bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase II trial of oral S-1 plus bevacizumab for patients with metastatic colorectal cancer refractory to standard chemotherapies (CCOG-1105 study).
Authors: Ezaka Kazuhiro , Nakayama Goro , Yokoyama Hiroyuki , Matsui Takanori , Umeda Shinichi , Sunagawa Yuki , Murotani Kenta , Ando Yuichi , Kodera Yasuhiro
Published: January 2019

841

Background: The aim of this multicenter, single-arm phase II trial was to investigate the efficacy and safety of S-1 plus bevacizumab (BEV) as a salvage treatment for patients with metastatic colorectal cancer (mCRC) refractory to standard chemotherapies. Methods: Patients who had unresectable mCRC with mutant-type KRAS; were refractory to fluoropyrimidine, irinotecan, oxaliplatin; and had previous treatment with BEV were enrolled and received S-1 plus BEV therapy (bevacizumab 7.5 mg/kg on day 1 and S-1 40-60 mg bid on day 1-14, every 3 weeks). The primary endpoint was progression-free survival (PFS), and secondary end points included overall survival (OS), tumor response, and safety. Results: A total of 27 patients were enrolled. After a median follow-up period of 12.3 months, the events of disease progression and death occurred in 26 patients (96%) and 20patients (74%), respectively. The median number of treatment cycles was 3 (range, 1-17 cycles). Median PFS was 2.3 months (95% confidence interval [CI], 2.2-2.4 months), and the median OS was 7.7 months (95% CI, 4.3-10.1 months). The overall response and disease control rates were 0% and 33%, respectively. The median tumor shrinkage rate (DpR) was -15% (range, -59 to 15%). The frequencies of hematological and non-hematological adverse events above grade three were 25% and 8%, respectively. Conclusions: S-1 plus BEV therapy could be feasible salvage line treatment for Japanese patients with mCRC refractory to standard chemotherapies. Clinical trial information: UMIN000006476.
A new look at the IDEA classification: Defining novel predictive and prognostic markers in stage III colon cancer.
Authors: Margalit Ofer , Mamtani Ronac , Yang Yu-Xiao , Reiss Kim Anna , Golan Talia , Halpern Naama , Aderka Dan , Giantonio Bruce J. , Shacham-Shmueli Einat , Boursi Shimon Ben
Published: January 2019

845

Background: The IDEA pooled analysis compared 3 to 6 months of adjuvant chemotherapy for newly defined low- and high-risk stage III colon cancer patients, suggesting low-risk patients may be offered only 3 months of treatment. We aimed to evaluate the benefit of monotherapy vs doublet chemotherapy in low and high IDEA risk groups. Methods: Using the NCDB (2004-2014) we identified 56,728 and 47,557 individuals as low and high IDEA risk groups, respectively. We used multivariate COX regression to evaluate the magnitude of survival differences between IDEA risk groups, according to treatment intensity (doublet vs monotherapy). In a secondary analysis, we examined the predictive value of subgroups of age. Results: Low and high IDEA risk groups derived similar benefit from doublet chemotherapy compared to monotherapy, with hazard ratios of 0.83 (95%CI 0.79-0.86) and 0.80 (95%CI 0.78-0.83), respectively. The only subpopulations that did not benefit from doublet chemotherapy were low-risk patients above the age of 72 (HR = 0.95, 95%CI 0.90-1.01) and high-risk patients above the age of 85 (HR = 0.90, 95%CI 0.77-1.05). Conclusions: IDEA risk classification does not predict benefit from doublet chemotherapy in stage III colon cancer. However, omission of oxaliplatin can be considered in IDEA low-risk patients above the age of 72.
Adenocarcinoma Ex goblet cell: A retrospective experience.
Authors: Das Satya , Berlin Jordan , Du Liping , Shi Chanjuan
Published: January 2019

847

Background: Adenocarcinoma ex goblet cell tumors (AGCC) represent rare appendiceal neoplasms with neuroendocrine and adenocarcinoma features. They represent the most aggressive subset of goblet cell carcinoids (Group B and C) and are often categorized as chemotherapy unresponsive [Am J SurgPathol.2008;32(10):1429-43]. Despite this, most patients with AGCC are treated with colon cancer chemotherapy regimens. We explored outcomes in patients treated at our institution with these regimens. Methods: We performed a single center retrospective analysis of 22 biopsy-proven AGCC patients (13 men, 9 women, median age at diagnosis 54.5) at Vanderbilt who had undergone treatment for local or metastatic disease. PFS and OS were determined for each patient and stratified by features listed on Table 1. Patients who were lost to follow up were censored based on their last recorded clinic date. Results: 16 patients received chemotherapy in the metastatic setting and all 16 had peritoneal involvement; of these patients 4 underwent HIPEC. Median PFS and OS in HIPEC treated patients was 17 months and 33 months respectively. 8 patients received adjuvant chemotherapy with FOLFOX; 6 in the local setting and 2 in the metastatic setting. Patients with metastatic AGCC had a median PFS of 21.5 months and a median OS of 32.9 months. Patients with local disease had a median PFS of 32.8 months and an OS that was not reached (median duration of follow up 12.4 months). Conclusions: AGCC have a predilection for peritoneal spread. Patients who received either adjuvant FOLFOX post definitive surgery or FOLFOX/FOLFIRI in the metastatic setting post optimal cytoreduction had prolonged periods of PFS and OS. [Table: see text]
Relation between irinotecan-induced cholinergic syndrome and prognosis of colorectal cancer patients.
Authors: Fujii Hiroyuki , Hirata Taizo , Mura Takuya , Okada Yuko , Tashiro Hirotaka
Published: January 2019

