Spatial-temporal-demand clustering for solving large-scale vehicle routing problems with time windows

Several metaheuristics use decomposition and pruning strategies to solve large-scale instances of the vehicle routing problem (VRP). Those complexity reduction techniques often rely on simple, problem-specific rules. However, the growth in available data and advances in computer hardware enable data-based approaches that use machine learning (ML) to improve scalability of solution algorithms. We propose a decompose-route-improve (DRI) framework that groups customers using clustering. Its similarity metric incorporates customers' spatial, temporal, and demand data and is formulated to reflect the problem's objective function and constraints. The resulting sub-routing problems can independently be solved using any suitable algorithm. We apply pruned local search (LS) between solved subproblems to improve the overall solution. Pruning is based on customers' similarity information obtained in the decomposition phase. In a computational study, we parameterize and compare existing clustering algorithms and benchmark the DRI against the Hybrid Genetic Search (HGS) of Vidal et al. (2013). Results show that our data-based approach outperforms classic cluster-first, route-second approaches solely based on customers' spatial information. The newly introduced similarity metric forms separate sub-VRPs and improves the selection of LS moves in the improvement phase. Thus, the DRI scales existing metaheuristics to achieve high-quality solutions faster for large-scale VRPs by efficiently reducing complexity. Further, the DRI can be easily adapted to various solution methods and VRP characteristics, such as distribution of customer locations and demands, depot location, and different time window scenarios, making it a generalizable approach to solving routing problems

Optimizing of preoperative computed tomography for diagnosis in patients with peritoneal carcinomatosis

<p>Abstract</p> <p>Background and Objective</p> <p>This study evaluates whether Computer Tomography is an effective procedure for preoperative staging of patients with Peritoneal Carcinomatosis.</p> <p>Method</p> <p>A sample of 37 patients was analyzed with contrast enhanced abdominal Computer Tomography, followed by surgical staging. All Computer Tomography scans were evaluated 3 times by 2 radiologists with one radiologist reviewing 2 times. The efficacy of Computer Tomography was evaluated using the Spearman correlation coefficient. Correlations were analyzed by abdominopelvic region to assess results of the Peritoneal Carcinomatosis Index (PCI) aggregating the 13 regions. Surgical findings were compared to radiological findings.</p> <p>Results</p> <p>Results indicate high correlations between the surgical and radiological Peritoneal Carcinomatosis Indices. Analyses of the intra-class correlation between the first and second reading of one radiologist suggest high intra-observer reliability. Correlations by abdominopelvic region show higher values in the upper and middle regions and relatively lower values in the lower regions and the small bowel (correlation coefficients range between 0.418 and 0.726, p < 0.010; sensitivities range between 50% and 96%; and specificities range between 62% and 100%).</p> <p>Conclusion</p> <p>Computer Tomography represents an effective procedure in the preoperative staging of patients with PC. However, results by abdominopelvic region show lower correlation, therefore suggest lower efficacy. These results are supported by analyses of sensitivity and accuracy by lesion size. This suggests that Computer Tomography is an effective procedure for pre-operative staging but less for determining a tumor's accurate extent.</p

Analysing Large Scale Structure: I. Weighted Scaling Indices and Constrained Randomisation

The method of constrained randomisation is applied to three-dimensional simulated galaxy distributions. With this technique we generate for a given data set surrogate data sets which have the same linear properties as the original data whereas higher order or nonlinear correlations are not preserved. The analysis of the original and surrogate data sets with measures, which are sensitive to nonlinearities, yields information about the existence of nonlinear correlations in the data. We demonstrate how to generate surrogate data sets from a given point distribution, which have the same linear properties (power spectrum) as well as the same density amplitude distribution. We propose weighted scaling indices as a nonlinear statistical measure to quantify local morphological elements in large scale structure. Using surrogates is is shown that the data sets with the same 2-point correlation functions have slightly different void probability functions and especially a different set of weighted scaling indices. Thus a refined analysis of the large scale structure becomes possible by calculating local scaling properties whereby the method of constrained randomisation yields a vital tool for testing the performance of statistical measures in terms of sensitivity to different topological features and discriminative power.Comment: 10 pages, 5 figures, accepted for publication in MNRA

Evaluation of Best Supportive Care and Systemic Chemotherapy as Treatment Stratified according to the retrospective Peritoneal Surface Disease Severity Score (PSDSS) for Peritoneal Carcinomatosis of Colorectal Origin

