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To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ejor.2008.07.015 Byline: Julian Molina (c), Luis V. Santana (a), Alfredo G. Hernandez-Diaz (b), Carlos A. Coello Coello (a), Rafael Caballero (c) Keywords: Multiple-criteria decision making; Interactive methods; Preference information; Reference point Abstract: One of the main tools for including decision maker (DM) preferences in the multiobjective optimization (MO) literature is the use of reference points and achievement scalarizing functions [A.P. Wierzbicki, The use of reference objectives in multiobjective optimization, in: G. Fandel, T. Gal (Eds.), Multiple-Criteria Decision Making Theory and Application, Springer-Verlag, New York, 1980, pp. 469-486.]. The core idea in these approaches is converting the original MO problem into a single-objective optimization problem through the use of a scalarizing function based on a reference point. As a result, a single efficient point adapted to the DM's preferences is obtained. However, a single solution can be less interesting than an approximation of the efficient set around this area, as stated for example by Deb in [K. Deb, J. Sundar, N. Udaya Bhaskara Rao, S. Chaudhuri, Reference point based multiobjective optimization using evolutionary algorithms, International Journal of Computational Intelligence Research, 2(3) (2006) 273-286]. In this paper, we propose a variation of the concept of Pareto dominance, called g-dominance, which is based on the information included in a reference point and designed to be used with any MO evolutionary method or any MO metaheuristic. This concept will let us approximate the efficient set around the area of the most preferred point without using any scalarizing function. On the other hand, we will show how it can be easily used with any MO evolutionary method or any MO metaheuristic (just changing the dominance concept) and, to exemplify its use, we will show some results with some state-of-the-art-methods and some test problems. Author Affiliation: (a) CINVESTAV-IPN, Computer Science Department, Mexico (b) Pablo de Olavide University, Seville, Spain (c) University of Malaga, Applied Economics (Mathematics), Campus El Ejido s./n., 29071, Malaga, Spain Article History: Received 1 February 2007; Accepted 7 July 2008

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ejor.2008.05.013 Byline: Kaisa Miettinen (a), Julian Molina (b), Mercedes Gonzalez (b), Alfredo Hernandez-Diaz (c), Rafael Caballero (b) Keywords: Multiple criteria programming; MCDM; Preference information; Pareto optimality; Visualization; Interactive methods Abstract: Because of the conflicting nature of criteria or objectives, solving a multiobjective optimization problem typically requires interaction with a decision maker who can specify preference information related to the objectives in the problem in question. Due to the difficulties of dealing with multiple objectives, the way information is presented plays a very important role. Questions posed to the decision maker must be simple enough and information shown must be easy to understand. For this purpose, visualization and graphical representations can be useful and constitute one of the main tools used in the literature. In this paper, we propose to use box indices to represent information related to different solution alternatives of multiobjective optimization problems involving at least three objectives. Box indices are an intelligible and easy to handle way to represent data. They are based on evaluating the solutions in a natural and rough enough scale in order to let the decision maker easily recognize the main characteristics of a solution at a glance and to facilitate comparison of two or more solutions in an easily understandable way. Author Affiliation: (a) Department of Mathematical Information Technology, P.O. Box 35 (Agora), FI-40014, University of Jyvaskyla, Finland (b) University of Malaga, Malaga, Spain (c) Pablo de Olavide University, Seville, Spain Article History: Received 23 April 2007; Accepted 17 May 2008

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ejor.2005.10.017 Byline: Rafael Caballero (a), Mercedes Gonzalez (a), Flor Ma Guerrero (b), Julian Molina (a), Concepcion Paralera (b) Keywords: Location routing problems; Multiobjective combinatorial optimization; Metaheuristics Abstract: In this work we present a multiobjective location routing problem and solve it with a multiobjective metaheuristic procedure. In this type of problem, we have to locate some plants within a set of possible locations to meet the demands of a number of clients with multiple objectives. This type of model is used to solve a problem with real data in the region of Andalusia (Spain). Thus, we study the location of two incineration plants for the disposal of solid animal waste from some preestablished locations in Andalusia, and design the routes to serve the different slaughterhouses in this region. This must be done while taking into account certain economic objectives (start-up, maintenance, and transport costs) and social objectives (social rejection by towns on the truck routes, maximum risk as an equity criterion, and the negative implications for towns close to the plant). Author Affiliation: (a) Faculty of Economics, Department of Applied Economics (Mathematics), University of Malaga, Campus El Ejido, 29007 Malaga, Spain (b) Department of Economy and Business, University Pablo de Olavide, Ctra. de Utrera, Km. 1- 41013 Sevilla, Spain