859

Background: It is well known that a cetuximab induced rash is strongly associated with improved survival of colorectal cancer patients. Irinotecan Induced Cholinergic Syndrome (IICS), manifesting in such events as early diarrhea and diaphoresis, is a notorious adverse effect of irinotecan. In this study, we reveal the relation between IICS and prognosis of colorectal cancer patients and examine the validity of IICS as a surrogate marker for the efficacy of irinotecan. Methods: We retrospectively reviewed data from 52 colorectal cancer patients who were treated with a chemotherapeutic regimen that included irinotecan at Kure Medical Center between 2012 and 2017. First, to assess the relation between adverse events and efficacy of irinotecan, patients who experienced IICS (n = 11) and did not experience IICS (n = 41) were analyzed from the aspect of overall survival (OS), progression-free survival (PFS), sex, age, dose, performance status (PS) and previous chemotherapy (PC). Kaplan-Meier survival curves were drawn for OS and PFS, and compared by means of a log-rank test. Secondly, to determine the response rate of butylscopolamine for IICS, we injected butylscopolamine 20mg into the irinotecan infusion bag and administered both agents through the intravenous line together to 11 patients who experienced IICS. Results: The presence of IICS was associated with a prolonged median OS (589 vs. 280 days, log-rank p = 0.0282; adjusted hazard ratio (HR) 0.27, 95% confidence interval [CI] 0.06-0.79, p = 0.0140), and prolonged median PFS (317 vs. 154 days, log-rank p = 0.1474; adjusted HR 0.56, 95% CI 0.22-1.25, p = 0.1635). There was no statistically significant difference between the two groups in terms of sex, age, dose, PS and PC. Ten patients of 11 patients who were administered butylscopolamine, experienced complete or partial improvement of IICS. The response rate was nearly 90%. Conclusions: The presence of IICS is associated with an improved OS for colorectal cancer patients and tends to have a positive correlation with PFS. IICS is a viable surrogate biomarker of the antitumor efficacy of irinotecan. As a prophylaxis of IICS, mixing butylscopolamine into the irinotecan infusion bag was remarkably effective.
Baseline factors associated with acute progression of metastatic lesions after primary tumor resection in patients with unresectable colorectal cancer.
Authors: Akashi Momoko , Ando Takayuki , Hosokawa Ayumu , Yoshita Hiroki , Nanjyo Sohachi , Ueda Akira , Mihara Hiroshi , Fujinami Haruka , Kajiura Shinya , Ogawa Kohei , Sugiyama Toshiro
Published: January 2019

860

Background: In patients with unresectable colorectal cancer, primary tumor resection is expected not only local control but also prolongation of survival time. However, in some cases, metastatic tumors have been known to rapidly progress after primary tumor resection. We examined clinical factors associated with acute metastatic progress after primary tumor resection, and it might lead to worse survival. Methods: We retrospectively analyzed 183 patients who were newly diagnosed with unresectable colorectal cancer in our institution between April 2007 and April 2016. Among all patients, 83 patients received resection of primary tumor without the presence of symptoms. They were divided into progression and non-progression group according to metastatic progression that evaluated CT scan from four to six weeks after surgery. We analyzed clinicopathological factors related to acute progression after primary tumor resection using Cox proportional hazards. Results: After resection of the primary tumor, 25 patients were classified into progression group and 58 patients were classified into non-progression group. In progression group, the median percent change in the sum of the longest diameters of target lesions was 29.6% (10.0-191.7%), and 22 (88.0%) patients showed to have new lesions after resection of the primary tumor. Multivariate analysis revealed LDH (HR 4.44, 95%CI 1.15-18.5, p = 0.02), number of liver metastasis (HR 3.28, 95% CI 1.09-10.0, p = 0.03) and RAS status (HR 3.08, 95% CI 1.05-9.46, p = 0.03) were independent baseline factors associated with acute progression after resection of the primary tumor. The median overall survival (OS) was 12.3 and 27.8 months in progression and non-progression group, respectively. Conclusions: Serum LDH, number of liver metastasis, and RAS mutation were baseline factors associated with acute progression of metastatic tumors after resection of primary tumor in patients with unresectable colorectal cancer. These results indicated that the resection of the primary tumor in patients with these factors might be avoided when they have no clinical symptoms.
Three-year outcomes of two phase II studies of adjuvant chemotherapy with S-1 plus oxaliplatin or capecitabine plus oxaliplatin in patients with stage III gastric cancer after D2 gastrectomy.
Authors: Nakamura Yoshiaki , Yamanaka Takeharu , Chin Keisho , Cho Haruhiko , Katai Hitoshi , Terashima Masanori , Ito Seiji , Hirao Motohiro , Yoshida Kazuhiro , Oki Eiji , Sasako Mitsuru , Emi Yasunori , Bando Hideaki , Kawashima Yoshiyuki , Fukunaga Tetsu , Gotoh Masahiro , Ishibashi Takako , Shitara Kohei
Published: January 2019

