Visually normal cells adjacent to, and extending from, tumors of the lung may carry molecular alterations characteristic of the tumor itself - an effect referred to as airway field of cancerization. This airway field has been postulated as a model for early events in lung cancer pathogenesis. Yet the genomic landscape of somatically acquired molecular alterations in airway epithelia of lung cancer patients has remained unknown. To begin to fill this void, we sought to comprehensively characterize the genomic architecture of chromosomal alterations inducing allelic imbalance (AI) in the airway field of the most common type of lung tumors, non-small cell lung cancer (NSCLC). To do so we conducted a genome-wide survey of multiple spatially distributed normal-appearing airways, multi-region tumor specimens and uninvolved normal tissues or blood, from 45 patients with early-stage NSCLC. We detected alterations in airway epithelia from 22 patients, with an increased frequency in NSCLCs of squamous histology. Our data also indicated a spatial gradient of AI in samples at closer proximity to the NSCLC. Chromosome 9 displayed the highest levels of AI and comprised recurrent independent events. Further, the airway field AI included oncogenic gains and tumor suppressor losses in known NSCLC drivers. Our results demonstrate that genome-wide AI is common in the airway field of cancerization, providing insights into early events in the pathogenesis of NSCLC that may comprise targets for early treatment and chemoprevention.
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Cancer Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Δευτέρα 23 Μαΐου 2016
Allelic imbalance in the airway field cancerization
EGFR/cMet bispecific Ab in EGFR TKI resistant lung tumors
Non-small cell lung cancers (NSCLCs) with activating EGFR mutations become resistant to tyrosine kinase inhibitors (TKIs), often through second-site mutations in EGFR (T790M) and/or activation of the cMet pathway. We engineered a bispecific EGFR-cMet antibody (JNJ-61186372) with multiple mechanisms of action to inhibit primary/secondary EGFR mutations and the cMet pathway. JNJ-61186372 blocked ligand-induced phosphorylation of EGFR and cMet and inhibited phospho-ERK and phospho-AKT more potently than the combination of single receptor-binding antibodies. In NSCLC tumor models driven by EGFR and/or cMet, JNJ-61186372 treatment resulted in tumor regression through inhibition of signaling/receptor downmodulation and Fc-driven effector interactions. Complete and durable regression of human lung xenograft tumors was observed with the combination of JNJ-61186372 and a third generation EGFR TKI. Interestingly, treatment of cynomolgus monkeys with JNJ-61186372 resulted in no major toxicities, including absence of skin rash observed with other EGFR-directed agents. These results highlight the differentiated potential of JNJ-61186372 to inhibit the spectrum of mutations driving EGFR TKI resistance in NSCLC.
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TRAP1 and SDH as therapeutic targets of HCC.
S-nitrosoglutathione reductase (GSNOR) represents the best-documented denitrosylase implicated in regulating the levels of proteins post-translationally modified by nitric oxide (NO) on cysteine residues by S-nitrosylation. GSNOR controls a diverse array of physiological functions, including cellular growth and differentiation, inflammation and metabolism. Chromosomal deletion of GSNOR results in pathological protein S-nitrosylation that is implicated in human hepatocellular carcinoma (HCC). Here we identify a metabolic hallmark of aberrant S-nitrosylation in HCC and exploit it for therapeutic gain. We find that hepatocyte GSNOR deficiency is characterized by mitochondrial alteration and by marked increases in succinate dehydrogenase (SDH) levels and activity. We find that this depends on the selective S-nitrosylation of Cys501 in the mitochondrial chaperone TRAP1, which mediates its degradation. As a result, GSNOR-deficient cells and tumors are highly sensitive to SDH inhibition, namely to α-tocopheryl succinate, an SDH-targeting molecule that induced RIP1/PARP1-mediated necroptosis and inhibited tumor growth. Our work provides a specific molecular signature of aberrant S-nitrosylation in HCC and thereby a novel molecular target in SDH, and a first-in-class therapy to treat the disease.
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Pharmacological inhibition of LIMK effect on breast tumors
LIM kinases (LIMK) are emerging targets for cancer therapy and they function as network hubs to coordinate actin and microtubule dynamics. When LIMK are inhibited, actin microfilaments are disorganized and microtubules are stabilized. Owing to their stabilizing effect on microtubules, LIMK inhibitors may provide an therapeutic strategy to treat taxane-resistant cancers. In this study, we investigated the effect of LIMK inhibition on breast tumor development and on paclitaxel resistant tumors, using a novel selective LIMK inhibitor termed Pyr1. Treatment of breast cancer cells, including paclitaxel-resistant cells, blocked their invasion and proliferation in vitro and their growth in vivo in tumor xenograft assays. The tumor invasive properties of Pyr1 were investigated in vivo by intravital microscopy of tumor xenografts. A striking change in cell morphology was observed with a rounded phenotype arising in a subpopulation of cells while other cells remained elongated. Notably, although Pyr1 decreased the motility of elongated cells it increased the motility of rounded cells in the tumor. Pyr1 administration prevented the growth of metastasis but not their spread. Overall, our results provided a preclinical proof of concept concerning how a small molecule inhibitor of LIMK kinases may offer a strategy to treat taxane-resistant breast tumors and metastases.
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Dicer represses AXL and elicits paclitaxel sensitization
Paclitaxel is a standard-of-care chemotherapy for breast cancer, despite the increasing recognition of its poor effectiveness in the treatment of patients with advanced disease. Here we report that adenovirus type 5 E1A-mediated elevation of the microRNA processing enzyme Dicer is sufficient to enhance paclitaxel sensitization and reduce cancer stem-like cell properties in this setting. Elevating Dicer expression increased levels of the AXL kinase targeting microRNA miR-494, thereby repressing AXL expression to increase paclitaxel sensitivity. We found that Dicer expression was regulated at the transcription level by E1A, through activation of a MAPK14/CEBPα pathway. Our findings define a mechanism of E1A-mediated chemosensitization for paclitaxel which is based upon the suppression of breast cancer stem-like cells, with potential implications for the diagnosis and treatment of breast cancer patients.
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YAP promotes tumirogenesis via activation of EGFR
The Hippo-YAP pathway has emerged as a major driver of tumorigenesis in many human cancers. YAP is a transcriptional co-activator and while details of YAP regulation are quickly emerging, it remains unknown what downstream targets are critical for YAP's oncogenic functions. To determine the mechanisms involved and identify disease-relevant targets, we examined YAP's role in neurofibromatosis type 2 (NF2) using cell and animal models. We found that YAP function is required for NF2-null Schwann cell survival, proliferation and tumor growth in vivo. Moreover, YAP promotes transcription of several targets including PTGS2, which codes for COX-2, a key enzyme in prostaglandin biosynthesis, and AREG, which codes for the EGFR ligand, amphiregulin. Both AREG and prostaglandin E2 converge to activate signaling through EGFR. Importantly, treatment with the COX-2 inhibitor Celecoxib significantly inhibited the growth of NF2-null Schwann cells and tumor growth in a mouse model of NF2.