c-Met is a receptor tyrosine kinase shown to be overexpressed in malignant pleural mesothelioma (MPM). Whereas MET mutations have been identified in 3%-16% of MPMs, MET amplification has recently been reported in a single epithelioid MPM. We studied c-Met expression and MET amplification in a large MPM cohort and correlated results with morphologic and clinical features. We report the first case of MET amplification in sarcomatoid MPM. MPMs from surgical pathology files (1989-2014) were reviewed. c-Met immunohistochemistry was performed. Staining intensity and distribution were multiplied (H-score). Staining localization (cytoplasmic and/or membranous) was noted. Fluorescence in situ hybridization was performed using probes for MET and centromere 7. One hundred forty-nine patients (median age, 68.0 years; interquartile range, 61-75) had epithelioid (n = 97), biphasic (n = 18), or sarcomatoid (n = 34) MPM. Median follow-up was 10.1 months (range, 0.1-222.5). One hundred thirty patients died of disease; 2 were alive with disease. c-Met was expressed in 147 MPMs. c-Met staining intensity, distribution, and H-score differed among the histologic subtypes ( P = .015; P = .0001, and P = .0005, respectively), but none were predictive of survival. Epithelioid subtype had greater c-Met expression. MET amplification was identified in 1 sarcomatoid MPM and MET duplication in 1 epithelioid MPM; both had poor outcomes. Chromosome 7 aneusomy was observed in 54 of 144 (37.5%) MPMs and associated with decreased overall survival in sarcomatoid MPMs (hazard ratio = 2.81; 95% confidence interval, 1.21-6.51; P = .01). In conclusion, c-Met is expressed in MPM, with significant differences in expression among histologic subtypes. MET amplification is a rare event in MPM, making it an unlikely common pathogenesis for c-Met expression. [ABSTRACT FROM AUTHOR]

Pulmonary artery (PA) agenesis in the absence of associated cardiac abnormalities is a rare congenital abnormality. It may remain undiagnosed until adulthood when patients present with respiratory symptoms such as hemoptysis, dyspnea, repeated respiratory infections, or pulmonary hypertension. Herein we present a case of a 50-year-old woman who was found to have multiple, morphologically distinct non-small cell lung cancers in association with agenesis of the PA. This instance represents the fourth reported case of such association in the English literature. [ABSTRACT FROM AUTHOR]

Introduction To assess the efficacy and the Src-kinase inhibitor saracatinib (AZD-0530) after four cycles of platinum-based chemotherapy for extensive stage small cell lung cancer (SCLC). Methods Patients with at least stable disease received saracatinib at a dose of 175mg/day by mouth until disease progression, unacceptable toxicity, or patient refusal. The primary endpoint was the 12-week progression-free survival (PFS) rate from initiation of saracatinib treatment. Planned interim analysis in first 20 patients, where 13 or more patients alive and progression-free at 12-weeks would allow continued enrollment to 40 total patients. Results All 23 evaluable patients received platinum based standard chemotherapy. Median age was 58 years (range: 48-82). 96% of patients had a performance status of 0/1. Median of two cycles given (range: 1-34). All 23 (100%) patients have ended treatment, most for disease progression (19/23). The 12-week PFS rate was 26% (6/23; 95% CI: 10-48%). From start of standard chemotherapy, median PFS was 4.7 months (95% CI: 4.5-5.1) and median OS was 11.2 months (95% CI: 9.9-13.8). Eight (35%) and three (13%) patients experienced at least one grade 3/4 or grade 4 AE, respectively. Commonly occurring grade 3/4 adverse events were thrombocytopenia (13%), fatigue (9%), nausea (9%), and vomiting (9%). Conclusions Saracatinib at a dose of 175mg/day by mouth is well tolerated. However, the PFS rate observed at the pre-planned interim analysis did not meet the criteria for additional enrollment. [ABSTRACT FROM AUTHOR]