94

Background: Two phase II trials of oxaliplatin-based adjuvant chemotherapy for patients (pts) with gastric cancer (GC) after D2 gastrectomy have been conducted in Japan; the J-CLASSIC study of capecitabine plus oxaliplatin (CAPOX) and the SOXaGC study of S-1 plus oxaliplatin (SOX). In the current study, we evaluated survival outcomes of the two trials. Methods: The J-CLASSIC, enrolling stage II and III pts from 12 centers between July 2012 and July 2013, evaluated eight cycles of CAPOX. The SOXaGC, enrolling stage III pts from 11 centers between July 2013 and February 2014, evaluated seven cycles of SOX after one cycle of S-1 monotherapy. The two studies were conducted sequentially and most centers (9 centers) participated in both trials. In this pooled analysis, we updated relapse-free survival (RFS) and overall survival (OS) information. The median follow-up time was 49 months in the J-CLASSIC and 39 months in the SOXaGC. Results: Fifty-nine stage III pts treated with CAPOX and 62 stage III pts treated with SOX were analyzed. The 3-year RFS and OS rates of SOX were 70.9% (57.8-80.5%) and 75.7% (63.0-84.6%), respectively, whereas the 3-year RFS and OS rates of CAPOX were 67.8% (54.3-78.1%) and 79.3% (66.5-87.7%), respectively. The hazard ratio (HR) of SOX in comparison to CAPOX was 0.925 (0.498-1.720) for RFS, suggesting the efficacy of the two treatments was similar. Trend of a different efficacy was observed in some particular subgroups; the HR for RFS was 1.732 (0.506-5.927) in the intestinal type and 0.735 (0.353-1.528) in the diffuse type, while that was 2.008 (0.447-9.016) in stage IIIA, 0.872 (0.266-2.857) in stage IIIB, and 0.597 (0.258-1.383) in stage IIIC. Conclusions: This is the first report of survival follow-up in Japanese GC pts with oxaliplatin-based adjuvant chemotherapy, which suggests comparable outcomes in both treatments for stage III GC. Different trend in the treatment effect by histologic type or stage warrants further evaluation in a larger cohort. Clinical trial information: UMIN000026883.
Morbidity and mortality of laparoscopic D2 gastrectomy with complete mesogastrium excision (D2+CME) versus conventional D2 gastrectomy for advanced gastric cancer: An interim report of a single-center, prospective, randomized trial (NCT01978444).
Authors: Xie Daxing
Published: January 2019

TPS190

Background: In our previous research, laparoscopic D2 lymphadenectomy plus Complete Mesogastrium Excision (D2+CME) has been proven to be an optimal surgical approach for advanced gastric cancer (AGC). However, there is a lack of evidence regarding its oncologic safety. Here, we conducted a single-centre, prospective, randomized controlled trial comparing the morbidity and mortality of laparoscopic D2+CME with conventional D2 gastrectomy in AGC. Methods: Patients eligibly criteria were pathologically-proven adenocarcinoma, 18 to 75 years old, cT2-4N0-3M0 at preoperative evaluation, expected curative resection via laparoscopic distal gastrectomy, no history of other cancers, chemotherapy or radiotherapy, no history of upper abdominal operation and perioperative ASA class I, II or III. The primary end-point was 3-year disease-free survival. The morbidity and mortality were compared to evaluate the safety of this trial. We hypothesized that the morbidity of this study was not significantly different from that of previous reports on laparoscopic distal gastrectomy (5.7%-15.5%). This study is registered at ClinicalTrials.gov, ID number is NCT01978444. Clinical trial information: NCT01978444.
A phase II study of durvalumab following multimodality therapy for locally advanced esophageal adenocarcinoma: Big Ten Cancer Research Consortium BTCRC-ESO14-012 study.
Authors: Mamdani Hirva Mansurali , Abushahin Laith I. , Schneider Bryan J. , Chowdhery Rozina A. , Hrinczenko Borys , Lee Ahran , Perkins Susan M. , Kesler Kenneth , Jalal Shadia Ibrahim
Published: January 2019

TPS194

Background: The standard of care for locally advanced esophageal adenocarcinoma is concurrent chemoradiation (CRT) followed by esophagectomy with lymphadenectomy. Approximately 30% of patients achieve a complete pathologic response (pCR) with this multimodality approach, which has been correlated with improved disease-free survival. The risk of relapse in the remaining 70% of patients who have pathologic evidence of persistent disease in the surgical specimen is extremely high and estimated at 60-70%. Preclinical studies have demonstrated that radiation with or without concurrent chemotherapy upregulates the programmed cell death receptor- 1 (PD-1) pathway by inducing a local inflammatory response, an effect that persists for a number of months after cessation of therapy. Durvalumab is a selective, high affinity, engineered human IgG1 monoclonal antibody that blocks PD-L1 binding to PD-1 and CD80, and has shown activity in metastatic esophageal cancer. The aim of this study is to evaluate efficacy of post-operative durvalumab with respect to decreasing the relapse rate in patients who do not achieve pCR following CRT. Methods: Patients with esophageal adenocarcinoma who have pathologic evidence of persistent disease in the surgical specimen following neoadjuvant concurrent CRT (carboplatin plus paclitaxel or cisplatin plus 5-FU) and R0 resection are eligible for enrollment on this single arm phase II study. Durvalumab 1500mg IV every 4 weeks is started within 1-3 months of surgery and continued for up to 1 year. The primary endpoint is 1-year relapse free survival (RFS). Secondary endpoint is to assess the incidence and severity of overall and treatment related adverse events. Exploratory endpoints include PDL1 expression in tumor and tumor infiltrating lymphocytes, assessment of Immunoscore within the center and invasive margin of the tumor, and the correlation between changes in circulating tumor cell numbers in response to PD-L1 inhibition. The study is currently open to accrual at 5 sites in the Big Ten Cancer Research Consortium and 17 of the planned 23 patients have been enrolled within the past 14 months. Clinical trial information: NCT02639065.
Personalized antibodies for gastroesophageal adenocarcinoma (PANGEA): A phase II precision medicine trial (NCT02213289).
Authors: Joshi Smita Suhas , Maron Steven Brad , Lomnicki S , Polite Blase N. , Sharma Manish , Ibe Jennifer , Allen Kenisha , Racette Christine , Rampurwala Murtuza M. , Amico Andrea Louise , Shergill Ardaman , Kozloff Mark , Phillips Brooke Elizabeth , Suh Grace K. , Narula Sunil , Rayani Shayan , Kipping-Johnson Kristen , Wojak Erin , Kindler Hedy L. , Catenacci Daniel V.T.
Published: January 2019