Background: We evaluate the long-term survival of patients with peritoneal carcinomatosis (PC) treated with systemic chemotherapy regimens, and the impact of the of the retrospective peritoneal disease severity score (PSDSS) on outcomes. Methods: One hundred sixty-seven consecutive patients treated with PC from colorectal cancer between years 1987-2006 were identified from a prospective institutional database. These patients either received no chemotherapy, 5-FU/Leucovorin or Oxaliplatin/Irinotecan-based chemotherapy. Stratification was made according to the retrospective PSDSS that classifies PC patients based on clinically relevant factors. Survival analysis was performed using the Kaplan-Meier method and comparison with the log-rank test. Results: Median survival was 5 months (95% CI, 3-7 months) for patients who had no chemotherapy, 11 months (95% CI, 6-9 months) for patients treated with 5 FU/LV, and 12 months (95% CI, 4-20 months) for patients treated with Oxaliplatin/Irinotecan-based chemotherapy. Survival differed between patients treated with chemotherapy compared to those patients who did not receive chemotherapy (p = 0.026). PSDSS staging was identified as an independent predictor for survival on multivariate analysis [RR 2.8 (95%CI 1.5-5.4); p < 0.001]. Conclusion: A trend towards improved outcomes is demonstrated from treatment of patients with PC from colorectal cancer using modern systemic chemotherapy. The PSDSS appears to be a useful tool in patient selection and prognostication in PC of colorectal origin

Variants in a Novel Epidermal Collagen Gene (COL29A1) Are Associated with Atopic Dermatitis

Atopic dermatitis (AD) is a common chronic inflammatory skin disorder and a major manifestation of allergic disease. AD typically presents in early childhood often preceding the onset of an allergic airway disease, such as asthma or hay fever. We previously mapped a susceptibility locus for AD on Chromosome 3q21. To identify the underlying disease gene, we used a dense map of microsatellite markers and single nucleotide polymorphisms, and we detected association with AD. In concordance with the linkage results, we found a maternal transmission pattern. Furthermore, we demonstrated that the same families contribute to linkage and association. We replicated the association and the maternal effect in a large independent family cohort. A common haplotype showed strong association with AD (p = 0.000059). The associated region contained a single gene, COL29A1, which encodes a novel epidermal collagen. COL29A1 shows a specific gene expression pattern with the highest transcript levels in skin, lung, and the gastrointestinal tract, which are the major sites of allergic disease manifestation. Lack of COL29A1 expression in the outer epidermis of AD patients points to a role of collagen XXIX in epidermal integrity and function, the breakdown of which is a clinical hallmark of AD

Modeling of miRNA and Drug Action in the EGFR Signaling Pathway

MicroRNAs have gained significant interest due to their widespread occurrence and diverse functions as regulatory molecules, which are essential for cell division, growth, development and apoptosis in eukaryotes. The epidermal growth factor receptor (EGFR) signaling pathway is one of the best investigated cellular signaling pathways regulating important cellular processes and its deregulation is associated with severe diseases, such as cancer. In this study, we introduce a systems biological model of the EGFR signaling pathway integrating validated miRNA-target information according to diverse studies, in order to demonstrate essential roles of miRNA within this pathway. The model consists of 1241 reactions and contains 241 miRNAs. We analyze the impact of 100 specific miRNA inhibitors (anit-miRNAs) on this pathway and propose that the embedded miRNA-network can help to identify new drug targets of the EGFR signaling pathway and thereby support the development of new therapeutic strategies against cancer

miR-199a-5p Is Upregulated during Fibrogenic Response to Tissue Injury and Mediates TGFbeta-Induced Lung Fibroblast Activation by Targeting Caveolin-1

As miRNAs are associated with normal cellular processes, deregulation of miRNAs is thought to play a causative role in many complex diseases. Nevertheless, the precise contribution of miRNAs in fibrotic lung diseases, especially the idiopathic form (IPF), remains poorly understood. Given the poor response rate of IPF patients to current therapy, new insights into the pathogenic mechanisms controlling lung fibroblasts activation, the key cell type driving the fibrogenic process, are essential to develop new therapeutic strategies for this devastating disease. To identify miRNAs with potential roles in lung fibrogenesis, we performed a genome-wide assessment of miRNA expression in lungs from two different mouse strains known for their distinct susceptibility to develop lung fibrosis after bleomycin exposure. This led to the identification of miR-199a-5p as the best miRNA candidate associated with bleomycin response. Importantly, miR-199a-5p pulmonary expression was also significantly increased in IPF patients (94 IPF versus 83 controls). In particular, levels of miR-199a-5p were selectively increased in myofibroblasts from injured mouse lungs and fibroblastic foci, a histologic feature associated with IPF. Therefore, miR-199a-5p profibrotic effects were further investigated in cultured lung fibroblasts: miR-199a-5p expression was induced upon TGFβ exposure, and ectopic expression of miR-199a-5p was sufficient to promote the pathogenic activation of pulmonary fibroblasts including proliferation, migration, invasion, and differentiation into myofibroblasts. In addition, we demonstrated that miR-199a-5p is a key effector of TGFβ signaling in lung fibroblasts by regulating CAV1, a critical mediator of pulmonary fibrosis. Remarkably, aberrant expression of miR-199a-5p was also found in unilateral ureteral obstruction mouse model of kidney fibrosis, as well as in both bile duct ligation and CCl4-induced mouse models of liver fibrosis, suggesting that dysregulation of miR-199a-5p represents a general mechanism contributing to the fibrotic process. MiR-199a-5p thus behaves as a major regulator of tissue fibrosis with therapeutic potency to treat fibroproliferative diseases. © 2013 Lino Cardenas et al