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Regulation of AR by miR-320
Targeting androgen receptor (AR) by pharmacological intervention is one of the effective approaches for treatment of malignant prostate cancers. Histone deacetylase (HDAC) alters the epigenetic status of tumor-associated genes, including those for microRNAs (miRNAs), and affects the behavior of cancers. Here, we examined the molecular effects of a HDAC inhibitor, OBP-801, on AR expression and tumor cell growth in prostate cancers. Treatment with OBP-801 efficiently suppressed cell growth of three prostate cancer lines (22Rv1, VCaP, and LNCaP), together with AR downregulation, regardless of their hormone sensitivity. Intriguingly, this effect by OBP-801 was not due to decreased transcriptional activity of the AR gene, but due to post-transcriptional regulation, namely by miRNA-mediated suppression. Among the upregulated miRNAs after OBP-801 treatment in the three prostate cancer cell lines, miR-320a, whose expression was significantly correlated with prognosis of prostate cancers (P=0.0185), was the most closely associated with AR expression. An miR-320a mimic suppressed AR protein expression together with growth suppression, while anti-miR-320a oligonucleotide significantly abrogated the growth suppression by OBP-801 treatment. Fluorescent in situ hybridization analysis revealed that miR-320a was highly expressed in human normal prostate luminal cells, but was rarely expressed in prostate cancer cells. In an AR-dependent prostate tumorigenic rat model, OBP-801 treatment profoundly increased miR-320a expression and repressed prostate tumorigenesis. Our data demonstrated that OBP-801 effectively suppressed AR activity via epigenetic upregulation of miR-320a, which resulted in tumor cell growth suppression of prostate cancers. OBP-801 may be a potent AR-targeting therapeutic reagent in AR-positive prostate cancer regardless of androgen dependency.
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Enhanced antiproliferative effects of Mito-Metformin
Metformin (Met) is an approved antidiabetic drug currently being explored for repurposing in cancer treatment based on recent evidence of its apparent chemopreventive properties. Met is weakly cationic and targets the mitochondria to induce cytotoxic effects in tumor cells, albeit not very effectively. We hypothesized that increasing its mitochondria-targeting potential by attaching a positively-charged lipophilic substituent would enhance the antitumor activity of Met. In pursuit of this question, we synthesized a set of mitochondria-targeted Met analogs (Mito-Mets) with varying alkyl chain lengths containing a triphenylphosphonium cation (TPP+). In particular, the analog Mito-Met10, synthesized by attaching TPP+ to Met via a 10-carbon aliphatic side chain, was nearly 1,000 times more efficacious than Met at inhibiting cell proliferation in pancreatic ductal adenocarcinoma (PDAC). Notably, in PDAC cells Mito-Met10 potently inhibited mitochondrial complex I, stimulating superoxide and AMPK activation, but had no effect in non-transformed control cells. Moreover, Mito-Met10 potently triggered G1 cell cycle phase arrest in PDAC cells, enhanced their radiosensitivity and more potently abrogated PDAC growth in preclinical mouse models, compared to Met. Collectively, our findings show how improving the mitochondrial targeting of Met enhances its anticancer activities, including in aggressive cancers like PDAC in great need of more effective therapeutic options.
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Genetic evolution of early-stage metastatic melanoma
Cancer genome sequencing has shed light on the underlying genetic aberrations that drive tumorigenesis. However, current sequencing-based strategies, which focus on a single tumor biopsy, fail to take into account intratumoral heterogeneity. To address this challenge and elucidate the evolutionary history of melanoma, we performed whole-exome and transcriptome sequencing of 41 multiple melanoma biopsies from eight individual tumors. This approach revealed heterogeneous somatic mutations in the range of 3-38% in individual tumors. Known mutations in melanoma drivers BRAF and NRAS were always ubiquitous events. Using RNA sequencing, we found that the majority of mutations were not expressed or were expressed at very low levels, and preferential expression of a particular mutated allele did not occur frequently. In addition, we found that the proportion of ultraviolet B (UVB) radiation-induced C>T transitions differed significantly (P<0.001) between early and late mutation acquisition, suggesting that different mutational processes operate during the evolution of metastatic melanoma. Finally, clinical history reports revealed that patients harboring a high degree of mutational heterogeneity were associated with more aggressive disease progression. In conclusion, our multi-region tumor sequencing approach highlights the genetic evolution and non-UVB mutational signatures associated with melanoma development and progression, and may provide a more comprehensive perspective of patient outcome.
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Adipocyte exosomes: a new link between obesity and cancer
Malignant progression results from a dynamic cross-talk between stromal and cancer cells. Recent evidence suggests that this cross-talk is mediated to a significant extent by exosomes, nanovesicles secreted by most cell types and which allow the transfer of proteins, lipids and nucleic acids between cells. Adipocytes are a major component of several tumor microenvironments including that of invasive melanoma, where cells have migrated to the adipocyte-rich hypodermic layer of the skin. We show that adipocytes secrete exosomes in abundance, which are then taken up by tumor cells, leading to increased migration and invasion. Using mass spectrometry, we analyzed the proteome of adipocyte exosomes. Interestingly, these vesicles carry proteins implicated in fatty acid oxidation (FAO), a feature highly specific to adipocyte exosomes. We further show that, in the presence of adipocyte exosomes, FAO is increased in melanoma cells. Inhibition of this metabolic pathway completely abrogates the exosome-mediated increase in migration. Moreover, in obese mice and humans, both the number of exosomes secreted by adipocytes as well as their effect on FAO-dependent cell migration are amplified. These observations might in part explain why obese melanoma patients have a poorer prognosis than their non-obese counterparts.
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Omentin as a Novel Biomarker for Colorectal Cancer Risk
Omentin is a novel biomarker shown to exert metabolic, inflammatory and immune-related properties, and thereby could be implicated in the risk of colorectal cancer (CRC). So far, the association between omentin and CRC risk has not been evaluated in prospective cohort studies. We investigated the association between pre-diagnostic plasma omentin concentrations and risk of CRC in a case-cohort comprising 251 incident CRC cases diagnosed over a mean follow-up time of 10.4 years and 2,295 persons who remained free of cancer in the European Prospective Investigation into Cancer and Nutrition-Potsdam study. Hazard ratios as a measure of relative risk (RR) and 95% confidence intervals (CI-s) were computed using a Prentice modified Cox regression. In a model adjusted for established CRC risk factors, age, sex, education, dietary and lifestyle factors, body mass index (BMI) and waist circumference, higher omentin concentrations were associated with a higher CRC risk (RRcontinuously per doubling of omentin concentrations=1.98, 95%CI: 1.45-2.73). Additional adjustment for metabolic biomarkers, including glycated hemoglobin, high-density lipoprotein cholesterol and C-reactive protein, did not alter the results. In stratified analyses, the positive association between omentin and CRC risk was retained in participants with BMI< 30 (RRcontinuously per doubling of omentin concentrations=2.26; 95%CI: 1.57-3.27), whereas among participants with BMI{greater than or equal to} 30 no association was revealed (RRcontinuously per doubling of omentin concentrations =1.07; 95%CI: 0.63-1.83; Pinteraction= 0.005). These novel findings provide the first lines of evidence for an independent association between pre-diagnostic omentin concentrations and CRC risk and suggest a potential interaction with the adiposity state of the individual.
