP<120/80 mmHg) (n=6) and prehypertensive (BPS 120–139 mmHg and/or BPD 80–89 mmHg) (n=6) women with mean age of 47.3±14.0 years, who did not take antihypertensive medicine, participated in the study. Blood pressure (BP) was measured with aneroid sphygmomanometer Riester Precisa N (Germany). Thereafter with the JAMAR hydraulic hand dynamometer (USA) maximal isometric contraction (MVC) was recorded. After a rest of 3 min, the subject was asked to perform the isometric contraction at 30% of MVC for 2 min and that was repeated for four times with rest of 1 min after each bout of contraction. BP was measured again after a rest of 3 min and 3 hrs. 3 min after isometric exercise no statistically significant changes in BPS and BPD was observed. But clinically meaningful BPS decrease was observed and confirmed by subgroup analysis with decrease in BPS among prehypertensive subjects. 3 hrs after isometric exercise BPS and BPD were significantly reduced and the decrease in BPS was also clinically meaningful. Subgroup findings showed among normotensive significant and clinically meaningful reduction in BPS and BPD, respectively, as well as clinically meaningful reduction in BPS among prehypertensive subjects. According to this study we suggest that isometric handgrip training could be considered as BP lowering training method.
World Literature in Estonia: the Construction of National Translation Ethics
Authors: Kaldjärv Klaarika , Gielen Katiliina
Published: January 2019

In addition to many other functions, translating may (and often does) also have a national agenda. Such agenda determines what is going to be translated, how and by whom. Depending on what the national agenda might be, various questions of ethics come into play. Such questions of ethics may be reflected in the translation norms, they may be concealed but still have an important role in constructing the image of translators as well as the idea of what translations should be like.

In Estonia, translation has been of pivotal importance among other things in the formation of the national canon and in developing the Estonian language. In addition to that, translation can be considered to be a means of implementing new ideologies as well as means of resistance. In the present paper, we will ask questions rather than try to answer them: What does ethics of translation mean in the Estonian cultural context? Considering Estonian translation history, can translation ethics be said to be dependent on a particular historical-political situation? And, who has the right to judge translations and the activity of translators?