Identification of Disparities in Personalized Cancer Care—A Joint Approach of the German WERA Consortium

(1) Background: molecular tumor boards (MTBs) are crucial instruments for discussing and allocating targeted therapies to suitable cancer patients based on genetic findings. Currently, limited evidence is available regarding the regional impact and the outreach component of MTBs; (2) Methods: we analyzed MTB patient data from four neighboring Bavarian tertiary care oncology centers in Würzburg, Erlangen, Regensburg, and Augsburg, together constituting the WERA Alliance. Absolute patient numbers and regional distribution across the WERA-wide catchment area were weighted with local population densities; (3) Results: the highest MTB patient numbers were found close to the four cancer centers. However, peaks in absolute patient numbers were also detected in more distant and rural areas. Moreover, weighting absolute numbers with local population density allowed for identifying so-called white spots—regions within our catchment that were relatively underrepresented in WERA MTBs; (4) Conclusions: investigating patient data from four neighboring cancer centers, we comprehensively assessed the regional impact of our MTBs. The results confirmed the success of existing collaborative structures with our regional partners. Additionally, our results help identifying potential white spots in providing precision oncology and help establishing a joint WERA-wide outreach strategy

Akute Graft-versus-Host-Disease(GvHD) nach allogener Stammzelltransplantation - neue Risikofaktoren und prädiktive Parameter für das Auftreten einer behandlungsbedürftigen GvHD und der transplantationsassoziierten Mortalität