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K14 HPV49 E6/E7 transgenic mice
The beta genus of human papillomaviruses (ß-HPV) includes approximately 50 different viral types that are subdivided into five species (ß-1 through ß-5). Non-melanoma cancers may involve some ß-1 and ß-2 HPV types, but the biology of most ß-HPV types and their possible connections to human disease are still little characterized. In this study, we studied the effects of ß-3 type HPV49 in a novel transgenic (Tg) mouse model, using a cytokeratin K14 promoter to drive expression of the E6 and E7 genes from this virus in the basal skin epidermis and the mucosal epithelia of the digestive tract (K14 HPV49 E6/E7-Tg mice). Viral oncogene expression only marginally increased cellular proliferation in the epidermis of Tg animals, compared with wild-type (WT) littermates, and we observed no spontaneous tumor formation during their entire lifespan. However, we found that K14 HPV49 E6/E7-Tg mice were highly susceptible to upper digestive tract carcinogenesis upon initiation with 4-nitroquinoline 1-oxide (4NQO). This was a selective effect, as the same mice did not exhibit any skin lesions after chronic UV irradiation. Opposite results were observed in an analogous Tg model expressing the ß-2 HPV38 E6 and E7 oncogenes at the same anatomical sites. While these mice were highly susceptible to UV-induced skin carcinogenesis, as previously shown, they were little affected by 4NQO treatment. Overall, our findings highlight important differences in the biological properties of certain ß-type HPV that affect their impact on carcinogenesis in an anatomical site-specific manner.
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Metabolic reprogramming of cancer cells
Somatic copy number alterations frequently occur in the cancer genome affecting not only oncogenic or tumor suppressive genes, but also passenger and potential co-driver genes. An intrinsic feature resulting from such genomic perturbations is the deregulation in the metabolism of tumor cells. In this study, we have shown that metabolic and cancer causing genes are unexpectedly often proximally positioned in the chromosome and share loci with co-altered copy numbers across multiple cancers (19 cancer types from The Cancer Genome Atlas). We have developed an analysis pipeline - Identification of Metabolic Cancer Genes (iMetCG), to infer the functional impact on metabolic remodeling from such co-amplifications and co-deletions and delineate genes driving cancer metabolism from those that are neutral. Using our identified metabolic genes we were able to classify tumors based on their tissue and developmental origins. These metabolic genes were similar to known cancer genes in terms of their network connectivity, isoform frequency and evolutionary features. We further validated these identified metabolic genes by (i) using gene essentiality data from several tumor cell-lines, (ii) showing that these identified metabolic genes are strong indicators for patient survival, and (iii) observing a significant overlap between our identified metabolic genes and known cancer metabolic genes. Our analyses revealed a hitherto unknown generic mechanism for large-scale metabolic reprogramming in cancer cells based on linear gene proximities between cancer causing and metabolic genes. We have identified 119 new metabolic cancer genes likely to be involved in rewiring cancer cell metabolism.
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Thyroid cancer imaging in vivo
The high prevalence of thyroid nodules in the adult population and the relatively low incidence of thyroid cancer make the preoperative identification of malignant lesions challenging. The β-galactoside binding protein galectin-3 is widely expressed in well- differentiated thyroid carcinomas, but not in normal thyrocytes and benign thyroid nodules. This molecule offers a candidate biomarker to improve thyroid cancer diagnosis. Here we report the development of an immunoPET approach for noninvasive imaging of thyroid cancer. The method employs a 89Zr-labeled monoclonal antibody to galectin-3 which shows high specificity and binding affinity in vitro. Reliable and specific immunoPET imaging was obtained of thyroid cancer in vivo in murine xenograft models of human thyroid cancer. Our findings provide a method to improve the clinical management of patients with thyroid nodules while reducing unnecessary surgery and social costs.
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Integrin beta3 and immune suppression in cancer
Integrin beta3 is critical for tumor invasion, neoangiogenesis, and inflammation making it a promising cancer target. However, preclinical and clinical data of integrin beta3 antagonists have demonstrated no benefit or worse outcomes. We hypothesized that integrin beta3 could affect tumor immunity and evaluated tumors in mice with deletion of integrin beta3 in macrophage lineage cells (β3KOM). β3KOM mice had increased melanoma and breast cancer growth with increased tumor-promoting M2 macrophages and decreased CD8+ T-cells. Integrin beta3 antagonist, cilengitide, also enhanced tumor growth and increased M2 function. We uncovered a negative feedback loop in M2 myeloid cells wherein integrin beta3 signaling favored STAT1 activation, an M1 polarizing signal, and suppressed M2 polarizing STAT6 activation. Finally, disruption of CD8+ T-cells, macrophages, or macrophage integrin beta3 signaling blocked the tumor-promoting effects of integrin beta3 antagonism. These results suggest that effects of integrin beta3 therapies on immune cells should be considered to improve outcomes.
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Three-dimensional tumor progression model
Tumor size is strongly correlated with breast cancer metastasis and patient survival. Increased tumor size contributes to hypoxic and metabolic gradients in the solid tumor and to an aggressive tumor phenotype. Thus, it is important to develop three-dimensional (3D) breast tumor models that recapitulate size-induced microenvironmental changes and consequently, natural tumor progression in real time without the use of artificial culture conditions or gene manipulations. Here, we developed size-controlled multicellular aggregates ("microtumors") of subtype-specific breast cancer cells by using non-adhesive polyethylene glycol dimethacrylate hydrogel microwells of defined sizes (150-600 μm). These 3D microtumor models faithfully represent size-induced microenvironmental changes such as hypoxic gradients, cellular heterogeneity and spatial distribution of necrotic/proliferating cells. These microtumors acquire hallmarks of tumor progression in the same cell lines within 6 days. Of note, large microtumors of hormone receptor positive cells exhibited an aggressive phenotype characterized by collective cell migration and upregulation of mesenchymal markers at mRNA and protein level, which was not observed in small microtumors. Interestingly, triple negative breast cancer (TNBC) cell lines did not show size-dependent upregulation of mesenchymal markers. In conclusion, size-controlled microtumor models successfully recapitulated clinically observed positive association between tumor size and aggressive phenotype in hormone receptor positive breast cancer while maintaining clinically proven poor correlation of tumor size with aggressive phenotype in TNBC. Such clinically relevant 3D models generated under controlled experimental conditions can serve as precise preclinical models to study mechanisms involved in breast tumor progression as well as antitumor drug effects as a function of tumor progression.
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Psychological Distress and Posttraumatic Stress Symptoms in Adolescents and Young Adults with Cancer and Their Parents
Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.
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Relationship between Efficacy Outcomes and Weight Gain during Treatment of Advanced, Nonsquamous, Non-small Cell Lung Cancer Patients
Weight gain was compared to outcomes in patients with advanced nonsquamous NSCLC using pooled data from three phase III trials. Weight gain of >5% occurred after initiation of platinum-based chemotherapy in 18% of patients. This subgroup exhibited a positive correlation between weight gain and improved survival (p<0.001). Weight gain during treatment may be an early indicator of clinical benefit.
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How to report toxicity associated with targeted therapies?
For cytotoxic drugs, the incidence of AE was traditionally reported as frequency and intensity. This simple measure is not sufficient to summarize AE for MTT. Prevalence permits to obtain a time profile of AE and Q-TWiST assesses the "risk-benefit" ratio of a treatment. These methods are helpful for physicians in their treatment choice, to counsel patients and to optimize supportive care .
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PAN-EX: A pooled analysis of two trials of neoadjuvant chemotherapy followed by chemoradiotherapy in MRI-defined, locally advanced rectal cancer
This analysis confirms that administering neoadjuvant chemotherapy (NACT) before chemoradiotherapy (CRT) could be a potential option for high-risk, locally advanced rectal cancer. In this setting, MRI tumour regression grade is an independent prognostic factor and, when assessed after NACT, may predict the probability and magnitude of incremental benefit from sequential CRT.
