bluuebunny/crossref_metadata_2025 huggingface dataset:
Perceptions of neighborhood environments and their association with overweight in children, adolescents, and caretakers in a medium-sized city in Brazil
Authors: Leite Maria Alvim , de Assis Maíra Macário , Silva Bruna Pires Luz , Matozinhos Fernanda Penido , Padez Cristina , Cândido Ana Paula Carlos , Mendes Larissa Loures
Published: March 2017

Background

Previous studies conducted in developed countries have suggested associations between perceptions of neighborhood characteristics and weight gain. However, there are few studies regarding the adult perception of the residential environment and overweight in children and adolescents in countries with low and medium income. The aim of the study was to assess the associations between caretakers’ perceptions of environmental characteristics and overweight in themselves and in their children, in a medium-sized city in Brazil.

Methods

Cross-sectional study was performed with 708 children and adolescents and their caretakers. Anthropometric measurements and a structured questionnaire filled out by caretakers concerning child and family characteristics were completed. For environmental assessment, 408 caretakers answered the Portuguese version of the “Neighborhood Environment Walkability Scale” by telephone call. A 95% confidence interval (95%CI) was used in the analysis. Unadjusted prevalence ratios (PR) were calculated, as were PR adjusted for age, gender, family income, and total time of exercise the children or adolescents practiced (from Poisson regression models predicting children’s and adolescents’ overweight), and for age and family income (from Poisson regression models predicting caretakers’ overweight). Statistical significance was defined as a p value <0.05.

Results

Adult perceptions about the absence of sidewalks on most streets (PR = 0.49, 95%CI = 0.42–0.98) and the absence of interesting things to look at (esthetics) in the neighborhood (PR = 0.65, 95%CI = 0.44–0.90) were inversely associated with the prevalence of overweight in the children and adolescents after adjustment. The absence of hills in the neighborhood (PR = 1.24, 95%CI = 1.05–1.45) and the perception of heavy exhaust fumes (PR = 1.26, 95%CI = 1.02–1.56) were directly associated with the prevalence of overweight in the caretakers. Finally, the high speed of traffic on the street (PR = 0.76, 95%CI = 0.63–0.92) was inversely associated with the prevalence of adult overweight.

Conclusions

The results showed, in Brazil, the importance of understanding aspects related to obesogenic environment in the context of medium-sized Brazilian cities.
Choosing face: The curse of self in profile image selection
Authors: White David , Sutherland Clare A. M. , Burton Amy L.
Published: March 2017

People draw automatic social inferences from photos of unfamiliar faces and these first impressions are associated with important real-world outcomes. Here we examine the effect of selecting online profile images on first impressions. We model the process of profile image selection by asking participants to indicate the likelihood that images of their own face (“self-selection”) and of an unfamiliar face (“other-selection”) would be used as profile images on key social networking sites. Across two large Internet-based studies (n = 610), in line with predictions, image selections accentuated favorable social impressions and these impressions were aligned to the social context of the networking sites. However, contrary to predictions based on people’s general expertise in self-presentation, other-selected images conferred more favorable impressions than self-selected images. We conclude that people make suboptimal choices when selecting their own profile pictures, such that self-perception places important limits on facial first impressions formed by others. These results underscore the dynamic nature of person perception in real-world contexts.
Full-waveform inversion via source-receiver extension
Authors: Huang Guanghui , Nammour Rami , Symes William
Published: March 2017

Full-waveform inversion produces highly resolved images of the subsurface and quantitative estimation of seismic wave velocity, provided that its initial model is kinematically accurate at the longest data wavelengths. If this initialization constraint is not satisfied, iterative model updating tends to stagnate at kinematically incorrect velocity models producing suboptimal images. The source-receiver extension overcomes this “cycle-skip” pathology by modeling each trace with its own proper source wavelet, permitting a good data fit throughout the inversion process. Because source wavelets should be constant (or vary systematically) across a shot gather, a measure of source trace dependence, for example, the mean square of the signature-deconvolved wavelet scaled by time lag, can be minimized to update the velocity model. For kinematically simple data, such measures of wavelet variance are mathematically equivalent to traveltime misfit. Thus, the model obtained by source-receiver extended inversion is close to that produced by traveltime tomography, even though the process uses no picked times. For more complex data, in which energy travels from source to receiver by multiple raypaths, Green’s function spectral notches may lead to slowly decaying trace-dependent wavelets with energy at time lags unrelated to traveltime error. Tikhonov regularization of the data-fitting problem suppresses these large-lag signals. Numerical examples suggest that this regularized formulation of source-receiver extended inversion is capable of recovering reasonably good velocity models from synthetic transmission and reflection data without stagnation at suboptimal models encountered by standard full-waveform inversion, but with essentially the same computational cost.
Fast-Fourier-based error propagation for the gravimetric terrain correction
Authors: McCubbine J. C. , Featherstone W. E. , Kirby J. F.
Published: March 2017

We have identified a gap in the literature on error propagation in the gravimetric terrain correction. Therefore, we have derived a mathematical framework to model the propagation of spatially correlated digital elevation model errors into gravimetric terrain corrections. As an example, we have determined how such an error model can be formulated for the planar terrain correction and then be evaluated efficiently using the 2D Fourier transform. We have computed 18.3 billion linear terrain corrections and corresponding error estimates for a 1 arc-second ([Formula: see text]) digital elevation model covering the whole of the Australian continent.
Mafic intrusions, hydrothermal venting, and the basalt-sediment transition: Linking onshore and offshore examples from the North Atlantic igneous province
Authors: Angkasa Syahreza S. , Jerram Dougal A. , Millett John M. , Svensen Henrik H. , Planke Sverre , Taylor Ross A. , Schofield Nick , Howell John
Published: March 2017

