Hybrid metaheuristic for combinatorial optimization based on immune network for optimization and VNS

Metaheuristics for optimization based on the immune network theory are often highlighted by being able to maintain the diversity of candidate solutions present in the population, allowing a greater coverage of the search space. This work, however, shows that algorithms derived from the aiNET family for the solution of combinatorial problems may not present an adequate strategy for search space exploration, leading to premature convergence in local minimums. In order to solve this issue, a hybrid metaheuristic called VNS-aiNET is proposed, integrating aspects of the COPT-aiNET algorithm with characteristics of the trajectory metaheuristic Variable Neighborhood Search (VNS), as well as a new fitness function, which makes it possible to escape from local minima and enables it to a greater exploration of the search space. The proposed metaheuristic is evaluated using a scheduling problem widely studied in the literature. The performed experiments show that the proposed hybrid metaheuristic presents a convergence superior to two approaches of the aiNET family and to the reference algorithms of the literature. In contrast, the solutions present in the resulting immunological memory have less diversity when compared to the aiNET family approaches

Beneficial autoimmunity at body surfaces – immune surveillance and rapid type 2 immunity regulate tissue homeostasis and cancer

Epithelial cells line body surface tissues and provide a physicochemical barrier to the external environment. Frequent microbial and non-microbial challenges such as those imposed by mechanical disruption, injury or exposure to noxious environmental substances including chemicals, carcinogens, ultraviolet-irradiation or toxins cause activation of epithelial cells with release of cytokines and chemokines as well as alterations in the expression of cell surface ligands. Such display of epithelial stress is rapidly sensed by tissue resident immunocytes, which can directly interact with self-moieties on epithelial cells and initiate both local and systemic immune responses. Epithelial cells are thus key drivers of immune surveillance at body surface tissues. However, epithelial cells have a propensity to drive type 2 immunity (rather than type 1) upon non-invasive challenge or stress – a type of immunity whose regulation and function still remain enigmatic. Here we review the induction and possible role of type 2 immunity in epithelial tissues and propose that rapid immune surveillance and type 2 immunity are key regulators of tissue homeostasis and carcinogenesis

Amino-acid PET versus MRI guided re-irradiation in patients with recurrent glioblastoma multiforme (GLIAA) – protocol of a randomized phase II trial (NOA 10/ARO 2013-1)

Background: The higher specificity of amino-acid positron emission tomography (AA-PET) in the diagnosis of gliomas, as well as in the differentiation between recurrence and treatment-related alterations, in comparison to contrast enhancement in T1-weighted MRI was demonstrated in many studies and is the rationale for their implementation into radiation oncology treatment planning. Several clinical trials have demonstrated the significant differences between AA-PET and standard MRI concerning the definition of the gross tumor volume (GTV). A small single-center non-randomized prospective study in patients with recurrent high grade gliomas treated with stereotactic fractionated radiotherapy (SFRT) showed a significant improvement in survival when AA-PET was integrated in target volume delineation, in comparison to patients treated based on CT/MRI alone. Methods: This protocol describes a prospective, open label, randomized, multi-center phase II trial designed to test if radiotherapy target volume delineation based on FET-PET leads to improvement in progression free survival (PFS) in patients with recurrent glioblastoma (GBM) treated with re-irradiation, compared to target volume delineation based on T1Gd-MRI. The target sample size is 200 randomized patients with a 1:1 allocation ratio to both arms. The primary endpoint (PFS) is determined by serial MRI scans, supplemented by AA-PET-scans and/or biopsy/surgery if suspicious of progression. Secondary endpoints include overall survival (OS), locally controlled survival (time to local progression or death), volumetric assessment of GTV delineated by either method, topography of progression in relation to MRIor PET-derived target volumes, rate of long term survivors (> 1 year), localization of necrosis after re-irradiation, quality of life (QoL) assessed by the EORTC QLQ-C15 PAL questionnaire, evaluation of safety of FET-application in AA-PET imaging and toxicity of re-irradiation. Discussion: This is a protocol of a randomized phase II trial designed to test a new strategy of radiotherapy target volume delineation for improving the outcome of patients with recurrent GBM. Moreover, the trial will help to develop a standardized methodology for the integration of AA-PET and other imaging biomarkers in radiation treatment planning. Trial registration: The GLIAA trial is registered with ClinicalTrials.gov (NCT01252459, registration date 02.12.2010), German Clinical Trials Registry (DRKS00000634, registration date 10.10.2014), and European Clinical Trials Database (EudraCT-No. 2012-001121-27, registration date 27.02.2012)

Implementation of neuro-oncology service reconfiguration in accordance with NICE guidance provides enhanced clinical care for patients with glioblastoma multiforme.