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Frequent PD-L1 expression in primary and metastatic penile squamous cell carcinoma: potential opportunities for immunotherapeutic approaches
Novel immunotherapeutics that target tumor PD-L1 expression are emerging treatment options for patients with advanced cancer. In this study, we show that the majority of penile squamous cell carcinomas (SqCC) express PD-L1, which is associated with high-risk clinicopathologic features and poor clinical outcome. These data provide a rational basis for immunotherapeutics in advanced penile SqCC.
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Oral health and risk of colorectal cancer: results from three cohort studies and a meta-analysis
Data from three large prospective cohort studies and a meta-analysis did not support that oral health plays a major role in the development of colorectal cancer.
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Application of Metal Implant 16-Bit Imaging: New Technique in Radiotherapy
Objective:
This study aimed to evaluate the computed tomography number and the variation of dose distribution based on 12-bit, 16-bit, and revised 16-bit images while the metal bars were inserted.
Methods:The phantoms containing stainless steel, titanium alloy, and aluminum bar were scanned with computed tomography. These images were reconstructed with 12-bit and 16-bit imaging technologies. The "cupping artifacts" computed tomography value of the metal object revised by Matlab software was called the revised 16-bit image. The computed tomography values of these metal materials were analyzed. Two radiotherapy treatment plans were designed using the treatment plan system: (1) gantry was of 0° irradiation field and (2) gantry was of 90° and 270° for 2 opposed irradiation fields. The dose profile and dose–volume histogram of a structure of interest were analyzed in various images. The analysis was based on the radiotherapy plan differences between 3 different imaging techniques (12-bit imaging, 16-bit imaging, and revised 16-bit imaging technologies).
Results:For low-density metal object (computed tomography value <3071 Hounsfield unit, HU), the radiotherapy plan results were consistent based on 3 different imaging techniques. For high-density metal object (computed tomography value >3071 HU), the difference in radiotherapy plan results was obvious. The dose of 12-bit was 15.9% higher than revised 16-bit on average for the downstream of titanium rod. For stainless steel, this number reached up to 42.7%.
Conclusion:A 16-bit imaging technology of metal implants can distinguish the computed tomography value of different metal materials. Furthermore, the revised 16-bit imaging technology can improve the dose computational accuracy of radiotherapy plan with high-density metal implants.
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Accelerated Brain DCE-MRI Using Iterative Reconstruction With Total Generalized Variation Penalty for Quantitative Pharmacokinetic Analysis: A Feasibility Study
Purpose:
To investigate the feasibility of using undersampled k-space data and an iterative image reconstruction method with total generalized variation penalty in the quantitative pharmacokinetic analysis for clinical brain dynamic contrast-enhanced magnetic resonance imaging.
Methods:Eight brain dynamic contrast-enhanced magnetic resonance imaging scans were retrospectively studied. Two k-space sparse sampling strategies were designed to achieve a simulated image acquisition acceleration factor of 4. They are (1) a golden ratio–optimized 32-ray radial sampling profile and (2) a Cartesian-based random sampling profile with spatiotemporal-regularized sampling density constraints. The undersampled data were reconstructed to yield images using the investigated reconstruction technique. In quantitative pharmacokinetic analysis on a voxel-by-voxel basis, the rate constant K trans in the extended Tofts model and blood flow F B and blood volume V B from the 2-compartment exchange model were analyzed. Finally, the quantitative pharmacokinetic parameters calculated from the undersampled data were compared with the corresponding calculated values from the fully sampled data. To quantify each parameter's accuracy calculated using the undersampled data, error in volume mean, total relative error, and cross-correlation were calculated.
Results:The pharmacokinetic parameter maps generated from the undersampled data appeared comparable to the ones generated from the original full sampling data. Within the region of interest, most derived error in volume mean values in the region of interest was about 5% or lower, and the average error in volume mean of all parameter maps generated through either sampling strategy was about 3.54%. The average total relative error value of all parameter maps in region of interest was about 0.115, and the average cross-correlation of all parameter maps in region of interest was about 0.962. All investigated pharmacokinetic parameters had no significant differences between the result from original data and the reduced sampling data.
Conclusion:With sparsely sampled k-space data in simulation of accelerated acquisition by a factor of 4, the investigated dynamic contrast-enhanced magnetic resonance imaging pharmacokinetic parameters can accurately estimate the total generalized variation-based iterative image reconstruction method for reliable clinical application.
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Online Tool Helps Users Distinguish Moles from Melanoma
As Melanoma/Skin Cancer Detection and Prevention Month comes to a close and summer begins, NCI has launched a new online tool called Moles to Melanoma: Recognizing the ABCDE Features.
The new tool is intended to help educate the public about the appearance and features of common moles (nevi), which pose no health risk, as well as those of atypical moles (dysplastic nevi), which can increase melanoma risk, and actual melanomas.
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Combined effect of tobacco smoking and alcohol drinking in the risk of head and neck cancers: a re-analysis of case–control studies using bi-dimensional spline models
Abstract
The synergistic effect of tobacco smoking and alcohol consumption on the risk of head and neck cancers has been mainly investigated as a cross-product of categorical exposure, thus leading to loss of information. We propose a bi-dimensional logistic spline model to investigate the interacting dose–response relationship of two continuous exposures (i.e., ethanol intake and tobacco smoking) on the risk of head and neck cancers, representing results through three-dimensional graphs. This model was applied to a pool of hospital-based case–control studies on head and neck cancers conducted in Italy and in the Vaud Swiss Canton between 1982 and 2000, including 1569 cases and 3147 controls. Among never drinkers and for all levels of ethanol intake, the risk of head and neck cancers steeply increased with increasing smoking intensity, starting from 1 cigarette/day. The risk associated to ethanol intake increased with incrementing exposure among smokers, and a threshold effect at approximately 50 g/day emerged among never smokers. Compared to abstainers from both tobacco and alcohol consumption, the combined exposure to ethanol and/or cigarettes led to a steep increase of cancer risk up to a 35-fold higher risk (95 % confidence interval 27.30–43.61) among people consuming 84 g/day of ethanol and 10 cigarettes/day. The highest risk was observed at the highest levels of alcohol and tobacco consumption. Our findings confirmed a combined effect of tobacco smoking and alcohol drinking on head and neck cancers risk, providing evidence that bi-dimensional spline models could be a feasible and flexible method to explore the pattern of risks associated to two interacting continuous-exposure variables.
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Carotenoid intake and head and neck cancer: a pooled analysis in the International Head and Neck Cancer Epidemiology Consortium
Abstract
Food and nutrition play an important role in head and neck cancer (HNC) etiology; however, the role of carotenoids remains largely undefined. We explored the relation of HNC risk with the intake of carotenoids within the International Head and Neck Cancer Epidemiology Consortium. We pooled individual-level data from 10 case–control studies conducted in Europe, North America, and Japan. The analysis included 18,207 subjects (4414 with oral and pharyngeal cancer, 1545 with laryngeal cancer, and 12,248 controls), categorized by quintiles of carotenoid intake from natural sources. Comparing the highest with the lowest quintile, the risk reduction associated with total carotenoid intake was 39 % (95 % CI 29–47 %) for oral/pharyngeal cancer and 39 % (95 % CI 24–50 %) for laryngeal cancer. Intakes of β-carotene equivalents, β-cryptoxanthin, lycopene, and lutein plus zeaxanthin were associated with at least 18 % reduction in the rate of oral and pharyngeal cancer (95 % CI 6–29 %) and 17 % reduction in the rate of laryngeal cancer (95 % CI 0–32 %). The overall protective effect of carotenoids on HNC was stronger for subjects reporting greater alcohol consumption (p < 0.05). The odds ratio for the combined effect of low carotenoid intake and high alcohol or tobacco consumption versus high carotenoid intake and low alcohol or tobacco consumption ranged from 7 (95 % CI 5–9) to 33 (95 % CI 23–49). A diet rich in carotenoids may protect against HNC. Persons with both low carotenoid intake and high tobacco or alcohol are at substantially higher risk of HNC.