The emplacement of large intrusive complexes into sedimentary basins can have profound effects on host sedimentary rocks including deformation, thermal aureole metamorphic reactions, alteration of fluid-flow pathways, and the formation of associated hydrothermal vent complexes (HVCs). These processes can in turn have major implications for petroleum systems on the local and regional scale, and can contribute to global climate change due to the production and outgassing of greenhouse gases, such as [Formula: see text] and [Formula: see text]. Imaging these features and assessing their implications from seismic data beneath extrusive volcanic cover is challenging due to heterogeneities in the volcanic pile and at the basalt-sediment transition. We have evaluated combined field and laboratory petrophysical data from the Isle of Skye, Scotland, where we identify a seismic-scale example of extensive intrusions interacting with the base-basalt transition. We have also evaluated a unique onshore example of a linked sill and associated HVC cutting up through the lava sequence. We compare these field results with HVCs from reflection seismic data across the Vøring Marginal High, offshore Norway, where subbasalt saucer-shaped intrusions are also seen associated with HVCs cutting the lava sequence. Seismic imaging problems associated with the velocity heterogeneity of volcanic sequences, along with a historical lack of high-quality 3D data in volcanic regions worldwide, is suggested as having largely precluded the identification of these features in the past. The under-representation of these hydrothermal vents in the literature has key implications for the future appraisal of intrusion-related outgassing effects on the global climate such as those related to the Palaeocene Eocene Thermal Maximum, along with subbasalt petroleum prospectivity where they may alter maturation and migration pathways.
Germline ATM mutations in families with early-onset and familial gastroesophageal and colorectal cancers.
Authors: Hall Michael J. , Olopade Olufunmilayo I. , Daly Mary Beryl , Kupfer Sonia
Published: March 2017

11

Background: ATM is involved in repair of DNA damage due to radiation and environmental toxins via downstream interaction with CHEK2, BRCA1, and other proteins involved in double strand break repair. Mutations in ATM (Ataxia-Telangiectasia Mutated, 11q22) are among the most common hereditary cancer risk mutations in the general population (0.5-1.0% carrier rate), yet beyond risks of breast (BC) and pancreatic cancer (PC), the spectrum of clinically relevant cancer risks in ATM+ individuals remains uncertain. Thompson (JNCI 2005) previously reported possible risk of colorectal (CRC) (RR 2.54; 1.06-6.09) and gastric cancer (GC)(RR 3.39; 0.86-13.4) in ATM+ individuals, while more recently Hansford (JAMA Onc 2015) performed panel gene testing including CDH1 in patients meeting criteria for hereditary diffuse gastric cancer, and found possibly pathogenic ATM mutations in 3/144 (2%) CDH1-negative probands. In addition to GC, families contained multiple cases of BC, PC and CRC (5 cases, 2 < 50). To further describe the frequency of upper and lower GI cancer in ATM+ families, we reviewed pedigrees from 20 families seen for risk assessment in two high-risk clinics and found to have germline ATM mutations. Methods: Pedigrees from ATM+ families evaluated at Fox Chase Cancer Center and the University of Chicago are included in this analysis. Cancer type, age at diagnosis, number of genes clinically tested, and ATM mutation were collected. Cancers < 50 yrs are considered early-onset. Results: Among 20 total ATM+ families, 22 GI cancers were reported, with 5 families containing 16/22 (73%) of all GI cancers (see Table). Early-onset GI cancers were common in the 5 families (7/16, 44%), including 2/6 (33%) cases of GC, a 23 yr old man and his 45 yr old father both with GEJxn cancer (2/2, 100%), and 3/6 (50%) cases of CRC all from one large family. Conclusions: Our data lend evidence to support the need for early CRC and GC screening in ATM+ patients. [Table: see text]
HER2 testing in gastric cancer diagnosis: Insights on variables influencing HER2-positivity from a large, multicenter, observational study in Germany.
Authors: Baretton Gustavo Bruno , Kreipe Hans Heinrich , Schirmacher Peter , Gaiser Timo , Hofheinz Ralf D. , Berghäuser Karl Heinz , Koch Winfried , Holzer Britta , Morris Stefanie , Rüschoff Josef ,   The NIU HER2 Study Group
Published: March 2017

15

Background: HER2 testing is routine for metastatic gastric or gastroesophageal junction cancer (mGC/GEJC). Differing HER2-positivity rates are considered to be potential indicators of inter- and intra-laboratory deviations in testing quality. The influence of patient-, sample-, or method-related factors on HER2-positivity has not been assessed systematically. Methods: This observational, prospective study collected routine HER2 test result, patient- and tumor-related factors, sample source, and testing method data to identify factors influencing HER2-positivity rates in mGC/GEJC. Influencing factors were identified using stepwise multiple logistic regression and a statistical model was developed to predict probability of HER2-positivity. Institutes with deviations in HER2-positivity rates were identified by comparing 95% confidence intervals (CI) of documented and predicted rates. Results: From Jan 2013 to Dec 2015, data were collected from 2761 mGC/mGEJC routine diagnostic specimens at 50 pathology institutes in Germany. Final analyses included 2033 specimens with HER2 test results (1554 mGC and 479 mGEJC cases). Overall HER2-positivity rates across centers was 19.8% for mGC and 30.5% for mGEJC. Lauren classification showed the highest correlation with HER2-positivity, followed by HER2 testing rate, tumor location, type of sample (resection vs biopsy), and testing method (immunohistochemistry vs fluorescence in situ hybridization) (all P < .05). Four institutes were identified with predicted HER2-positivity rates outside the 95% CI of the documented rate. Conclusions: This is the first study to report on multifactorial parameters that impact HER2-positivity rates in routine mGC/GEJC diagnostics. Results suggest that effective assessment of HER2 testing quality based on positivity rates should consider tumor characteristics, testing rate, type of specimen, and testing method, as they affect HER2-positivity. As therapy options for HER2-positive mGC/GEJC continue to evolve, reliably identifying the right patients is key.
Iron deficiency anemia in gastric cancer: A single site retrospective cohort study.
Authors: Tang Grace , Hart Rachel , Sholzberg Michelle , Brezden-Masley Christine
Published: March 2017