Die Transplantation hämatopoetischer Stammzellen hat in den letzten Jahrzehnten für die Therapie hämatologisch-onkologischer Erkrankungen zunehmend an Bedeutung gewonnen und ist heute integraler Bestandteil vieler Therapiekonzepte. Sie bietet Hochrisikopatienten als primär angestrebte Therapie, häufiger aber als sekundäre Therapie die Chance auf eine dauerhafte Remission. In Anbetracht der hohen transplantationsassoziierten Morbidität und Mortalität ist jedoch vor jeder Transplantation eine sorgfältige Indikationsstellung unter Berücksichtigung von Nutzen und Risiko notwendig. Trotz großer Fortschritte in der Behandlung gilt die Graft-versus-Host-Disease (GvHD) nach wie vor als eine Hauptkomplikation nach allogener Stammzelltransplantation. Sie tritt bei ca. 30-60 % aller Patienten in den ersten Monaten auf und trägt wesentlich zur hohen Frühmortalität bei (Holler et al. 2001). In die vorliegende Arbeit wurden 169 Patienten aus der Abteilung für Hämatologie und internistische Onkologie des Klinikums der Universität Regensburg eingeschlossen, welche sich im Zeitraum zwischen Januar 1998 und November 2003 auf Grund hämatologischer Neoplasien einer allogenen Stammzelltransplantation unterzogen hatten. Zielsetzung war, durch sorgfältige Analyse aller innerhalb des verwendeten Datenerfassungsbogens retrospektiv gesammelten Daten, Faktoren oder Faktorenkonstellationen zu erarbeiten, die eine individuelle Vorhersage für das Auftreten und den Schweregrad der akuten GvH-Reaktion sowie die damit verbundene therapieassoziierte Mortalität ermöglichen. Vergleichbar mit anderen Untersuchungen entwickelten 83% unserer Patienten eine behandlungsbedürftige GvHD vom Grad I-IV, davon 27% eine schwere GvHD vom Grad III-IV. 55 Patienten (61,8% aller Todesfälle) verstarben an transplantationsassoziierten Komplikationen, welche sehr häufig Folge einer GvHD waren. Wie in vorangegangen Studien bereits publiziert, erwies sich auch in unserem Patientenkollektiv ein Patientenalter >45 Jahre sowie ein fortgeschrittenes Tumorstadium zum Zeitpunkt der Transplantation als unabhängige Risikofaktoren der GvHD sowie der transplantationsassoziierten Mortalität. Erstmals konnte im Rahmen der multivariaten Analyse ein CRP >60mg/dl am Tag 10 nach SZT sowie die Anzahl der Fiebertage >2,5 bis zum Erreichen des Take als unabhängige Risikofaktoren für das Auftreten einer GvHD identifiziert werden. Zudem konnte der von Holler et al. (2004, 2006) bereits publizierte Risikofaktor NOD2-Mutation erneut bestätigt werden. So ergab sich für Patienten mit einer Mutation im SNP 8 bzw. für Patienten mit einer Spendermutation im SNP 13 im Vergleich zum restlichen Patientenkollektiv eine signifikant höhere Wahrscheinlichkeit an einer transplantationsassoziierten Komplikation zu versterben (p<0,001) (67,4% vs. 36,9%). Aus den drei genannten Variablen CRP am Tag 10 nach SZT, Anzahl der Fiebertage bis zum Erreichen des Take sowie der NOD2-Mutation bildeten wir einen HIGH-RISK-Score I für das Auftreten einer GvHD. Die Verteilung des Patientenkollektivs in diesem Risiko-Score zeigt einen hochsignifikanten Zusammenhang zwischen dem Gesamtüberleben und den im Score zusammengefassten unabhängigen Risikofaktoren. Unter dem Namen �Combined CRP d0/4� (CRP >75mg/dl am Tag der Cortisongabe und/oder ein CRP >30mg/dl am Tag 4 nach Cortisongabe) bildeten wir eine neue Variable, welche zusammen mit einer Darm-GvHD >I und der NOD2-Mutation ebenfalls als unabhängige Risikofaktoren für die TRM während einer GvHD identifiziert werden konnte. Diese drei Parameter waren die Grundlage für die Entwicklung eines HIGH-RISK-Scores II während des Auftretens einer GvHD, welcher hochsignifikant mit dem Gesamtüberleben unserer Patienten korrelierte. Während bei unseren statistischen Auswertungen ein deutlicher Trend für den Zusammenhang zwischen der Höhe des Fibrinogens und dem Auftreten der therapieassoziierten Mortalität zwar zu erkennen, dies jedoch nicht signifikant war, konnten die Variablen Bilirubin und Pseudocholinersterase als Risikofaktoren der GvHD in unserem Patientenkollektiv nicht nachgewiesen werden. Zuletzt konnte kein Zusammenhang zwischen dem Auftreten von Infektionen während der neutropenischen Phase und der transplantationsassoziierten Mortalität nachgewiesen werden. Mit den Ergebnissen dieser Arbeit wurde die Basis für die Entwicklung neuer, risikoadaptierter First-Line-Therapie-Konzepte gelegt, mit deren Hilfe eine individuellere Behandlung von Patienten mit akuter GvHD nach allogener Stammzelltransplantation und damit eine deutliche Reduktion der Morbidität und Mortalität möglich scheint. Die Ergebnisse werden aktuell in einer prospektiven Multicenterstudie auf ihre Validität überprüft

Multimodal therapy in treatment of rectal cancer is associated with improved survival and reduced local recurrence - a retrospective analysis over two decades

Background The management of rectal cancer (RC) has substantially changed over the last decades with the implementation of neoadjuvant chemoradiotherapy, adjuvant therapy and improved surgery such as total mesorectal excision (TME). It remains unclear in which way these approaches overall influenced the rate of local recurrence and overall survival. Methods Clinical, histological and survival data of 658 out of 662 consecutive patients with RC were analyzed for treatment and prognostic factors from a prospectively expanded single-institutional database. Findings were then stratified according to time of diagnosis in patient groups treated between 1993 and 2001 and 2002 and 2010. Results The study population included 658 consecutive patients with rectal cancer between 1993 and 2010. Follow up data was available for 99.6% of all 662 treated patients. During the time period between 2002 and 2010 significantly more patients underwent neoadjuvant chemoradiotherapy (17.6% vs. 60%) and adjuvant chemotherapy (37.9% vs. 58.4%). Also, the rate of reported TME during surgery increased. The rate of local or distant metastasis decreased over time, and tumor related 5-year survival increased significantly with from 60% to 79%. Conclusion In our study population, the implementation of treatment changes over the last decade improved the patient’s outcome significantly. Improvements were most evident for UICC stage III rectal cancer