Lung cancer is the leading cause of cancer-related mortality not only in the United States but also around the world. In North America, lung cancer has become more predominant among former than current smokers. Yet in some countries, such as China, which has experienced a dramatic increase in the cigarette smoking rate during the past 2 decades, a peak in lung cancer incidence is still expected. Approximately two-thirds of adult Chinese men are smokers, representing one-third of all smokers worldwide. Non-small cell lung cancer accounts for 85% of all lung cancer cases in the United States. After the initial diagnosis, accurate staging of non-small cell lung cancer using computed tomography or positron emission tomography Is crucial for determining appropriate therapy. When feasible, surgical resection remains the single most consistent and successful option for cure. However, close to 70% of patients with lung cancer present with locally advanced or metastatic disease at the time of diagnosis. Chemotherapy is beneficial for patients with metastatic disease, and the administration of concurrent chemotherapy and radiation is indicated for stage Ill lung cancer. The introduction of angiogenesis, epidermal growth factor receptor inhibitors, and other new anti-cancer agents is changing the present and future of this disease and will certainly increase the number of lung cancer survivors. We identified studies for this review by searching the MEDLINE and PubMed databases for English-language articles published from January 1, 1980, through January 31, 2008. Key terms used for this search included non-small cell lung cancer, adenocarcinoma, squamous cell carcinoma, bronchioalveolar cell carcinoma, large cell carcinoma, lung cancer epidemiology, genetics, survivorship, surgery, radiation therapy, chemotherapy, targeted therapy, bevacizumab, eriotinib, and epidermal growth factor receptor. [ABSTRACT FROM AUTHOR]

Background & Aims: This study explored the eyes absent 4 (EYA4) gene promoter methylation in noncolitic colorectal tissues and assessed its discrimination for neoplasia in chronic ulcerative colitis (CUC). Methods: The methylation status of noncolitic specimens was confirmed by direct bisulfite sequencing. Methylation-specific polymerase chain reaction (MSP) primers were designed to evaluate colorectal tissues, including 50 noncolitic patients comprising 24 normal epithelia, 14 polyps, and 12 cancers. The assay was tested on tissues from 67 CUC patients including 31 surveillance neoplasia-positive patients and nonneoplastic controls including 22 CUC surveillance-negative and 14 CUC short-disease duration. Remote colonic tissue was included from each of 27 of the 31 CUC neoplasia cases. The expression of EYA4 was quantified in cell lines by use of reverse-transcription polymerase chain reaction. Results: Within noncolitic tissues, bisulfite sequencing showed EYA4 promoter hypermethylation in 80% (8 of 10) of colorectal cancers but in none (0 of 9) of the normal tissues. MSP was positive in 81% (21 of 26) of cancers and polyps and in only 4% (1 of 14) of normal mucosa. In CUC, MSP was positive in 81% (25 of 31) of neoplastic cases but in none (0 of 36) of the nonneoplastic controls. RNA expression was decreased in methylated compared with unmethylated cell lines (P < .001). Treatment with 5-Aza-2′-deoxycytidine (DAC)/Trichostatin (TSA) increased the overall messenger RNA expression (P = .005). Conclusions: The EYA4 gene promoter is hypermethylated commonly in sporadic and colitic neoplasia and may be associated with gene silencing. EYA4 methylation represents a candidate marker for CUC surveillance. [Copyright &y& Elsevier]

Background: Gender has been reported as a predictor for nonsmall cell lung cancer (NSCLC) survival. Most of the reports are limited to selected groups of patients. The magnitude of gender effect on NSCLC survival across disease stage, tumor histology, and therapies needs to be further characterized.Methods: A cohort of 4,618 patients diagnosed with NSCLC was prospectively enrolled and actively followed. Vital status of each patient was verified through multiple complementary sources. Cox proportional hazards models were developed to compare postdiagnosis survival between genders adjusting for age at diagnosis, tumor histology and grade, stage, pack-years smoked, and treatment received (resection, radiation, or chemotherapy).Results: There were 2,724 men (59%) and 1,894 women (41%), with a median age at diagnosis of 68 years in men and 66 in women (p < 0.01). More men smoked and were heavier smokers than women. Adenocarcinoma was the most frequent histology in both genders. No difference was found in stage and treatment between genders. The estimated survival in men was 51% (95% CI: 49%, 53%) and 15% (95% CI: 12%, 17%) at one and five years, respectively, and in women was 60% (95% CI: 58%, 62%) and 19% (95% CI: 16%, 22%). Men were at a significantly increased risk of mortality compared to women following a diagnosis of NSCLC (adjusted relative risk: 1.20, 95% CI: 1.11, 1.30), particularly for patients with stage III/IV disease or adenocarcinoma.Conclusions: Male gender is confirmed to be an independent unfavorable prognostic indicator for NSCLC survival. [Copyright &y& Elsevier]