188

Background: Gastric cancer is highly prevalent amongst men and women. While many studies have identified the prevalence and association of iron deficiency anemia (IDA) in all cancer patients, few have focused on the gastric cancer population. The primary objective of this study was to determine the proportion of patients with gastric cancer who developed IDA, and chemotherapy induced anemia (CIA) at our institution. Secondary objectives were to identify types and frequencies of IDA therapies used. Methods: A retrospective study was carried out in 110 consecutive gastric cancer patients from 2006 to 2014 at St. Michael’s Hospital, Toronto, Canada. Patient demographics, previous history of IDA, and IDA based therapies were reviewed. IDA was defined as hemoglobin (Hb) < 130 g/L in men and < 120g/L in women and iron deficiency (ID) was defined as a ferritin < 15m/L. SAS 9.3 was used to calculate frequencies and proportions. Results: Of the 110 patients (median age 68.5 [interquartile range (IQR): 58-76]), 72 (65%) were male. Most patients were diagnosed at stage IV (35%) with a mean Hb of 118 g/L (standard deviation (SD): 19.7 g/L). Only 18 (16%) patients had a history of IDA prior to cancer diagnosis, and 63 (57%) had IDA at time of gastric cancer diagnosis. Only 29 patients (45%) had ferritin levels tested at first oncology visit. Of the 110 patients, 71 patients had an open (32%) or laparoscopic (68%) surgery. A total of 66 patients received chemotherapy, and 50 (76%) developed CIA. In this sample, 9 (14%) experienced a chemotherapy dose delay and 20 (30%) had a dose reduction. At last follow up, 87 (79%) of patients were diagnosed with IDA. Red blood cell (RBC) transfusions were most frequently prescribed (95%), compared to oral (29%) or intravenous iron (12%). Conclusions: A total of 87 (79%) gastric cancer patients were diagnosed with IDA and nearly all patients received a RBC transfusion. We found that the diagnosis of IDA increased by 22% from the time of gastric cancer diagnosis to last follow up. There was a high proportion of IDA in our gastric cancer population despite inconsistent screening for ID. This highlights the need for consistent screening and targeted therapy for ID to reduce transfusions and improve quality of life in this patient population.
Complement component C9 as a new biomarker for esophageal adenocarcinoma.
Authors: Joshi Virendra , Shah Alok , Brown Ian , Winterford Clay , Hill Michelle
Published: March 2017

19

Background: Esophageal adenocarcinoma (EAC) continues an upward trend. Mortality rate and treatment costs for EAC are very high overall and significantly increase with disease stage. Diagnosis at early stage (T1) compared to advanced stage (T3) improves 5 year survival from 20% to 80-90%. Endoscopic surveillance has been ineffective in reducing EAC. Therefore the need for better diagnostic tools for early detection.Previously we reported validation of a list of serum glycoprotein biomarker candidates for EAC in an Australian cohort (Shah et al. 2015 Mol Cell Proteomics. 14:3023-39.). Here we further evaluate the serum and tissue expression of top candidate C9 in an independent cohort from the USA. Methods: Serum samples (n=38) and FFPE tissue sections (n=34) were collected from participants with IRB approved protocol, from the Ochsner Clinic undergoing endoscopic surveillance for Barrett’s and esophageal cancer. Serum glycoprotein candidates were measured using lectin magnetic bead array-coupled multiple reaction monitoring assay (Shah et al. 2015 Mol Cell Proteomics. 14:3023-39.). Immunohistochemistry was optimised for complement component C9 antibody. Initial evaluation of 2 different antibodies gave similar results, thereafter, a polyclonal antibody from Sigma Aldrich was used. Staining was assessed by a gastrointestinal pathologist. Results: Specific glycosylated forms of 3 candidate serum biomarkers were confirmed to be significantly different between EAC and benign groups (p<0.05, Kruskal-Wallis). The diagnostic value for the 3 individual markers, complement component C9, gelsolin and alpha-1-antichymotrypsin (Serpin A3) was 0.71 to 0.82 area under the receiver operating curve (AUROC). A multivariate panel consisting of 8 glycoprotein biomarkers achieved AUROC of 0.96, indicative of high diagnostic value. Immunohistochemistry of tissues detected high levels of C9 in BE and EAC compared to normal squamous epithelium. Infiltrated lymphocytes showed variable staining. Conclusions: We propose a novel candidate biomarker complement component C9 which could add to current endoscopic surveillance strategy for early detection of adenocarcinoma.
Nivolumab (ONO-4538/BMS-936558) as salvage treatment after second or later-line chemotherapy for advanced gastric or gastro-esophageal junction cancer (AGC): A double-blinded, randomized, phase III trial.
Authors: Kang Yoon-Koo , Satoh Taroh , Ryu Min-Hee , Chao Yee , Kato Ken , Chung Hyun Cheol , Chen Jen-Shi , Muro Kei , Kang Won Ki , Yoshikawa Takaki , Oh Sang Cheul , Tamura Takao , Lee Keun-Wook , Boku Narikazu , Chen Li-Tzong
Published: March 2017