TPS198

Background: Targeted therapies (tx) in GEA have had limited efficacy despite recognition of numerous ‘targetable’ molecular events. This may be due to the molecular heterogeneity (MH) that exists between patients (pts), within the primary tumor (PT), between PT and synchronous metastatic lesions (MLs), and in lesions over time. Current biomarker profiling (BP) is performed on one site, usually the PT, yet this fails to capture the MH of GEA, with likely major clinical implications. Classic trial designs are challenged by MH, low frequency oncogenic drivers, and scarcity of tissue. There is need for novel trial designs and BP technologies that address these concerns, provide tx algorithms for pts with multiple aberrations, and have access to several txs. Methods: This phase IIa, open-label, non-randomized ‘platform trial’ enrolls pts with newly diagnosed metastatic GEA or recurrent disease after curative-intent surgery. Baseline tumor BP is performed on PT/ML along with circulating free (cf)DNA. Pts receive first line (1L) mFOLFOX6 + biologic tx based on BP of the ML using a prioritized tx algorithm (HER2+: trastuzumab; MET+: none; FGFR2+: none; EGFR+: ABT806; MSI-H: nivolumab; ‘RAS-like’: ramucirumab). MET/FGFR2 arms (~10% of all pts) are tx’d with cytotoxics only and followed for natural outcome until/if tx becomes available on study. At first progression (PD1), pts undergo biopsy of growing ML and change to 2L FOLFIRI + biologic agent as assigned in 1L tx. Upon results of PD1 biopsy, pts change to a new biologic tx if the molecular category evolves. At PD2, pts change to 3L FOLTAX + biologic as determined after PD1, and switch biologic tx from PD2 biopsy result. All PD1/PD2 tumor/cfDNA samples undergo BP to assess evolution and resistance mechanisms. Co-primary endpoints: safety, feasibility, and overall survival (OS) of this personalized treatment strategy (excluding MET/FGFR2) compared to historical controls (HR 0.66). Secondary endpoints include rate of baseline MH between PT and ML leading to new treatment assignment; utility of cfDNA; overall progression-free survival (PFS)/response rate (RR); OS/PFS/RR in each targetable group. Since 8/2015, 38 of 68 planned pts have been accrued. Clinical trial information: NCT02213289.
Personalized vaccine for advanced HCC.
Authors: Lausoontornsiri Wirote , Har-Noy Michael , Wongwiwatcha Jitraporn , Bloch Miriam , Suparak Supaporn , Ahooja Anucha , Bishop Michael , Sukeepaisarnjaroen Wattana
Published: January 2019

TPS527

Background: The chronic inflammation and viral infection associated with HCC combined with liver tolerogenic mechanisms creates a profoundly immunosuppressive microenvironment. Modulating the microenvironment with checkpoint blockade benefits ~20% of patients. The non-responders and those with poor liver function are an unmet need. Checkpoint blockade requires effector cells to be resident within tumors. However, the majority of HCC lesions lack effector cells. Therefore, a strategy for amplifying the tumor-specific immune response, while counteracting the immunosuppressive mechanisms may provide an improved immunotherapy. Endogenous heat shock proteins (HSP) chaperone tumor neoantigens. A concentrated composition of calreticulin, hsp70, hsp90 and gr94/gp96 (CRCL) is purified from biopsy samples. In addition, a bioengineered allograft (BAG) derived from healthy blood donors with a Th1 memory phenotype, CD3/CD28-coated microbeads and high expression of CD40L has potent immunomodulatory and counter-regulatory properties. The combination of CRCL with BAG is being evaluated as a strategy to amplify tumor-specific immunity and counter-regulate the immunosuppressive microenvironment. Methods: An open-label Phase II clinical trial evaluating the safety and efficacy of CRCL+BAG vaccine in Child-Pugh A/B advanced/metastatic HCC w/o Sorafenib. Approximately 6-10 cores of tumor are collected at baseline. The tumor is lysed and CRCL purified using an isoelectric focusing technique. Subjects are primed with multiple intradermal injections of BAG cells alone to increase the titer of allo-specific Th1/Tc1 cells. Next, multiple intradermal injections of BAG+CRCL are administered to elicit increased titers of tumor-specific Th1/Tc1 cells. Subsequent intravenous infusions of BAG cells activate allo- and tumor-specific memory cells, enabling their infiltration into tumor lesions. The BAG allo-rejection response creates a type I cytokine storm which serves to down-regulate suppressor circuits. Response is evaluated by mRECIST and experimental biomarkers. Longitudinal CT scans with concurrent biopsies as well as multiple collections of PBMC and plasma permits immunomonitoring of these immune mechanisms. Clinical trial information: NCT02409524.
A multicenter randomized phase II study of nivolumab in combination with gemcitabine/cisplatin or ipilimumab as first-line therapy for patients with advanced unresectable biliary tract cancer.
Authors: Sahai Vaibhav , Griffith Kent A. , Zalupski Mark
Published: January 2019