Summary: Background: Chemotherapy has historically proven ineffective in advanced differentiated thyroid cancers, but the realisation that various tyrosine kinases are activated in the disease suggested a potential therapeutic role for tyrosine-kinase inhibitors. We investigated the safety and efficacy of pazopanib. Methods: This phase 2 trial was done from Feb 22, 2008, to Jan 31, 2009, in patients with metastatic, rapidly progressive, radioiodine-refractory differentiated thyroid cancers. Each patient received 800 mg continuous pazopanib daily in 4-week cycles until disease progression, drug intolerance, or both occurred. Up to two previous therapies were allowed, and measurable disease with radiographic progression in the 6-month period before enrolment was a requirement for inclusion. The primary endpoint was any tumour response, according to the Response Evaluation Criteria in Solid Tumors 1.0. This study is registered with ClinicalTrials.gov, number NCT00625846. Findings: 39 patients were enrolled. One patient had received no previous radioiodine therapy and another withdrew consent before treatment. Clinical outcomes could, therefore, be assessed in 37 patients (19 [51%] men, median age 63 years). The study is closed to accrual of new patients, but several enrolled patients are still being treated. Patients received a median of 12 cycles (range 1 to >23, total >383). Confirmed partial responses were recorded in 18 patients (response rate 49%, 95% CI 35–68), with likelihood of response lasting longer than 1 year calculated to be 66%. Maximum concentration of pazopanib in plasma during cycle one was significantly correlated with radiographic response (r=−0·40, p=0·021). 16 (43%) patients required dose reductions owing to adverse events, the most frequent of which (any grade) were fatigue (29 patients), skin and hair hypopigmentation (28), diarrhoea (27), and nausea (27). Two patients who died during treatment had pre-existing contributory disorders. Interpretation: Pazopanib seems to represent a promising therapeutic option for patients with advanced differentiated thyroid cancers. The correlation of the patient''s response and pazopanib concentration during the first cycle might indicate that treatment can be individualised to achieve optimum outcomes. Assessment of pazopanib in an expanded cohort of patients with differentiated thyroid cancer, as well as in cohorts of patients with medullary and anaplastic thyroid cancers, is presently being done. Funding: National Cancer Institute, supported in part by NCI CA15083 and CM62205. [Copyright &y& Elsevier]

Angiogenesis Is a common factor in the pathogenesis of cancer and In exudative age-related macular degeneration (AMD). Therefore, angiogenesis inhibition has been developed as a therapeutic strategy. We report 2 cases of recurrent exudative AMD in which oral sorafenib, a tyrosine kinase Inhibitor approved for cancer, was added to intravitreal ranibizumab, an antibody to vascular endothelial growth factor. These 2 patients were followed up by determination of visual acuity, fluorescein angiography, fundoscopy, and optical coherence tomography. The visual acuity of I patient Improved from 20/70 to 20/60 while he was receiving sorafenib therapy; that of the other did not. Marked improvement was noted in both patients on optical coherence tomography. Additionally, both patients appeared to receive some benefit when low-dose oral sorafenib was used as monotherapy after Its initial addition to ranibizumab therapy. Randomized trials of adding sorafenib to standard therapy for patients with neo-vascular AMD should be considered. [ABSTRACT FROM AUTHOR]