2

Background: Recent clinical trials have established 1st and 2nd line chemotherapy as the standard treatment for advanced gastric or gastro-esophageal junction cancer (AGC). However, prognosis of AGC is still poor. Nivolumab (ONO-4538/BMS-936558) is a human monoclonal IgG4 antibody which blocks the human programmed cell death-1 (PD-1) receptor. We evaluated the efficacy and safety of nivolumab as salvage treatment after failure of the standard chemotherapy for AGC. Methods: 493 patients aged ≥ 20 years with ECOG PS 0-1 and unresectable advanced or recurrent AGC who had failed two or more previous chemotherapy regimens were randomized in a 2:1 ratio to receive 3 mg/kg nivolumab (N=330) or placebo ( N=163) every 2 weeks until unacceptable toxicity or disease progression. Primary endpoint was overall survival (OS) in Intention-to-Treat population. This trial is registered in ClinicalTrials.gov (NCT02267343). Results: As of the data cut-off on Aug 13th2016, 5.6 months after last patient randomized, median OS was 5.32 months with nivolumab versus 4.14 months with placebo (hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.50-0.78; p<0.0001), and OS rates at 6 and 12 month were 46.4% versus 34.7% and 26.6% versus 10.9%, respectively. The overall response rate (ORR) was 11.2% (95% CI, 7.7-15.6) with nivolumab versus 0% (95% CI, 0.0-2.8) with placebo (p<0.0001). Median progression-free survival (PFS) was 1.61 months with nivolumab versus 1.45 months with placebo (HR, 0.60; 95% CI, 0.49-0.75; p<0.0001). Grade ≥ 3 drug-related adverse events (AEs) occurred in 11.5 % of nivolumab and 5.5 % of placebo; 2.7% and 2.5%, respectively, discontinued of study treatment due to drug-related AEs (any grade). Conclusions: Nivolumab was effective as the salvage treatment for pretreated AGC with significantly improved OS, PFS and ORR compared to placebo. Funding:Ono Pharmaceutical Co., Ltd. and Bristol-Myers Squibb. Clinical trial information: NCT02267343.
The usefulness of Roux-en-Y reconstruction with aboral pouch following total gastrectomy for gastric cancer.
Authors: Iwagami Shirou , Hidetaka Sugihara , Mizumoto Takao , Kubota Tatsuo , Miyanari Nobutomo , Baba Hideo ,   Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University
Published: March 2017

209

Background: Patients with gastric cancer that involves the upper part of the stomach should undergo total gastrectomy for their curative resection. Roux-en-Y reconstruction is the most common procedure followingtotal gastrectomy. However, this reconstruction causes them various postgastrectomy symptoms and problems of their nutritional status and QOL. Although the development of the new reconstruction to prevent these symptoms have being carried out, we have not generally established procedures. Methods: To compare the feasibility and the nutritional parameters of the patients with Roux-en-Y reconstruction with aboral pouch following total gastrectomy to the simple Roux-en-Y. From February 2011 to June 2014, sixty three patients with gastric cancer underwent total gastrectomy. We analyzed the short-term outcome of surgery and the nutritional parameters in two groups. Results: The aboral pouch was created as a side to side anastomosis approximately 50 cms distal to the esophagojejunostomy, 12 cm in length. Most nutritional parameters after surgery were similar in two groups. However, lymphocyte, serum albumin and prognostic nutritional index in aboral pouch group one year later were good tendency compared with simple Roux-en-Y group. Conclusions: Roux-en-Y reconstruction with aboral pouch might become one of the standard methods after total gastrectomy for gastric cancer.
Results of a randomized phase II trial of an anti-notch 2/3, tarextumab (OMP-59R5, TRXT, anti-Notch2/3), in combination with nab-paclitaxel and gemcitabine (Nab-P+Gem) in patients (pts) with untreated metastatic pancreatic cancer (mPC).
Authors: O'Reilly Eileen Mary , Sahai Vaibhav , Bendell Johanna C. , Bullock Andrea J. , LoConte Noelle K. , Hatoum Hassan , Ritch Paul S. , Hool Hugo , Leach Joseph W. , Sanchez James , Sohal Davendra , Strickler John H. , Patel Ravindranath , Wang-Gillam Andrea , Firdaus Irfan , Kapoun Ann M. , Holmgren Eric , Zhou Lei , Dupont Jakob , Picozzi Vincent J.
Published: March 2017

279

Background: Tarextumab (TRXT), fully human IgG2 antibody inhibits signaling of Notch2/ 3 receptors. Tumor regression seen in Notch3 (N3) expressing pt-derived pancreatic cancer xenografts when TRXT combined with Nab-P+Gem. Phase 2, randomized, placebo-controlled trial conducted to evaluate efficacy, safety of combination in mPC. Methods: Pts randomized 1:1 to TRXT or placebo (PL). TRXT given IV at 15 mg/kg q 2wks (D 1, 15), nab-P 125 mg/m2, GEM 1000mg/m2 on D1, 8, 15 q 28 days. Tissue for N3 gene expression determination was required. Primary endpoints: overall survival (OS) in all and in 3 subgroups determined by Notch 3 gene expression. Secondary: safety, progression-free survival (PFS) and overall response rate (ORR). Results: N = 177 pts randomized. Performance status (0 or 1), CA19-9 stratum (0 – ULN, > ULN – 59ULN, ≥ 59ULN) balanced. Clinical trial information: NCT01647828. .  Conclusions: Addition of TRXT to Nab-P+Gem did not improve OS in 1st line mPC. A potential detrimental effect on PFS and ORR was seen in subjects with N3 < 25%ile.[Table: see text]
Genomic profiling of ampullary adenocarcinoma (AA): Insights from a comparative analysis of pancreatic and intestinal adenocarcinoma and opportunities for targeted therapies use.
Authors: Perkins Geraldine , Bouchet-Doumenq Cecile , Svrcek Magali , Colussi Orianne , Voron Thibault , Sauvanet Alain , Hammel Pascal , Cros Jerome , Paye Francois , Andre Thierry , Vaillant Jean-Christophe , Bachet Jean Baptiste , Bardier Armelle , Berger Anne , Meatchi Tchao , Nordlinger Bernard , Emile Jean-Francois , Cojean-Zelek Isabelle , Taieb Julien , Laurent-Puig Pierre
Published: March 2017