TPS541

Background: Patients (pts) with advanced biliary tract cancers (BTC) have poor prognosis with a median overall survival (OS) less than 12 months. This randomized, multi-institutional, phase 2, two-arm study is designed to investigate the role of combinational immunotherapy, using nivolumab with chemotherapy (gemcitabine/cisplatin) or as dual immunotherapy (nivolumab and ipilimumab) in pts with advanced BTC. Methods: Key eligibility criteria include histologically confirmed advanced, unresectable biliary adenocarcinoma (intrahepatic or extrahepatic and gallbladder) without prior systemic treatment, measurable disease per RECISTv1.1, ECOG PS 0-1, and absence of autoimmune disease and/or chronic steroid use. Primary objective is to evaluate the progression-free survival (PFS) rate at 6 months. Secondary objectives include evaluation of overall response rate (ORR), median PFS and OS and safety in this patient population. Exploratory objectives include identification of biomarker predictors of response and mechanisms of resistance through serial (before, on and post therapy) biopsies and blood collection, including sequential whole exome/transcriptomic analysis and immune cell subset analysis (tissue and blood). Arm A therapy provides gemcitabine 1000 mg/m2, cisplatin 25 mg/m2 on days 1, 8 with nivolumab 360 mg on day 1 every 3 weeks for 6 months. In the absence of disease progression, pts may continue single agent nivolumab for up to 2 years. Arm B therapy includes nivolumab 240 mg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks for up to 2 years in absence of disease progression. Accrual goal is 32 evaluable pts per arm. Using a null hypothesis value of 59% median PFS at 6 months, and an 80% alternative hypothesis, this ongoing study has > 80% power, with a one-sided alpha of 0.05 to identify treatment efficacy in one or both study arms. Clinical trial information: NCT03101566.
PI3Kβ—A Versatile Transducer for GPCR, RTK, and Small GTPase Signaling
Authors: Bresnick Anne R , Backer Jonathan M
Published: January 2019

The phosphoinositide 3-kinase (PI3K) family includes eight distinct catalytic subunits and seven regulatory subunits. Only two PI3Ks are directly regulated downstream from G protein–coupled receptors (GPCRs): the class I enzymes PI3Kβ and PI3Kγ. Both enzymes produce phosphatidylinositol 3,4,5-trisposphate in vivo and are regulated by both heterotrimeric G proteins and small GTPases from the Ras or Rho families. However, PI3Kβ is also regulated by direct interactions with receptor tyrosine kinases (RTKs) and their tyrosine phosphorylated substrates, and similar to the class II and III PI3Ks, it binds activated Rab5. The unusually complex regulation of PI3Kβ by small and trimeric G proteins and RTKs leads to a rich landscape of signaling responses at the cellular and organismic levels. This review focuses first on the regulation of PI3Kβ activity in vitro and in cells, and then summarizes the biology of PI3Kβ signaling in distinct tissues and in human disease.
Monopolatic motion vision in the butterfly Papilio xuthus
Authors: Stewart Finlay J. , Kinoshita Michiyo , Arikawa Kentaro
Published: January 2019

The swallowtail butterfly Papilio xuthus can perceive the linear polarization of light. Using a novel polarization projection system, we recently demonstrated that P. xuthus can detect visual motion based on polarization contrast. In the present study, we attempt to infer via behavioural experiments the mechanism underlying this polarization-based motion vision. Papilio xuthus do not perceive contrast between unpolarized and diagonally polarized light, implying that they cannot unambiguously estimate angle and degree of polarization, at least as far as motion detection is concerned. Furthermore, they conflate brightness and polarization cues, such that bright vertically polarized light resembles dim unpolarized light. These observations are consistent with a one-channel ‘monopolatic’ detector mechanism. We extend our existing model of motion vision in P. xuthus to incorporate these polarization findings, and conclude that the photoreceptors likely to form the basis for the putative monopolatic polarization detector are R3 and R4, which respond maximally to horizontally polarized green light. R5–R8, we propose, form a polarization-insensitive secondary channel tuned to longer wavelengths of light. Consistent with this account, we see greater sensitivity to polarization for green-light stimuli than for subjectively equiluminant red ones. Somewhat counter-intuitively, our model predicts greatest sensitivity to vertically polarized light; owing to the non-linearity of photoreceptor responses, light polarized to an angle orthogonal to a monopolatic detector's orientation offers the greatest contrast with unpolarized light.
Making Moves Matter: Experimental Evidence on Incentivizing Bureaucrats through Performance-Based Postings
Authors: Khan Adnan Q. , Khwaja Asim Ijaz , Olken Benjamin A.
Published: January 2019

Bureaucracies often post staff to better or worse locations, ostensibly to provide incentives. Yet we know little about whether this works, with heterogeneity in preferences over postings impacting effectiveness. We propose a performance-ranked serial dictatorship mechanism, whereby bureaucrats sequentially choose desired locations in order of performance. We evaluate this using a two-year field experiment with 525 property tax inspectors in Pakistan. The mechanism increases annual tax revenue growth by 30–41 percent. Inspectors whom our model predicts face high equilibrium incentives under the scheme indeed increase performance more. Our results highlight the potential of periodic merit-based postings in enhancing bureaucratic performance. (JEL C93, D73, H71, H83, J45, M54, O17)
Time for complete transparency about conflicts of interest in public health nutrition research
Authors: Hennessy Marita , Cullerton Katherine , Baker Phil , Brown Amy , Crawley Helen , Hayes Catherine , Kearney Patricia M. , Kelly Colette , McKee Martin , Mialon Melissa , Petticrew Mark , Rundall Patti , Trickey Heather , White Martin , Redsell Sarah
Published: January 2019