BACKGROUND: Brain tumours account for <2% of all primary neoplasms but are responsible for 7% of the years of life lost from cancer before age 70 years. The latest survival trends for patients with CNS malignancies have remained largely static. The objective of this study was to evaluate the change in practice as a result of implementing the Improving Outcomes Guidance from the UK National Institute for Health and Clinical Excellence (NICE). METHODS: Patients were identified from the local cancer registry and hospital databases. We compared time from diagnosis to treatment, proportion of patients discussed at multidisciplinary team (MDT) meetings, treatment received, length of inpatient stay and survival. Inpatient and imaging costs were also estimated. RESULTS: Service reconfiguration and implementation of NICE guidance resulted in significantly more patients being discussed by the MDT--increased from 66 to 87%, reduced emergency admission in favour of elective surgery, reduced median hospital stay from 8 to 4.5 days, increased use of post-operative MRI from 17 to 91% facilitating early discharge and treatment planning, and reduced cost of inpatient stay from £2096 in 2006 to £1316 in 2009. Patients treated with optimal surgery followed by radiotherapy with concomitant and adjuvant temozolomide achieved outcomes comparable to those reported in clinical trials: median overall survival 18 months (2-year survival 35%). CONCLUSIONS: Advancing the management of neuro-oncology patients by moving from an emergency-based system of patient referral and management to a more planned elective outpatient-based pattern of care improves patient experience and has the potential to deliver better outcomes and research opportunities

Cytogerontology since 1881: A reappraisal of August Weismann and a review of modern progress

Cytogerontology, the science of cellular ageing, originated in 1881 with the prediction by August Weismann that the somatic cells of higher animals have limited division potential. Weismann's prediction was derived by considering the role of natural selection in regulating the duration of an organism's life. For various reasons, Weismann's ideas on ageing fell into neglect following his death in 1914, and cytogerontology has only reappeared as a major research area following the demonstration by Hayflick and Moorhead in the early 1960s that diploid human fibroblasts are restricted to a finite number of divisions in vitro. In this review we give a detailed account of Weismann's theory, and we reveal that his ideas were both more extensive in their scope and more pertinent to current research than is generally recognised. We also appraise the progress which has been made over the past hundred years in investigating the causes of ageing, with particular emphasis being given to (i) the evolution of ageing, and (ii) ageing at the cellular level. We critically assess the current state of knowledge in these areas and recommend a series of points as primary targets for future research

Metabolism within the tumor microenvironment and its implication on cancer progression: an ongoing therapeutic target

Since reprogramming energy metabolism is considered a new hallmark of cancer, tumor metabolism is again in the spotlight of cancer research. Many studies have been carried out and many possible therapies have been developed in the last years. However, tumor cells are not alone. A series of extracellular components and stromal cells, such as endothelial cells, cancer-associated fibroblasts, tumor-associated macrophages and tumor-infiltrating T cells, surround tumor cells in the so-called tumor microenvironment. Metabolic features of these cells are being studied in deep in order to find relationships between metabolism within the tumor microenvironment and tumor progression. Moreover, it cannot be forgotten that tumor growth is able to modulate host metabolism and homeostasis, so that tumor microenvironment is not the whole story. Importantly, the metabolic switch in cancer is just a consequence of the flexibility and adaptability of metabolism and should not be surprising. Treatments of cancer patients with combined therapies including anti-tumor agents with those targeting stromal cell metabolism, anti-angiogenic drugs and/or immunotherapy are being developed as promising therapeutics.Mª Carmen Ocaña is recipient of a predoctoral FPU grant from the Spanish Ministry of Education, Culture and Sport. Supported by grants BIO2014-56092-R (MINECO and FEDER), P12-CTS-1507 (Andalusian Government and FEDER) and funds from group BIO-267 (Andalusian Government). The "CIBER de Enfermedades Raras" is an initiative from the ISCIII (Spain). The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript

Anti-cancer effects and mechanism of actions of aspirin analogues in the treatment of glioma cancer

INTRODUCTION: In the past 25 years only modest advancements in glioma treatment have been made, with patient prognosis and median survival time following diagnosis only increasing from 3 to 7 months. A substantial body of clinical and preclinical evidence has suggested a role for aspirin in the treatment of cancer with multiple mechanisms of action proposed including COX 2 inhibition, down regulation of EGFR expression, and NF-κB signaling affecting Bcl-2 expression. However, with serious side effects such as stroke and gastrointestinal bleeding, aspirin analogues with improved potency and side effect profiles are being developed. METHOD: Effects on cell viability following 24 hr incubation of four aspirin derivatives (PN508, 517, 526 and 529) were compared to cisplatin, aspirin and di-aspirin in four glioma cell lines (U87 MG, SVG P12, GOS – 3, and 1321N1), using the PrestoBlue assay, establishing IC50 and examining the time course of drug effects. RESULTS: All compounds were found to decrease cell viability in a concentration and time dependant manner. Significantly, the analogue PN517 (IC50 2mM) showed approximately a twofold increase in potency when compared to aspirin (3.7mM) and cisplatin (4.3mM) in U87 cells, with similar increased potency in SVG P12 cells. Other analogues demonstrated similar potency to aspirin and cisplatin. CONCLUSION: These results support the further development and characterization of novel NSAID derivatives for the treatment of glioma

Biological impact of geometric uncertainties: what margin is needed for intra-hepatic tumors?