300

Background: Ampullary adenocarcinoma (AA) is a rare entity. AA can originate from either intestinal or pancreaticobiliary ductal epithelium, and patients are often managed as those with pancreaticobiliary carcinomas. The study objectives were the genetic profiling of AA and the identification of specific molecular profiles according to these 2 pathological types. Methods: AA patients included in the AGEO retrospective multicenter cohort who underwent surgical resection of their tumor between 1999 and 2010 were selected. Formalin-fixed, paraffin-embedded (FFPE) archival tissue blocks were collected. Next generation sequencing (NGS) using a 50 gene panel (Ion AmpliSeq Cancer panel) on tumor DNA, and immunohistochemistry (IHC) panel including CK7, CK20, MUC1, MUC2 and CDX2, on tumor sections, were performed. Results: NGS was performed on 101 tumors from 6 hospitals, with 1 technical failure. In total, the most frequent gene mutations were: KRAS (45%), TP53 (40%), APC (15%), PIK3CA (12%), SMAD4 (9%), BRAF (8%), CDKN2A (6%). No mutation was found in 21% of tumors. According to IHC, the most common histological type was intestinal (51%), followed by pancreaticobiliary type (42%) and undetermined (7%). BRAF mutation was significantly associated with intestinal type (8 vs 0, p = 0.017). According to Cosmic database, similarities of molecular profiles exist between AA with intestinal type and colorectal adenocarcinoma, and between AA with pancreaticobiliary type and pancreas adenocarcinoma, respectively. Conclusions: This study shows that AA is a heterogeneous entity and that a large proportion of AA presents a molecular profile that is more similar to that of colorectal adenocarcinoma, compared to pancreatic adenocarcinoma. This important information could be interesting to guide treatment decision in patients with this rare disease.
Interim analysis of a phase 2 study of lenvatinib (LEN) monotherapy as second-line treatment in unresectable biliary tract cancer (BTC).
Authors: Morizane Chigusa , Ueno Makoto , Sasaki Takashi , Nagashima Fumio , Mizuno Nobumasa , Shimizu Satoshi , Hayata Nozomi , Ikezawa Hiroki , Suzuki Takuya , Nakajima Ryo , Dutcus Corina E. , Ikeda Masafumi
Published: March 2017

310

Background: LEN inhibits the activity of vascular endothelial growth factor receptor, fibroblast growth factor receptor, and platelet-derived growth factor receptor–α. These targets have been shown to be expressed in patients (pts) with BTC. The objective of this study is to evaluate LEN as a potential treatment option for these pts. Methods: This is an open-label, phase 2 study conducted in Japan. Pts aged ≥ 20 years with confirmed diagnosis of unresectable BTC, measureable disease per Response Evaluation Criteria in Solid Tumors v1.1, and 1 prior gemcitabine-based doublet chemotherapy, will receive LEN 24 mg/d. The primary endpoint is objective response rate. Secondary objectives include disease control rate (DCR), safety, and pharmacokinetics. Enrollment of 25 pts is planned. The study includes an interim evaluation for futility. If there is no objective response and disease control is achieved in < 5 pts of 15‒17 pts, the study will end. Results: An interim evaluation was performed with 17 pts enrolled (data cutoff: 25 July 2016). Ten (59%) pts were aged < 65 years, 10 (59%) were male, 2 (12%) had prior surgery, and 13 (76%) received prior gemcitabine + cisplatin therapy. Efficacy results appear in the table. One pt had a partial response (PR) and 13 had stable disease (SD). The DCR was 82%. All pts experienced treatment-emergent adverse events (TEAEs). Grade ≥ 3 TEAEs occurred in 11 (65%) and serious AEs (SAEs) occurred in 7 (41%) pts. There were no fatal SAEs. TEAEs leading to LEN discontinuation, dose reduction, and dose interruption occurred in 1 (6%), 12 (71%), and 9 (53%) pts, respectively. Analysis of trough plasma concentration in 13 pts from this study showed no difference versus that observed in a previous phase 3 study of LEN in differentiated thyroid cancer. Conclusions: Because results of this interim evaluation did not meet futility criteria, the study was continued, with findings suggesting possible activity of LEN in pts with unresectable BTC who failed gemcitabine-based doublet chemotherapy. Toxicities were generally manageable with dose modifications as only 1 pt required discontinuation from LEN. Clinical trial information: NCT02579616. [Table: see text]
A phase Ib/II pilot trial with nab-paclitaxel plus gemcitabine plus cisplatin in patients (pts) with stage IV pancreatic cancer.
Authors: Jameson Gayle S. , Borazanci Erkut Hasan , Babiker Hani M. , Poplin Elizabeth , Niewiarowska Anna A. , Gordon Michael S. , Barrett Michael T , Ansaldo Karen , Lebron Leticia , Stoll Amy C. , Rosenthal Adam , Shemanski Lynn R. , Korn Ronald Lee , Ramanathan Ramesh K. , Von Hoff Daniel D.
Published: March 2017