We are a group of researchers and academics with decades of experience in the protection and promotion of public health. We are writing to raise our concerns about how conflicts of interest are reported in public health nutrition research. We highlight examples of why it is important to accurately declare such conflicts, as well as providing examples of situations in which conflicts of interest have been inadequately reported. We call on researchers, and others, to be transparent about conflicts of interest in research. Journal editors in particular have an important responsibility in fully understanding how conflicts of interest can impact on research findings. They need to agree and adopt clear guidelines on conflicts of interest and ensure that authors abide by these to facilitate trust in the scientific process and the credibility of published articles.
Accounting for aetiology: can regional surveillance data alongside host biomarker-guided antibiotic therapy improve treatment of febrile illness in remote settings?
Authors: Chandna Arjun , White Lisa J. , Pongvongsa Tiengkham , Mayxay Mayfong , Newton Paul N. , Day Nicholas P. J. , Lubell Yoel
Published: January 2019

Background: Across Southeast Asia, declining malaria incidence poses a challenge for healthcare providers, in how best to manage the vast majority of patients with febrile illnesses who have a negative malaria test. In rural regions, where the majority of the population reside, empirical treatment guidelines derived from central urban hospitals are often of limited relevance. In these settings, relatively untrained health workers deliver care, often without any laboratory diagnostic support. In this paper, our aim was to model the impact on mortality from febrile illness of using point-of-care C-reactive protein testing to inform the decision to prescribe antibiotics and regional surveillance data to inform antibiotic selection, rooted in the real-world context of rural Savannakhet province, southern Laos.

Methods: Our model simulates 100 scenarios with varying quarterly incidence of six key pathogens known to be prevalent in rural Laos. In the simulations, community health workers either prescribe antibiotics in-line with current practice as documented in health facilities in rural Laos, or with the aid of the two interventions. We provide cost-effectiveness estimates for each strategy alone and then for an integrated approach using both interventions.

Results: We find that each strategy alone is predicted to be highly cost-effective, and that the combined approach is predicted to result in the biggest reduction in mortality (averting a predicted 510 deaths per year in rural Savannakhet, a 28% reduction compared to standard practice) and is highly cost-effective, with an incremental cost-effectiveness ratio of just $66 per disability-adjusted life year averted.

Conclusions: Substantial seasonal variation in the predicted optimal empirical antibiotic treatment for febrile illness highlights the benefits of up-to-date information on regional causes of fever. In this modelling analysis, an integrated system incorporating point-of-care host biomarker testing and regional surveillance data appears highly cost-effective, and may warrant piloting in a real-life setting.
On a class of N(k)-mixed generalized quasi-Einstein manifolds
Authors: Bhattacharyya Arindam , Pahan Sampa
Published: January 2019

The objective of the present paper is to study N(k)-mixed generalized quasi-Einstein manifolds. We prove the existence of these manifolds. Later we establish some curvature properties of N(k)-mixed generalized quasi-Einstein manifolds under certain conditions. In the last section, we give two examples of N(k)-mixed generalized quasi-Einstein manifolds.
On new extensions of the generalized Hermite matrix polynomials
Authors: Shehata Ayman
Published: January 2019

Various families of generating matrix functions have been established in diverse ways. The objective of the present paper is to investigate these generalized Hermite matrix polynomials, and derive some important results for them, such as, the generating matrix functions, matrix recurrence relations, an expansion of xnI, finite summation formulas, addition theorems, integral representations, fractional calculus operators, and certain other implicit summation formulae.
Second approximation of local functions in ideal topological spaces
Authors: Islam Md. Monirul , Modak Shyamapada
Published: January 2019

This paper gives a new dimension to discuss the local function in ideal topological spaces. We calculate error operators for various type of local functions and introduce more perfect approximation of the local functions for discussing their properties. We have also reached a topological space with the help of semi-closure.
On two integrability methods
Authors: Özgen H. N.
Published: January 2019

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Simplifying coefficients in a family of nonlinear ordinary differential equations
Authors: Qi Feng
Published: January 2019

By virtue of the Faá di Bruno formula, properties of the Stirling numbers and the Bell polynomials of the second kind, the binomial inversion formula, and other techniques in combinatorial analysis, the author finds a simple, meaningful, and signicant expression for coefficients in a family of nonlinear ordinary differential equations.
Behaviour of multivariate tail dependence coefficients
Authors: Pettere Gaida , Voronova Irina , Zariņa Ilze
Published: January 2019

In applications tail dependence is an important property of a copula. Bivariate tail dependence is investigated in many papers, but multivariate tail dependence has not been studied widely. We define multivariate upper and lower tail dependence coefficients as limits of the probability that values of one marginal will be large if at least one of other marginals will be as large also. Further we derive some relations between introduced tail dependence and bivariate tail dependence coefficients. Applications have shown that the multivariate t-copula has been successfully used in practice because of its tail dependence property. Therefore, t-copula can be used as an alternative method for risk assessment under Solvency II for insurance models. We have paid attention to the properties of the introduced multivariate tail dependence coefficient for t-copula and examine it in the simulation experiment.
Case compounding in Beserman Udmurt
Authors: Arkhangelskiy Timofey , Usacheva Maria
Published: January 2019