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Real-World Analysis of Medical Costs and Healthcare Resource Utilization in Elderly Women with HR+/HER2− Metastatic Breast Cancer Receiving Everolimus-Based Therapy or Chemotherapy
Abstract
Introduction
The objective of this study was to analyze medical costs and healthcare resource utilization (HRU) associated with everolimus-based therapy or chemotherapy among elderly women with hormone-receptor-positive, human-epidermal-growth-factor-receptor-2-negative (HR+/HER2−) metastatic breast cancer (mBC).
Methods
Elderly women (≥65 years) with HR+/HER2− mBC who failed a non-steroidal-aromatase-inhibitor and subsequently began a new line of treatment with everolimus-based therapy or chemotherapy for mBC (index therapy) during July 20, 2012 to March 31, 2014 were identified from two large commercial claims databases. All-cause, BC-, and adverse event (AE)-related medical costs (2014 USD), and all-cause and AE-related HRU per patient per month (PPPM) were compared between patients treated with everolimus-based therapy and chemotherapy across their first four lines of therapy for mBC. Adjusted costs and HRU differences were estimated by pooling all lines and using multivariable models adjusted for differences in patient characteristics.
Results
In total, 925 elderly patients (mean age approximately 73 years) with HR+/HER2− mBC met the inclusion criteria; 230 received everolimus-based therapy (240 lines) and 737 received chemotherapy (939 lines). Compared with chemotherapy, everolimus-based therapy was associated with significantly lower total all-cause PPPM medical services costs (adjusted mean difference: $4007), driven by lower inpatient ($1994) and outpatient ($1402) costs; lower BC-related medical services costs ($3129), driven by both BC-related inpatient ($1883) and outpatient costs ($913); and lower AE-related medical services costs ($1873; all P < 0.01). Additionally, compared to patients treated with chemotherapy, patients treated with everolimus-based therapy had fewer all-cause outpatient visits (adjusted incidence rate ratio = 0.69), BC-related outpatient visits (0.66), other-medical-service visits (0.65), and AE-related HRU (0.59), which was driven by significantly fewer AE-related outpatient visits (0.56; all P < 0.01). Subgroup analyses comparing medical costs of everolimus-based therapy with capecitabine monotherapy showed consistent results overall.
Conclusion
This retrospective claims database analysis of elderly women with HR+/HER2− mBC in the United States showed that everolimus-based therapy was associated with significantly lower all-cause, BC-related, and AE-related medical services costs and less use of healthcare resources compared with chemotherapy.
Funding
Novartis.
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Periodontal diseases and risk of oral cancer in Southern India: Results from the HeNCe Life study
Abstract
Some studies suggest that periodontal diseases may increase the risk of oral cancer, but contradictory results also exist. Inadequate control of confounders, including life course exposures, may have influenced prior findings. We estimate the extent to which high levels of periodontal disease, measured by gingival inflammation and recession, are associated with oral cancer risk using a comprehensive subset of potential confounders and applying a stringent adjustment approach. In a hospital-based case-control study, incident oral cancer cases (N=350) were recruited from two major referral hospitals in Kerala, South India, from 2008 to 2012. Controls (N=371), frequency-matched by age and sex, were recruited from clinics at the same hospitals. Structured interviews collected information on several domains of exposure via detailed life course questionnaires. Periodontal diseases, as measured by gingival inflammation and gingival recession, were evaluated visually by qualified dentists following a detailed protocol. The relationship between periodontal diseases and oral cancer risk was assessed by unconditional logistic regression using a stringent empirical selection of potential confounders corresponding to a 1% change-in-estimates. Generalized gingival recession was significantly associated with oral cancer risk (Odds Ratio=1.83, 95% Confidence Interval: 1.10-3.04). No significant association was observed for gingival inflammation and oral cancer. Our findings support the hypothesis that high levels of periodontal diseases increase the risk of oral cancer. This article is protected by copyright. All rights reserved.
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Vitronectin and dermcidin serum levels predict the metastatic progression of AJCC I-II early stage melanoma
Abstract
Like many cancers, an early diagnosis of melanoma is fundamental to ensure a good prognosis, although an important proportion of stage I-II patients may still develop metastasis during follow-up. The aim of this work was to discover serum biomarkers in patients diagnosed with primary melanoma that identify those at a high risk of developing metastasis during the follow-up period. Proteomic and mass spectrophotometry analysis was performed on serum obtained from patients who developed metastasis during the first years after surgery for primary tumors and compared with that from patients who remained disease-free for more than 10 years after surgery. Five proteins were selected for validation as prognostic factors in 348 melanoma patients and 100 controls by ELISA: Serum Amyloid A and Clusterin, immune system proteins; the cell adhesion molecules Plakoglobin and Vitronectin; and the antimicrobial protein Dermcidin. Compared to healthy controls, melanoma patients have high serum levels of these proteins at the moment of melanoma diagnosis, although the specific values were not related to the histopathological stage of the tumors. However, an analysis based on classification together with multivariate statistics showed that tumor stage, Vitronectin and Dermcidin levels were associated with the metastatic progression of patients with early-stage melanoma. Although melanoma patients have increased serum Dermcidin levels, the REPTree classifier showed that levels of Dermcidin <2.98 μg/ml predict metastasis in AJCC stage II patients. These data suggest that Vitronectin and Dermcidin are potent biomarkers of prognosis, which may help improve the personalized medical care of melanoma patients and their survival. This article is protected by copyright. All rights reserved.
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Effects of CYP3A5 polymorphism on the pharmacokinetics of a once-daily modified-release tacrolimus formulation and acute kidney injury in hematopoietic stem cell transplantation
Abstract
Background
Tacrolimus is metabolized by cytochrome P450 (CYP) 3A4 and 3A5. We investigated the influence of CYP3A5 polymorphism and concurrent use of azole antifungal agents (AZ) on the pharmacokinetics of a once-daily modified-release tacrolimus formulation (Tac-QD) in patients after hematopoietic stem cell transplantation (HSCT).
Design and methods
Twenty-four patients receiving allogeneic HSCT were enrolled. Genotyping for CYP3A5*3 was done by a PCR-restriction fragment length polymorphism method. Trough blood concentrations (C0) of tacrolimus were measured by chemiluminescence magnetic microparticle immunoassay. Continuous infusion of tacrolimus was administered from the day before transplantation and was switched to Tac-QD after adequate oral intake.