341

Background: Genomes of metastatic pancreatic cancers frequently contain intrachromosomal aberrations indicating DNA repair abnormalities associated with sensitivity to DNA damaging agents such as the platinums. Cisplatin was added to a nab-paclitaxel + gemcitabine regimen, which has been determined to improve survival over gemcitabine alone (NEJM 2013; 369:1691-1703). The objectives are to determine the efficacy and safety of nab-paclitaxel and gemcitabine plus cisplatin in patients with Stage IV pancreatic cancer. Methods: Eligibility criteria included Stage IV adenocarcinoma of the pancreas, no prior chemotherapy for systemic disease, KPS ≥ 70; life expectancy ≥ 12 weeks and measurable disease. Doses are nab-paclitaxel 125 mg/m2 undiluted, gemcitabine 1000 mg/m2 in 500 ml of normal saline (NS), each infused over 30 minutes on days 1 and 8 of a 21 day cycle, along with 3 different dose levels of cisplatin (25, 37.5 or 50 mg/m2) in 500 ml of NS infused over 60 minutes, after the nab-paclitaxel infusion. Pre and post cisplatin hydration was given. The maximum tolerated dose and phase II dose of cisplatin is 25 mg/m2. Results: 25 pts were treated; 24 were evaluable (baseline and ≥ 1 follow up CT scan). The most common drug related grade (gr) 3 - 4 adverse events (AEs), n = 25, were thrombocytopenia 76% (gr 3 = 36%, gr 4 = 40%) with no serious bleeding events, anemia 32% (gr 3 = 32%, gr 4 = 0%), neutropenia 24% (gr 3 = 20%, gr 4 = 4%), infection 20% (gr 3 = 16%, gr 4 = 4%), and diarrhea 16% (gr 3 = 16%, gr 4 = 0%). Peripheral neuropathy ≥ gr 3 was seen in only 1 pt (gr 3 = 4%). Grade 5 AEs were infection (1), cardiac arrest (1), and stroke (1). Median time on therapy was 5.5 months, range (1 – 9.5). By RECIST 1.1 criteria, 2 pts had complete response (8.3%), 15 partial response (62.5%), 4 stable disease (16.7%), and 3 progressive disease (12.5%). Median overall survival to date as of 11/10/16 is 16.5 months. Conclusions: Although a small study, the high response rate and landmark evolving median survival are very encouraging. This regimen is being expanded in patients with stage IV pancreatic cancer, neoadjuvant and adjuvant settings. Clinical trial information: NCT01893801.
A randomized phase II trial comparing different schedules of nab-paclitaxel (nabP) combined with gemcitabine (GEM) as first line treatment for metastatic pancreatic adenocarcinoma (PDAC).
Authors: Corrie Philippa , Qian Wendi , Basu Bristi , Jodrell Duncan Ian , Falk Stephen , Iwuji Chinenyu , Wasan Harpreet , Palmer Daniel H. , Scott-Brown Martin , Wadsley Jonathan , Arif Seema Safia , Babaoglan A. Burcu , Dalchau Katy Marie , Gopinathan Aarthi , Chhabra Anita , Machin Andrea , Neesse Albrecht , Tuveson David A. , Valle Juan W. ,   SIEGE Trial Investigators
Published: March 2017

342

Background: NabP+GEM chemotherapy improves survival compared with standard GEM monotherapy as treatment for advanced PDAC. A PDAC mouse model showed that delivery of nabP prior to GEM generated a higher intratumoural dFdC:dFdU ratio, which correlated with improved outcome. Therefore, scheduling may be critical to optimise clinical benefit. Methods: Patients were randomised to receive nabP+GEM, either concomitantly (CON) or sequentially (SEQ), 24 hours apart. After 6 cycles, patients benefiting from treatment could continue the same regimen until disease progression. The primary endpoint was progression-free survival (PFS) assessed by 8-weekly CT scanning; secondary endpoints included safety, response rate, overall survival (OS) and quality of life (QoL). Results: Between March 2014 and 2016, 146 patients (71 SEQ, 75 CON) from 19 UK sites were randomly assigned. Median age (range) was 66 (45-82) years; Karnofsky performance status was 70 (in 12% of patients), 80 (27%), 90 (38%) or 100 (24%); 47% of primary tumours were situated in the pancreatic head; 84% had liver metastases. Median number of cycles was 4 SEQ, 3 CON; 50 patients (34%) received ≥ 6 cycles of treatment (41% SEQ, 28% CON). A 24+2hr interval was achieved in over 90% SEQ administrations. Most patients stopped treatment prior to 6 cycles due to disease progression/death (42%) or toxicity (41%). Grade ≥ 3 adverse events experienced by ≥ 10% patients (SEQ, CON) were neutropaenia (54%, 30%), febrile neutropaenia (12%, 12%), fatigue (22%, 16%), vomiting (7%, 11%) and anaemia (10%, 5%). G-CSF was administered to 35 patients (23 SEQ, 12 CON). To date, 109 patients have died. 6-month PFS by SEQ and CON arms was 46.7% and 33.8%; median PFS was 5.8 and 4.3 months. 12-month OS by SEQ and CON arms was 29.1% and 20.1%; median OS was 10.1 and 7.9 months. The objective response rate was 44% SEQ and 30% CON. Mean baseline QoL Global health status was 60.6 SEQ and 63.4 CON. The change from baseline (mean) at 24 weeks was -2.1 SEQ and -12.1 CON. Conclusions: Sequential delivery of nabP and GEM improves progression-free and overall survival. Although more myelosuppressive, QoL was maintained. Clinical trial information: ISRCTN71070888.
Outcomes with sorafenib (SOR) followed by regorafenib (REG) or placebo (PBO) for hepatocellular carcinoma (HCC): Results of the international, randomized phase 3 RESORCE trial.
Authors: Finn Richard S. , Merle Philippe , Granito Alessandro , Huang Yi-Hsiang , Bodoky Gyorgy , Pracht Marc , Yokosuka Osamu , Rosmorduc Olivier , Gerolami René , Caparello Chiara , Cabrera Roniel , Chang Charissa , Sun Weijing , Han Guohong , Le Berre Marie-Aude , Baumhauer Annette , Meinhardt Gerold , Bruix Jordi ,   On Behalf of the RESORCE Investigators
Published: March 2017