The topic of this paper is case compounding, i.e. attachment of multiple case markers to a noun stem, in Beserman Udmurt, which we also briefly compare to Literary Udmurt. Almost all types of case compounding as described by Noonan (2008) are attested in the language, however derivational compounding and compounding due to suspended affixation only play a marginal role. We use referential communication experiments and corpus data to analyze the constraints on this phenomenon. We also argue that possessive marking, which is often said to be obligatory in compounding (e.g. Alatyrev 1983: 586, Winkler 2001: 43), is in fact triggered by informational-structural factors that are associated with compounding, rather than by compounding itself. The paper is based primarily on the data that we collected in the field in 2003–2017.Аннотация. Тимофей Архангельский и Мария Усачева: Множественное падежное маркирование в бесермянском диалекте удмуртского. Объектом нашего исследования является множественное падежное маркирование, т. е. наличие нескольких падежных показателей внутри одной словоформы, в бесермянском диалекте удмуртского, который мы также кратко сравниваем с литературным удмуртским. В этом идиоме засвидетельствованы почти все типы множественного маркирования согласно типологии Нунана (Noonan 2008), хотя деривационный тип и отложенная аффиксация явно маргинальны. Для изучения ограничений на это явление мы используем эксперименты на референциальную коммуникацию и корпусные данные. Мы также демонстрируем, что посессивное маркирование, которое часто считается обязательным в такой ситуации (см., напр., Алатырев 1983: 586, Winkler 2001: 43), на самом деле появляется благодаря тем же информационно-структурным факторам, что и множественное маркирование, а не вызывается непосредственно последним. Статья в основном основана на данных, собранных авторами в поле в 2003–2017 гг.Ключевые слова: удмуртский язык, бесермянский диалект, множественное падежное маркирование, информационная структураKokkuvõte. Timofey Arkhangelskiy ja Maria Usacheva: Käänete liitmine Bessermani udmurdi keeles. Artiklis uuritakse käänete liitmist, s.t noomenitüvele mitme käändelõpu lisamist Bessermani udmurdi keeles, võrreldes seda ka udmurdi kirjakeelega. Pea kõik käänete liitmise tüübid on Noonani (2008) kirjelduste järgi keeles kasutusel, kuigi tuletuslikul ja katkestatud lisamisega liitmisel on väike osatähtsus. Kasutame viitelise suhtluse eksperimente ja korpusandmestikku, et selle nähtuse piire analüüsida. Samuti väidame, et possessiivne märkimine, mida peetakse liitmisel sageli kohustuslikuks (nt Alatyrev 1983: 586, Winkler 2001: 43), ei tulene niivõrd mitte liitmisest endast, vaid informatsioonilis-struktuurilistest faktoritest, mis on liitmisega seotud. Artikkel põhineb peamiselt andmetel, mille oleme teema kohta kogunud aastatel 2003–2017.Märksõnad: udmurdi keel, Bessermani udmurdi keel, käänete liitmine, informatsiooniline struktuur
Adnominal possessive constructions in Mordvin, Mari and Permic
Authors: Pleshak Polina
Published: January 2019

This paper deals with adnominal possessive constructions in Moksha, Erzya, Meadow Mari, Hill Mari, Izhma Komi and Udmurt. The two main constructions that encode possessive relations in all the languages of the sample are the same: Dependentmarking and Double-marking. Izhma Komi also uses Head-marking and Juxtaposition. However, a more fine-grained analysis helps to find out many differences between the languages of the sample. Firstly, restrictions on the use of the genitive case and possessive markers can be slightly different in these languages. Secondly, there are factors that influence marking of NP elements (both the Head and the Dependent) in different ways. These factors are semantic relations, animacy hierarchy and syntactic function of an NP.Аннотация. Полина Плешак: Посессивные конструкции в мордовских, марийских и пермских языках. В данной статье обсуждаются результаты исследования приименных посессивных конструкций в мокшанском, эрзянском, луговом марийском, горномарийском, ижемском коми и удмуртском. Две основные стратегии, кодирующие посессивные отношения во всех рассматриваемых языках, – зависимостное маркирование и двойное маркирование, а также дополнительно вершинное маркирование и конструкция с соположением в ижемском коми. Однако более детальный анализ позволяет выявить большое количество различий между языками выборки. Во-первых, как генитив, так и посессивные показатели имеют разные области применения в разных языках. Во-вторых, существуют факторы, по-разному влияющие на маркирование членов ИГ (как вершины, так и зависимого). Таковыми являются семантические отношения, иерархия одушевлённости и синтаксическая позиция ИГ.Ключевые слова: внутригенетическая типология, посессивные конструкции, зависимостное маркирование, двойное маркирование, генитив, посессивный показатель, семантические отношения, иерархия одушевлённости, финно-угорские языкиKokkuvõte. Polina Pleshak: Adnominaalsed possessiivkonstruktsioonid mordva, mari ja permi keeltes. Artikkel käsitleb adnominaalseid possessiivkonstruktsioone mokša, ersa, niidumari, mäemari, ižmakomi ja udmurdi keeltes. Kaks põhikonstruktsiooni, mis possessiivseid suhteid väljendavad, on kõikides käsitletud keeltes samad: laiendi markeerimine ja topeltmarkeering. Ižmakomi keeles kasutatakse ka põhja markeerimist ja jukstapositsiooni. Peenekoelisem analüüs aitab aga käsitletavate keelte vahel leida rohkelt erinevusi. Esiteks võivad nendes keeltes mõneti erineda genitiivi ja possessiivmarkerite kooskasutuse piirangud. Teiseks on faktoreid, mille mõju tõttu markeeritakse NP elemente erinevalt (seda nii põhisõna kui ka laiendi puhul). Need faktorid on semantilised suhted, elususe hierarhia, ja NP süntaktiline funktsioon.Märksõnad: intrageneetiline tüpoloogia, possessiivkonstruktsioonid, laiendi markeering, topeltmarkeering, genitiiv, possessiivmarker, semantilised suhted, elususe hierarhia, soome-ugri keeled
Robust Optimization of Dose-Volume Metrics for Prostate HDR-Brachytherapy Incorporating Target and OAR Volume Delineation Uncertainties
Authors: Balvert Marleen , den Hertog Dick , Hoffmann Aswin L.
Published: January 2019