Results
Thirteen patients had a CYP3A5*3/*3 genotype, and 11 patients had a CYP3A5*1/*1 or *1/*3 genotype. No significant difference was observed in daily dosages and the C0 of tacrolimus between the two genotype groups without AZ. However, in patients who were co-administered AZ, the C0 values of tacrolimus were higher in patients with the CYP3A5*3/*3 allele than with the CYP3A5*1 allele (P = 0.034), although daily doses of Tac-QD in patients with CYP3A5*3/*3 were significantly lower than those with the CYP3A5*1 allele (P = 0.041). The cumulative incidence of acute kidney injury was higher in patients with the CYP3A5*3/*3 than with the CYP3A5*1 allele when AZ was co-administered. The decrement for daily dosage of Tac-QD was significantly greater in patients expressing the CYP3A5*3/*3 than the CYP3A5*1 allele.
Conclusions
CYP3A5 genotyping may be useful for safe and effective immunosuppressive therapy with Tac-QD in HSCT patients in whom the use of AZ is anticipated.
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Transarterial chemoembolization of hepatocellular carcinoma in a rat model: the effect of additional injection of survivin siRNA to the treatment protocol
Abstract
Background
Transarterial chemoembolization is one of the most widely accepted interventional treatment options for treatment of hepatocellular carcinoma. Still there is a lack of a standard protocol regarding the injected chemotherapeutics. Survivin is an inhibitor of Apoptosis protein that functions to inhibit apoptosis, promote proliferation, and enhance invasion. Survivin is selectively up-regulated in many human tumors. Small interfering RNA (siRNA) can trigger an RNA interference response in mammalian cells and induce strong inhibition of specific gene expression including Survivin. The aim of the study is to assess the effectiveness of the additional injection of Survivin siRNA to the routine protocol of Transarterial Chemoembolization (TACE) for the treatment of hepatocellular carcinoma in a rat model.
Methods
The study was performed on 20 male ACI rats. On day 0 a solid Morris Hepatoma 3924A was subcapsullary implanted in the liver. On day 12 MRI measurement of the initial tumor volume (V1) was performed. TACE was performed on day 13. The rats were divided into 2 groups; Group (A, n = 10) in which 0.1 mg mitomycin, 0.1 ml lipiodol and 5.0 mg degradable starch microspheres were injected in addition 2.5 nmol survivin siRNA were injected. The same agents were injected in Group (B,=10) without Survivin siRNA. MRI was repeated on day 25 to assess the tumor volume (V2). The tumor growth ratio (V2/V1) was calculated. Western blot and immunohistochemical analysis were performed.
Results
For group A the mean tumor growth ratio (V2/V1) was 1.1313 +/− 0.1381, and was 3.1911 +/− 0.1393 in group B. A statistically significant difference between both groups was observed regarding the inhibition of tumor growth (P < 0.0001) where Group A showed more inhibition compared to Group B. Similarly immunohistochemical analysis showed significantly lower (p < 0.002) VEGF staining in group A compared to group B. Western Blot analysis showed a similar difference in VEGF expression (P < 0.0001).
Conclusion
The additional injection of Survivin siRNA to the routine TACE protocol increased the inhibition of the hepatocellular carcinoma growth in a rat animal model compared to regular TACE protocol.
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Progesterone receptor blockade in human breast cancer cells decreases cell cycle progression through G2/M by repressing G2/M genes
Abstract
Background
The synthesis of specific, potent progesterone antagonists adds potential agents to the breast cancer prevention and treatment armamentarium. The identification of individuals who will benefit from these agents will be a critical factor for their clinical success.
Methods
We utilized telapristone acetate (TPA; CDB-4124) to understand the effects of progesterone receptor (PR) blockade on proliferation, apoptosis, promoter binding, cell cycle progression, and gene expression. We then identified a set of genes that overlap with human breast luteal-phase expressed genes and signify progesterone activity in both normal breast cells and breast cancer cell lines.
Results
TPA administration to T47D cells results in a 30 % decrease in cell number at 24 h, which is maintained over 72 h only in the presence of estradiol. Blockade of progesterone signaling by TPA for 24 h results in fewer cells in G2/M, attributable to decreased expression of genes that facilitate the G2/M transition. Gene expression data suggest that TPA affects several mechanisms that progesterone utilizes to control gene expression, including specific post-translational modifications, and nucleosomal organization and higher order chromatin structure, which regulate access of PR to its DNA binding sites.
Conclusions
By comparing genes induced by the progestin R5020 in T47D cells with those increased in the luteal-phase normal breast, we have identified a set of genes that predict functional progesterone signaling in tissue. These data will facilitate an understanding of the ways in which drugs such as TPA may be utilized for the prevention, and possibly the therapy, of human breast cancer.
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Comparative efficacy of graded doses of diaminazine aceturate and fixed doses of iron dextran and vitamin B complex in mice infected with Trypanosoma brucei brucei
Abstract
Trypanosomosis is a disease of both domestic animals and man. Trypanosomosis continues to be a menace in the livestock industry in Nigeria despite the agelong attempt to control the disease. The comparative effects of graded doses of diaminazine aceturate (DA) and fixed doses of iron dextran and vitamin B complex were experimentally investigated in the treatment of Trypanosoma brucei brucei-infected albino mice. A total of 40 albino mice were used and were randomly divided into eight groups of five mice each. All the mice in all the groups except group H were infected with T. brucei brucei, but group H served as the negative control. Groups A and B were treated with graded doses of DA at 3.5 and 7 mg/kg body weight (bw), respectively, groups C, D, E and F were treated as follows: 3.5 mg/kg bw DA and 1 ml/10 kg bw iron dextran, 7.0 mg/kg bw DA plus 1 ml/10 kg bw iron dextran, 3.5 mg/kg bw DA, 1 ml/10 kg bw iron dextran and 1 ml/10 kg bw vitamin B complex and 7.0 mg/kg bw DA, 1 ml/10 kg bw iron dextran and 1 ml/10 kg bw vitamin B complex, respectively. Group G served as the infected untreated control. Parameters used to assess the effect of the drugs include rectal temperature, body weight changes, packed cell volumes, haemoglobin concentration, daily parasitaemia, clinical signs and survivability. By day 5 PI, all the infected mice had become parasitaemic but following treatment on day 7 PI, the parasites cleared from the blood of the mice in group B and D within 42 hours, groups A, C, E and F before 96 h. There was a significant reduction (P < 0.05) in the mean body weight, packed cell volume and haemoglobin concentration and an increase in rectal temperature following infection but these were reversed by the various treatments. Iron dextran and vitamin B complex were combined with DA, there were improvement in their values, suggesting that combining trypanosomosis therapy with iron dextran and vitamin B complex will help in restoring the physiology of the animal.
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Therapeutic drug monitoring of 5-fluorouracil
Abstract
Purpose
For over 50 years, 5-FU has played a critical role in the systemic chemotherapy of cancer patients. 5-FU serves as the main backbone of combination chemotherapy for patients with colorectal cancer in both the adjuvant and metastatic disease settings. Herein, we review the current status of 5-FU therapeutic drug monitoring (TDM) and discuss its potential role in the clinical practice setting.
Method
PubMed and abstracts from the American Society of Clinical Oncology were searched up through September 2015 for clinical data relating to 5-FU TDM.
Results
5-FU dosing has been typically determined by using body surface area (BSA). However, it is now well established that BSA-based 5-FU dosing is correlated with a wide variation of 5-FU systemic exposure. Pharmacokinetic (PK) studies of 5-FU systemic exposure have shown a wide range of interpatient variation of 5-FU plasma drug levels. Over the past 30 years, increasing efforts have been placed on optimizing 5-FU dosing with the main goals of increasing antitumor efficacy while reducing drug-associated toxicity. There is growing evidence to show that 5-FU dosing based on plasma 5-FU drug level is feasible and that 5-FU TDM can improve clinical outcomes by improving efficacy of 5-FU-based combination regimens and reducing toxicities.