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Background: SOR is standard first-line systemic treatment for HCC unsuitable for locoregional therapy. RESORCE showed that REG improves overall survival (OS) in patients who progressed during SOR treatment (HR 0.63, 95% CI 0.50, 0.79; P < 0.001). This exploratory analysis describes outcomes for the sequence of SOR followed by REG. Methods: 573 patients were randomized 2:1 to receive REG 160 mg/day (d), 3 wks on/1 wk off or PBO. Data on prior SOR treatment and radiologic progression were prospectively collected. Efficacy and safety were evaluated by the last SOR dose. Time from the start of SOR to death was assessed. Results: Baseline characteristics were balanced. Times from the start of SOR to progression on SOR and times from progression on SOR to start of study drug were similar (Table). When analyzed based on last SOR dose 800 mg/d vs < 800 mg/d, rates of all grade treatment-emergent adverse events (TEAEs) on study were similar (REG: 100% vs 100%; PBO: 92% vs 93%). TEAE grades 3/4/5 by last SOR dose 800 mg/d vs < 800 mg/d were 52/11/15% vs 61/10/12%, respectively, with REG and 30/8/24% vs 32/7/14% with PBO. HRs (95% CI) REG/PBO for OS by last SOR dose were similar: 0.67 (0.51, 0.87) for 800 mg/d and 0.68 (0.48, 0.97) for < 800 mg/d. Median OS (95% CI) from the start of SOR was 26.0 months (22.6, 28.1) for REG and 19.2 months (16.3, 22.8) for PBO. Clinical trial information: NCT01774344. Conclusions: This exploratory subgroup analysis by prior SOR dose demonstrates a consistent survival benefit for REG. In addition, the safety profile of REG was not remarkably different when analyzed by the last SOR dose.[Table: see text]
Histologic classification and grading enhances gallbladder cancer staging: A population-based prognostic score validated by the U.S. Extrahepatic Biliary Malignancy Consortium.
Authors: Tran Thuy , Ethun Cecilia Grace , Pawlik Timothy M. , Buettner Stefan , Idrees Kamran , Isom Chelsea A , Fields Ryan C. , Krasnick Bradley , Weber Sharon M. , Salem Ahmed , Martin Robert C. G. , Scoggins Charles Raben , Shen Perry , Mogal Harveshp , Schmidt Carl Richard , Beal Eliza W , Hatzaras Ioannis , Shenoy Rivfka , Maithel Shishir Kumar , Poultsides George A.
Published: March 2017

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Background: Beyond the most common adenocarcinoma type, several gallbladder cancer (GBC) histologies have been described as being associated with more favorable (papillary) or less favorable outcome (adenosquamous, mucinous, signet ring). We sought to examine the added value of histologic type and grade on the existing AJCC staging system for resected GBC. Methods: Patients who underwent resection of GBC from 1988-2013 were identified using the Surveillance Epidemiology End Results (SEER) registry. A prognostic score was created by assigning points for T stage, N stage, grade and histology based on the regression coefficient in multivariate analysis. The score was externally validated using the US Extrahepatic Biliary Malignancy Consortium (USEBMC) database (2000-2015) and compared with the AJCC staging system. Results: Of 7,915 patients identified in SEER, 83% had adenocarcinoma, 7% papillary, 4% adenosquamous, 4% mucinous, and 2% signet ring. In the USEBMC database, the frequencies of the respective histologies were 86, 9, 2, 1 and 2%. Median survival per histologic type, for SEER and USEBMC respectively, were 45 and 110 mos for papillary, 16 and 24 mos for adenocarcinoma, 14 and 12mos for mucinous, 8 and 4mos for adenosquamous, and 9 and 15mos for signet ring (P between histologies < 0.001 for both cohorts). On multivariate analysis, T stage, N stage, grade and histology were independent predictors of survival. The developed prognostic score, based on points for each of these 4 variables, showed excellent discriminatory ability both in the SEER and USEBMC cohorts. The AUC for the prognostic score was significantly improved compared with the AJCC system (0.69 vs. 0.64,both P < 0.001 using SEER, and 0.76 vs. 0.66,both P < 0.001 using USEBMC). Conclusions: The incorporation of histology and grade into the TNM system allows for a simple and accurate tool to determine prognosis following resection of GBC. [Table: see text]
A phase 1b/2 study of INCB039110 + nab-paclitaxel (N) and gemcitabine (G) in patients (pts) with advanced solid tumors and pancreatic cancer (PC).
Authors: Beatty Gregory Lawrence , Shahda Safi , Beck J. Thaddeus , Uppal Nikhil Premparkash , Cohen Steven J. , Donehower Ross C. , Gabayan A. Eli , Assad Albert , Switzky Julie C. , Zhen Huiling , Von Hoff Daniel D.
Published: March 2017

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Background: JAK-STAT activity has been associated with malignant cell proliferation and production of proinflammatory cytokines involved in cancer progression. INCB039110 is a potent and selective inhibitor of JAK1. Methods: This was a 2-part phase 1b/2 open-label study evaluating INCB039110 (300 or 400 mg QD) in combination with N and G in pts with advanced or metastatic solid tumors (Part 1 [P1], dose optimization phase) and pts with advanced or metastatic PC who had not received prior chemotherapy (Part 2 [P2] and 2A [P2A]). Pts in P2 received the MTD established in P1: INCB039110 (300 mg QD) + N (125 mg/m2 day [d] 1, 8, 15) + G (1000 mg/m2 d 1, 8, 15), 28-d cycle. For exploratory purposes, pts in P2A underwent a 7-d induction phase with INCB039110 (200 mg QD) before receiving INCB039110 (200 mg QD) + N (125 mg/m2 d 1, 8, 15) + G (1000 mg/m2d 1, 8, 15). The primary objective was to evaluate safety/tolerability. Results: 55 pts were enrolled (27 P1, 20 P2, and 8 P2A). Most patients had advanced PC (n = 46). Median age was 65 (P1), 67 (P2), and 66 years (P2A). Prior therapy: 67% in P1, 30% in P2, and 0% in P2A. The most common reasons for treatment discontinuation were adverse events (AEs; 41% P1, 20% P2, 38% P2A), disease progression (37% P1, 45% P2, 0% P2A), and study termination by the sponsor (0% P1, 0% P2, 38% P2A). Median treatment durations were 84 d (P1), 121 d (P2), and 47 d (P2A). The most common non-hematologic AEs (all grades) were fatigue (59% P1, 75% P2, 88% P2A), nausea (41% P1, 50% P2, 38% P2A), pyrexia (37% P1, 40% P2, 13% P2A), and peripheral edema (30% P1, 50% P2, 25% P2A), with few grade 3 or 4 non-hematologic AEs. The most common grade 3 or 4 hematologic AEs (laboratory values) were neutropenia (33% P1, 60% P2, 13% P2A), lymphopenia (30% P1, 30% P2, 13% P2A), and leukopenia (30% P1, 45% P2, 0% P2A). The most common serious AEs occurring in ≥ 3 pts were pneumonia (n = 4 P1, n = 2 P2, n = 0 P2A) and anemia (n = 3 P1, n = 2 P2, n = 2 P2A). Among evaluable patients, ORR (all PRs) and DCR were 27% (13/48) and 75% (36/48), respectively. Responses were seen across INCB039110 doses. Conclusions: INCB039110 + N/G showed an acceptable safety profile in pts with advanced PC, with the combination demonstrating clinical activity. Clinical trial information: NCT01858883.
Clinical implication of inflammation-based prognostic score and perioperative nutrition control in pancreatic cancer.
Authors: Takano Nao , Yamada Suguru , Fujii Tsutomu , Tashiro Mitsuru , Tanaka Nobutake , Morimoto Daishi , Ninomiya Go , Niwa Yukiko , Takami Hideki , Iwata Naoki , Hayashi Masamichi , Kanda Mitsuro , Tanaka Chie , Kobayashi Daisuke , Nakayama Goro , Sugimoto Hiroyuki , Koike Masahiko , Fujiwara Michitaka , Kodera Yasuhiro
Published: March 2017