<p>Abstract</p> <p>Background</p> <p>To evaluate and compare the biological impact on different proposed margin recipes for the same geometric uncertainties for intra-hepatic tumors with different tumor cell types or clinical stages.</p> <p>Method</p> <p>Three different margin recipes based on tumor motion were applied to sixteen IMRT plans with a total of twenty two intra-hepatic tumors. One recipe used the full amplitude of motion measured from patients to generate margins. A second used 70% of the full amplitude of motion, while the third had no margin for motion. The biological effects of geometric uncertainty in these three situations were evaluated with Equivalent Uniform Doses (EUD) for various survival fractions at 2 Gy (SF₂).</p> <p>Results</p> <p>There was no significant difference in the biological impact between the full motion margin and the 70% motion margin. Also, there was no significant difference between different tumor cell types. When the margin for motion was eliminated, the difference of the biological impact was significant among different cell types due to geometric uncertainties. Elimination of the motion margin requires dose escalation to compensate for the biological dose reduction due to the geometric misses during treatment.</p> <p>Conclusions</p> <p>Both patient-based margins of full motion and of 70% motion are sufficient to prevent serious dosimetric error. Clinical implementation of margin reduction should consider the tumor sensitivity to radiation.</p

[(18)F]Fluoroethyltyrosine- positron emission tomography-guided radiotherapy for high-grade glioma

BACKGROUND: To compare morphological gross tumor volumes (GTVs), defined as pre- and postoperative gadolinium enhancement on T1-weighted magnetic resonance imaging to biological tumor volumes (BTVs), defined by the uptake of (18)F fluoroethyltyrosine (FET) for the radiotherapy planning of high-grade glioma, using a dedicated positron emission tomography (PET)-CT scanner equipped with three triangulation lasers for patient positioning. METHODS: Nineteen patients with malignant glioma were included into a prospective protocol using FET PET-CT for radiotherapy planning. To be eligible, patients had to present with residual disease after surgery. Planning was performed using the clinical target volume (CTV = GTV union or logical sum BTV) and planning target volume (PTV = CTV + 20 mm). First, the interrater reliability for BTV delineation was assessed among three observers. Second, the BTV and GTV were quantified and compared. Finally, the geometrical relationships between GTV and BTV were assessed. RESULTS: Interrater agreement for BTV delineation was excellent (intraclass correlation coefficient 0.9). Although, BTVs and GTVs were not significantly different (p = 0.9), CTVs (mean 57.8 +/- 30.4 cm(3)) were significantly larger than BTVs (mean 42.1 +/- 24.4 cm(3); p &lt; 0.01) or GTVs (mean 38.7 +/- 25.7 cm(3); p &lt; 0.01). In 13 (68%) and 6 (32%) of 19 patients, FET uptake extended &gt;or= 10 and 20 mm from the margin of the gadolinium enhancement. CONCLUSION: Using FET, the interrater reliability had excellent agreement for BTV delineation. With FET PET-CT planning, the size and geometrical location of GTVs and BTVs differed in a majority of patients

Study of TLR3, TLR4 and TLR9 in breast carcinomas and their association with metastasis

<p>Abstract</p> <p>Background</p> <p>Toll-like receptors (TLRs) have garnered an extraordinary amount of interest in cancer research due to their role in tumor progression. By activating the production of several biological factors, TLRs induce type I interferons and other cytokines, which drive an inflammatory response and activate the adaptive immune system. The aim of this study was to investigate the expression and clinical relevance of TLR3, 4 and 9 in breast cancer.</p> <p>Methods</p> <p>The expression levels of TLR3, TLR4 and TLR9 were analyzed on tumors from 74 patients with breast cancer. The analysis was performed by immunohistochemistry.</p> <p>Results</p> <p>Samples of carcinomas with recurrence exhibited a significant increase in the mRNA levels of TLR3, TLR4 and TLR9. Tumors showed high expression of TLRs expression levels by cancer cells, especially TLR4 and 9. Nevertheless, a significant percentage of tumors also showed TLR4 expression by mononuclear inflammatory cells (21.6%) and TLR9 expression by fibroblast-like cells (57.5%). Tumors with high TLR3 expression by tumor cell or with high TLR4 expression by mononuclear inflammatory cells were significantly associated with higher probability of metastasis. However, tumours with high TLR9 expression by fibroblast-like cells were associated with low probability of metastasis.</p> <p>Conclusions</p> <p>The expression levels of TLR3, TLR4 and TLR9 have clinical interest as indicators of tumor aggressiveness in breast cancer. TLRs may represent therapeutic targets in breast cancer.</p