Summary: Objectives: Standard treatment for patients with poor-risk, resected head and neck squamous cell carcinoma (HNSCC) is adjuvant radiation therapy combined with high-dose cisplatin. Many patients are treated with weekly cisplatin; it is not known whether weekly and high-dose cisplatin are equivalent. This study compares the outcomes of patients with locally-advanced HPV-negative HNSCC and HPV/p16-positive oropharynx HNSCC treated with adjuvant chemoradiation therapy with either high-dose or weekly cisplatin. Materials and methods: Retrospective review of patients with Stage III/IV HNSCC who had surgery followed by adjuvant chemoradiation therapy at Mayo Clinic, Rochester. HPV and/or p16 status was available for all oropharynx patients. Results: 104 Patients (51 high-dose, 53 weekly) were analyzed. The 3-year overall survival was 84% and 75% for patients who received high dose and weekly cisplatin, respectively (p =0.30). The 3-year recurrence free survival was 71% and 74% in the high dose and weekly cisplatin group, respectively (p =0.95). Patients with HPV/p16-positive oropharynx cancer who received adjuvant chemoradiation therapy with high-dose and weekly cisplatin had three-year overall survival rates of 91% and 86% (p =0.56), and 3-year recurrence free survival of 84% and 82% (p =0.93). Extracapsular extension did not affect prognosis in either group. Conclusions: No significant survival difference was seen between patients with locally advanced HNSCC treated with adjuvant chemoradiation therapy with high-dose or weekly cisplatin, although there was a trend for improved survival with high-dose cisplatin. Weekly cisplatin in the adjuvant setting may be a better treatment for patients with HPV-positive oropharynx cancer to preserve survival and minimize toxicity. [Copyright &y& Elsevier]

Summary: Small cell lung cancer is highly sensitive to chemotherapy, and a survival advantage with its use is well established. However, whether chemotherapy also confers such benefits to patients with severe organ dysfunction has not been extensively studied. The goal of this study was to provide further guidance for clinical decision-making. Medical records from small cell lung cancer patients who were seen at a single tertiary care institution between 1994 and 2002 were reviewed. All patients with severe organ dysfunction were identified. The latter was defined as creatinine ≥3mg/dl, total bilirubin ≥3mg/dl, and/or platelet count ≤50×106 per milliliter. An in depth review of treatment and outcome in this patient subgroup was then undertaken. A total of 993 small cell lung cancer patients were seen during this period, and 25 (2.5%) had severe organ dysfunction. Eleven had been treated with chemotherapy, 11 had not, and this information was not retrievable in 3. Cyclophosphamide, etoposide (oral or intravenous), paclitaxel, cisplatin, or carboplatin were prescribed as single agents or in combination; 8 of 11 patients received an initial dose reduction. With chemotherapy, three patients normalized their bilirubin, and one manifested a notable drop. Median survival was 150 days for chemotherapy-treated patients but only 10 days for those who did not receive it. One patient died a few days after chemotherapy; three others were hospitalized immediately thereafter; and two were lost to follow up. In five patients, no notable adverse events were noted in the medical record. These preliminary findings suggest that, even in the presence of severe organ dysfunction, a subgroup of small cell lung cancer patients can tolerate chemotherapy, normalize their laboratory parameters, and go on to live for several months. [Copyright &y& Elsevier]

Herein, we show that the hematopoietic-specific GEF VAV1 is ectopically expressed in primary pancreatic adenocarcinomas due to demethylation of the gene promoter. Interestingly, VAV1-positive tumors had a worse survival rate compared to VAV1-negative tumors. Surprisingly, even in the presence of oncogenic KRAS, VAV1 RNAi abrogates neoplastic cellular proliferation in vitro and in vivo, thus identifying Vav1 as a growth-stimulatory protein in this disease. Vav1 acts synergistically with the EGF receptor to stimulate pancreatic tumor cell proliferation. Mechanistically, the effects of Vav1 require its GEF activity and the activation of Rac1, PAK1, and NF-κB and involve cyclin D1 upregulation. Thus, the discovery of prooncogenic pathways regulated by Vav1 makes it an attractive target for therapeutic intervention. [Copyright &y& Elsevier]

This study proposes a methodology to serve as a guiding mechanism for the allocation and management of university financial resources taking efficiency as its objective. Specifically, an aid model is provided for decision making, so that the planning of staff policy within a university guarantees an equal treatment of all the teaching and research units, greater transparency in the allocation of financial resources, as well as a rational monitoring of the allocations made and their effects on the university efficiency levels. The model we provide is based on the use of two quantitative techniques: data envelopment analysis (DEA) and multiple criteria decision making (MCDM), both techniques being linked in a way which makes it possible to transfer information from one to the other. [Copyright &y& Elsevier]