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Background: Systemic inflammation and nutrition status are considered to influence survival in cancer patients. A variety of systemic inflammation-based prognostic scores have been explored; however, there has been no study to clarify which score could best reflect survival in resected pancreatic cancer patients. Methods: Between 2002 and 2016, 422 consecutive patients who underwent curative resection of pancreatic cancer were enrolled. The Glasgow Prognostic Score (GPS), modified GPS (mGPS), neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), prognostic index (PI), and prognostic nutritional index (PNI) scores for each patients were calculated. Survival of each score was evaluated, and correlations between the score selected on the basis of the prognostic significance and various clinicopathological factors were analyzed. On the other hand, the nutrition markers (pre-albumin, transferrin, and retinol-binding protein) of 30 patients who received the enteral nutrition during the perioperative period were also evaluated. Results: In the analysis of the GPS, the median survival time (MST) was 29.4 months for score 0, 25.5 for score 1, and 17.7 for score 2 ( p< 0.001), and mGPS was also found to be significant ( p= 0.003). On the contrary, there were no significance in MST between other scores (NLR, PLR, PI, or PNI). Multivariate analysis revealed that lymph node metastasis, positive peritoneal washing cytology, and a GPS score of 2 were significant prognostic factors. There was also statistically significant correlation between the GPS score and tumor location (head), tumor size ( > 2.0cm), bile duct invasion, and duodenal invasion. In terms of nutrition status, the postoperative nutrition markers of 30 patients managed by enteral nutrition tended to recover earlier than 79 patients managed by intravenous nutrition. Conclusions: Our results demonstrated that the GPS could be an independent predictive marker and was superior to other inflammation-based prognostic scores in patients with resected pancreatic cancer. The results also suggested that perioperative nutrition support and infection control would improve survival of pancreatic cancer patients.
Interim analysis of perioperative modified FOLFIRINOX (mFOLFIRINOX) in resectable pancreatic cancer (PC).
Authors: Cecchini Michael , Salem Ronald R , Zaheer Kidwai Wajih , Kortmansky Jeremy S. , Fischbach Neal A. , Patel Abhijit , Hochster Howard S. , Lacy Jill
Published: March 2017

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Background: The mortality of patients (pts) with resectable PC is > 70% with surgery and adjuvant therapy. Based on the favorable results of our prospective phase II study of mFOLFIRINOX in locally advanced PC (Stein SM et al. Br J Cancer. 2016), we are conducting a single arm open-label phase II trial to evaluate the efficacy of peri-operative mFOLFIRINOX in resectable PC. Here we report our interim results. Methods: Pts with untreated resectable PC were treated with 6 cycles of mFOLFIRINOX every 2 weeks before and after surgical resection. Pre-op FDG-PET and CT scans were obtained at baseline and after 3 and 6 cycles, respectively. After study treatment pts were followed with serial CT scans and CA 19-9 levels. We performed our validated test for circulating tumor DNA (ctDNA) at baseline and multiple time points thereafter. Results: At our interim analysis, 19 pts are enrolled; 1 pt withdrew consent after 1 cycle and is not included. Baseline characteristics: median age 64; male 12; median CA-19 94 (range 0.8-1926); head of pancreas tumor 14; biliary stent 9; ECOG 0 17. Two pts received < 6 cycles pre-op for reasons other than progression or treatment-related adverse events (AEs). Response by RECIST for the 17 pts who received ≥ 3 pre-op cycles was: CR/PR 1 (6%), SD 15 (88%) (8 with minor response defined as 10-30% decrease in target lesion), and PD 1 (6%). Six of 14 pts (43%) who received FDG-PET scans had > 50% decrease in SUV. At present, 2 pts have yet to complete 6 pre-op cycles. Fifteen pts have undergone surgical exploration, and 2 were not deemed resectable during exploration due to peritoneal implants and adhesions from chronic pancreatitis. Thirteen of 16 (82%) underwent resection; 12 (92%) were R0; 2 (15%), 5 (39%), and 6 (46%) pts had pathologic stage I, IIA, and IIB disease, respectively. 4 pts developed disease recurrence and died. AEs were not different than we previously reported and were manageable with protocol-mandated dose adjustments. Conclusions: Our interim analysis suggests that perioperative mFOLFIRINOX for resectable PC is feasible and associated with a 92% rate of R0 resection. Accrual will continue to 46 pts, and analysis of efficacy endpoints and correlative studies including ctDNA are ongoing. Clinical trial information: NCT02047474.