Conclusion
Dose adjustment of 5-FU is feasible, and PK-based dosing can significantly improve clinical outcomes by reducing toxicities and improving efficacy.
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Effects of CYP3A5 polymorphism on the pharmacokinetics of a once-daily modified-release tacrolimus formulation and acute kidney injury in hematopoietic stem cell transplantation
Abstract
Background
Tacrolimus is metabolized by cytochrome P450 (CYP) 3A4 and 3A5. We investigated the influence of CYP3A5 polymorphism and concurrent use of azole antifungal agents (AZ) on the pharmacokinetics of a once-daily modified-release tacrolimus formulation (Tac-QD) in patients after hematopoietic stem cell transplantation (HSCT).
Design and methods
Twenty-four patients receiving allogeneic HSCT were enrolled. Genotyping for CYP3A5*3 was done by a PCR-restriction fragment length polymorphism method. Trough blood concentrations (C0) of tacrolimus were measured by chemiluminescence magnetic microparticle immunoassay. Continuous infusion of tacrolimus was administered from the day before transplantation and was switched to Tac-QD after adequate oral intake.
Results
Thirteen patients had a CYP3A5*3/*3 genotype, and 11 patients had a CYP3A5*1/*1 or *1/*3 genotype. No significant difference was observed in daily dosages and the C0 of tacrolimus between the two genotype groups without AZ. However, in patients who were co-administered AZ, the C0 values of tacrolimus were higher in patients with the CYP3A5*3/*3 allele than with the CYP3A5*1 allele (P = 0.034), although daily doses of Tac-QD in patients with CYP3A5*3/*3 were significantly lower than those with the CYP3A5*1 allele (P = 0.041). The cumulative incidence of acute kidney injury was higher in patients with the CYP3A5*3/*3 than with the CYP3A5*1 allele when AZ was co-administered. The decrement for daily dosage of Tac-QD was significantly greater in patients expressing the CYP3A5*3/*3 than the CYP3A5*1 allele.
Conclusions
CYP3A5 genotyping may be useful for safe and effective immunosuppressive therapy with Tac-QD in HSCT patients in whom the use of AZ is anticipated.
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Combined effect of tobacco smoking and alcohol drinking in the risk of head and neck cancers: a re-analysis of case–control studies using bi-dimensional spline models
Abstract
The synergistic effect of tobacco smoking and alcohol consumption on the risk of head and neck cancers has been mainly investigated as a cross-product of categorical exposure, thus leading to loss of information. We propose a bi-dimensional logistic spline model to investigate the interacting dose–response relationship of two continuous exposures (i.e., ethanol intake and tobacco smoking) on the risk of head and neck cancers, representing results through three-dimensional graphs. This model was applied to a pool of hospital-based case–control studies on head and neck cancers conducted in Italy and in the Vaud Swiss Canton between 1982 and 2000, including 1569 cases and 3147 controls. Among never drinkers and for all levels of ethanol intake, the risk of head and neck cancers steeply increased with increasing smoking intensity, starting from 1 cigarette/day. The risk associated to ethanol intake increased with incrementing exposure among smokers, and a threshold effect at approximately 50 g/day emerged among never smokers. Compared to abstainers from both tobacco and alcohol consumption, the combined exposure to ethanol and/or cigarettes led to a steep increase of cancer risk up to a 35-fold higher risk (95 % confidence interval 27.30–43.61) among people consuming 84 g/day of ethanol and 10 cigarettes/day. The highest risk was observed at the highest levels of alcohol and tobacco consumption. Our findings confirmed a combined effect of tobacco smoking and alcohol drinking on head and neck cancers risk, providing evidence that bi-dimensional spline models could be a feasible and flexible method to explore the pattern of risks associated to two interacting continuous-exposure variables.
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Carotenoid intake and head and neck cancer: a pooled analysis in the International Head and Neck Cancer Epidemiology Consortium
Abstract
Food and nutrition play an important role in head and neck cancer (HNC) etiology; however, the role of carotenoids remains largely undefined. We explored the relation of HNC risk with the intake of carotenoids within the International Head and Neck Cancer Epidemiology Consortium. We pooled individual-level data from 10 case–control studies conducted in Europe, North America, and Japan. The analysis included 18,207 subjects (4414 with oral and pharyngeal cancer, 1545 with laryngeal cancer, and 12,248 controls), categorized by quintiles of carotenoid intake from natural sources. Comparing the highest with the lowest quintile, the risk reduction associated with total carotenoid intake was 39 % (95 % CI 29–47 %) for oral/pharyngeal cancer and 39 % (95 % CI 24–50 %) for laryngeal cancer. Intakes of β-carotene equivalents, β-cryptoxanthin, lycopene, and lutein plus zeaxanthin were associated with at least 18 % reduction in the rate of oral and pharyngeal cancer (95 % CI 6–29 %) and 17 % reduction in the rate of laryngeal cancer (95 % CI 0–32 %). The overall protective effect of carotenoids on HNC was stronger for subjects reporting greater alcohol consumption (p < 0.05). The odds ratio for the combined effect of low carotenoid intake and high alcohol or tobacco consumption versus high carotenoid intake and low alcohol or tobacco consumption ranged from 7 (95 % CI 5–9) to 33 (95 % CI 23–49). A diet rich in carotenoids may protect against HNC. Persons with both low carotenoid intake and high tobacco or alcohol are at substantially higher risk of HNC.
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Systemic manifestations of hepatitis C infection
Abstract
Chronic hepatitis C (HCV) is a common infection affecting 185 million people worldwide. The most common manifestation of chronic HCV is progressive liver fibrosis, cirrhosis, liver failure and hepatocellular carcinoma. However, several systemic manifestations of HCV have been recognized and reported in the literature. The purpose of this review is to assimilate published literature based on evidence to categorize these extrahepatic manifestations with the likelihood of a causal association with HCV. Exciting recent developments have resulted in simple all oral interferon-free highly effective therapy for HCV. However, this treatment is also expensive and less accessible to most affected individuals as treatment recommendations are based on stage of liver fibrosis. Expanding the scope of HCV therapy to those with extrahepatic manifestations beyond what is currently recommended will significantly reduce the morbidity and mortality in this aging population.
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EphrinB2/EphB4 pathway in postnatal angiogenesis: a potential therapeutic target for ischemic cardiovascular disease
Abstract
Ischemic cardiovascular disease remains one of the leading causes of morbidity and mortality in the world. Proangiogenic therapy appears to be a promising and feasible strategy for the patients with ischemic cardiovascular disease, but the results of preclinical and clinical trials are limited due to the complicated mechanisms of angiogenesis. Facilitating the formation of functional vessels is important in rescuing the ischemic cardiomyocytes. EphrinB2/EphB4, a novel pathway in angiogenesis, plays a critical role in both microvascular growth and neovascular maturation. Hence, investigating the mechanisms of EphrinB2/EphB4 pathway in angiogenesis may contribute to the development of novel therapeutics for ischemic cardiovascular disease. Previous reviews mainly focused on the role of EphrinB2/EphB4 pathway in embryo vascular development, but their role in postnatal angiogenesis in ischemic heart disease has not been fully illustrated. Here, we summarized the current knowledge of EphrinB2/EphB4 in angiogenesis and their interaction with other angiogenic pathways in ischemic cardiovascular disease.