In radiation therapy planning, uncertainties in the definition of the target volume yield a risk of underdosing the tumor. The traditional corrective action in the context of external beam radiotherapy (EBRT) expands the clinical target volume (CTV) with an isotropic margin to obtain the planning target volume (PTV). However, the EBRT-based PTV concept is not directly applicable to brachytherapy (BT) since it can lead to undesirable dose escalation. Here, we present a treatment plan optimization model that uses worst-case robust optimization to account for delineation uncertainties in interstitial high-dose-rate BT of the prostate. A scenario-based method was developed that handles uncertainties in index sets. Heuristics were included to reduce the calculation times to acceptable proportions. The approach was extended to account for delineation uncertainties of an organ at risk (OAR) as well. The method was applied on data from prostate cancer patients and evaluated in terms of commonly used dosimetric performance criteria for the CTV and relevant OARs. The robust optimization approach was compared against the classical PTV margin concept and against a scenario-based CTV margin approach. The results show that the scenario-based margin and the robust optimization method are capable of reducing the risk of underdosage to the tumor. As expected, the scenario-based CTV margin approach leads to dose escalation within the target, whereas this can be prevented with the robust model. For cases where rectum sparing was a binding restriction, including uncertainties in rectum delineation in the planning model led to a reduced risk of a rectum overdose, and in some cases, to reduced targetcoverage.

The online supplement is available at https://doi.org/10.1287/ijoc.2018.0815 .
Data-Driven Decisions for Problems with an Unspecified Objective Function
Authors: Sun Zhen , Dawande Milind , Janakiraman Ganesh , Mookerjee Vijay
Published: January 2019

This study develops a data-driven approach to solve constrained optimization problems in which the decision maker does not have an analytic form for the objective function but knows what decision variables affect the function. The approach makes direct use of the available data, rather than first using the data to estimate the objective function and then solving the problem as a traditional optimization problem. The difficulty in first estimating the unknown objective function is that the decision maker needs to have sufficient knowledge of its properties that are necessary to guide the estimation process. Thus, our approach is appropriate for situations where such structural knowledge is absent, either because the domain is very complex or because the knowledge is deliberately hidden by a partner firm that has a vested interest in the outcome of the decision. Our approach comes with a worst-case performance guarantee that improves with the characteristics (size, pervasiveness) of the available data. We illustrate our technique on a traffic-stream mixing problem encountered by a supply side Internet advertising network that wishes to optimize the click revenue earned from ads. A head-to-head comparison (with the existing method used) on real data shows a significant increase (≥10%, on average) in the revenue. We also demonstrate the value of our approach under more general conditions.

The online supplement is available at https://doi.org/10.1287/ijoc.2018.0818 .
Cost-effectiveness analysis of a placebo-controlled randomized trial evaluating the effectiveness of arthroscopic subacromial decompression in patients with subacromial shoulder pain
Authors: Rombach I. , Merritt N. , Shirkey B. A. , Rees J. L. , Cook J. A. , Cooper C. , Carr A. J. , Beard D. J. , Gray A. M.
Published: January 2019

Aims

The aims of this study were to compare the use of resources, costs, and quality of life outcomes associated with subacromial decompression, arthroscopy only (placebo surgery), and no treatment for subacromial pain in the United Kingdom National Health Service (NHS), and to estimate their cost-effectiveness.

Patients and Methods

The use of resources, costs, and quality-adjusted life-years (QALYs) were assessed in the trial at six months and one year. Results were extrapolated to two years after randomization. Differences between treatment arms, based on the intention-to-treat principle, were adjusted for covariates and missing data were handled using multiple imputation. Incremental cost-effectiveness ratios were calculated, with uncertainty around the values estimated using bootstrapping.

Results

Cumulative mean QALYs/mean costs of health care service use and surgery per patient from baseline to 12 months were estimated as 0.640 (standard error (se) 0.024)/£3147 (se 166) in the decompression arm, 0.656 (se 0.020)/£2830 (se 183) in the arthroscopy only arm and 0.522 (se 0.029)/£1451 (se 151) in the no treatment arm. Statistically significant differences in cumulative QALYs and costs were found at six and 12 months for the decompression versus no treatment comparison only. The probabilities of decompression being cost-effective compared with no treatment at a willingness-to-pay threshold of £20 000 per QALY were close to 0% at six months and approximately 50% at one year, with this probability potentially increasing for the extrapolation to two years.

Discussion

The evidence for cost-effectiveness at 12 months was inconclusive. Decompression could be cost-effective in the longer-term, but results of this analysis are sensitive to the assumptions made about how costs and QALYs are extrapolated beyond the follow-up of the trial.