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MicroRNA in late lung development and bronchopulmonary dysplasia: the need to demonstrate causality
Abstract
MicroRNA are emerging as powerful regulators of cell differentiation and tissue and organ development. Several microRNA have been described to play a role in branching morphogenesis, a key step in early lung development. However, considerably less attention has been paid to microRNA as regulators of the process of secondary septation, which drives lung alveolarization during late lung development. Secondary septation is severely perturbed in bronchopulmonary dysplasia (BPD), a common complication of preterm birth characterized by blunted alveolarization. A number of studies to date have reported microRNA microarray screens in animal models of BPD; however, only two studies have attempted to demonstrate causality. Although the expression of miR-150 was altered in experimental BPD, a miR-150−/− knockout mouse did not exhibit appreciable protection in a BPD animal model. Similarly, while the expression of miR-489 in the lung was reduced in clinical and experimental BPD, antagomiR and over-expression approaches could not validate a role for miR-489 in the impaired alveolarization associated with experimental BPD. This mini-review aims to highlight microRNA that have been revealed by multiple microarray studies to be potential causal players in normal and pathological alveolarization. Additionally, the challenges faced in attempting to demonstrate a causal role for microRNA in lung alveolarization are discussed. These include the tremendous variability in the animal models employed, and the limitations and advantages offered by the available tools, including antagomiRs and approaches for the validation of a specific microRNA-mRNA interaction during lung alveolarization.
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Second-Line Palliative Chemotherapy in Advanced Gall Bladder Cancer, CAP-IRI: Safe and Effective Option
Abstract
Introduction
Gall bladder cancer (GBC) has high prevalence in the Indo-Gangetic belt in India. While the first-line chemotherapy (CT1) has been established as gemcitabine–platinum doublet in advanced GBC, there is no standard recommendation or guidelines regarding feasibility of second-line therapy.
Methods
We performed a retrospective analysis of all patients who received second-line of chemotherapy (CT2) at our institution from July 2012 to December 2014. Patient records were examined for efficacy and toxicity of administered CT2, along with response rates (RR) and survival. Potential prognostic factors were also evaluated.
Results
Eighty-seven patients received CT2 in the predefined period. Ninety-nine percent of patients had received a gemcitabine-based regimen as CT1 with a median progression-free survival (PFS) of 5 months before CT2. 51.7 % patients had undergone surgery prior with 5.7 % patients having received radiotherapy previously. Prior to beginning CT2, PS was 0/1 in 67.8 % patients, albumin was >4 g% in 40.2 % and CA 19.9 was raised in a majority (66.7 %) patients, respectively. As per institution protocol, a majority of patients (89.6 %) were administered CAP-IRI regimen. Overall RR and disease control rates (DCR) were 21.8 % and 41.3 %, respectively. Median progression-free survival (PFS) and overall survival (OS) were 6 and 8 months, with no significant differences between CAP-IRI and other regimens. Adverse effects were tolerable, with dose reduced upfront in 23 % patients and 11.5 % patients during subsequent cycles of CT. ECOG Performance Status (PS) of 0/1 was a significant prognostic variable for OS on multivariate analysis (p = 0.003).
Conclusion
CAP-IRI is a well-tolerated second-line chemotherapeutic regimen in patients with advanced GBC. Careful selection of patients is required when administering second-line chemotherapy to advanced GBC patients, with particular emphasis on ECOG PS.
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Personalised Treatment in Gastric Cancer: Myth or Reality?
Abstract
Despite recent diagnostic and therapeutic advances, the survival of patients with gastric cancer is still poor. The majority of patients are diagnosed with advanced disease and chemotherapy represents the only possible therapeutic approach. However, chemotherapy seems to have reached an efficacy plateau in this setting. Gastric cancer is a complex and heterogeneous disease because it emerges from multiple interactions of genetic, environmental and host factors. A better understanding of its molecular characteristics may lead to an improvement of outcomes. The recent molecular classification by The Cancer Genome Atlas project divides gastric cancer into four subtypes that could be taken into consideration in future clinical trials with targeted agents. So far trastuzumab, a monoclonal antibody addressing the HER2 receptor, is the only targeted agent approved in the first-line setting, but only in patients overexpressing HER2. Negative data have been obtained in first-line therapy when antiangiogenics, anti-EGFR or anti-MET monoclonal antibodies have been studied in randomised controlled trials. Ramucirumab, a monoclonal antibody binding to VEGFR2, is the only antiangiogenic agent currently recommended in patients progressing after first-line treatment. In this review, we discuss whether personalised therapy may have a role in gastric cancer.
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A Novel Approach to the Nutrigenetics and Nutrigenomics of Obesity and Weight Management
Abstract
Nutrigenetics and nutrigenomics, as well as diet and exercise, play an important role in the development and treatment of obesity and its comorbidities. If an individual's susceptibility to becoming obese and their responsiveness to weight loss interventions are to be understood, then it needs to be addressed at a molecular and metabolic level, including genetic interaction. This review proposes a three-pillar approach to more fully comprehend the complexity of diet-gene interactions in obesity. Peroxisomal proliferating-activated receptor gamma (PPARG) and mitochondrial uncoupling protein-1 (UCP-1) are explored in detail. Illustrating how an understanding of nutritional biochemistry, nutrigenomics, and nutrigenetics may be the key to understanding differences observed in the obese phenotype that vary both within and across populations.
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Influences of BRAF Inhibitors on the Immune Microenvironment and the Rationale for Combined Molecular and Immune Targeted Therapy
Abstract
The identification of key driver mutations in melanoma has led to the development of targeted therapies aimed at BRAF and MEK, but responses are often limited in duration. There is growing evidence that MAPK pathway activation impairs antitumor immunity and that targeting this pathway may enhance responses to immunotherapies. There is also evidence that immune mechanisms of resistance to targeted therapy exist, providing the rationale for combining targeted therapy with immunotherapy. Preclinical studies have demonstrated synergy in combining these strategies, and combination clinical trials are ongoing. It is, however, becoming clear that additional translational studies are needed to better understand toxicity, proper timing, and sequence of therapy, as well as the utility of multidrug regimens and effects of other targeted agents on antitumor immunity. Insights gained through translational research in preclinical models and clinical studies will provide mechanistic insight into therapeutic response and resistance and help devise rational strategies to enhance therapeutic responses.
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The Use of Medical Marijuana in Cancer
Abstract
The use of medical marijuana in cancer care presents a dilemma for both patients and physicians. The scientific evidence is evolving, yet much of the known information is still insufficient to adequately inform patients as to risks and benefits. In addition, evidence-based dosing and administration information on medical marijuana is lacking. Medical marijuana is now legal, on some level, in 24 states plus the District of Columbia, yet is not legal on the federal level. This review addresses the current state of the research, including potential indications, risks and adverse effects, preliminary data on anticancer effects, as well as legal and quality issues. A summary of the clinical trials underway on medical marijuana in the oncology setting is discussed.
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Contemporary management of fibrolamellar hepatocellular carcinoma: diagnosis, treatment, outcome, prognostic factors, and recent developments
Abstract
Fibrolamellar hepatocellular carcinoma (FL-HCC) is a malignant liver tumor which is thought to be a variant of conventional hepatocellular carcinoma (HCC). It accounts for a small proportion of HCC cases and occurs in a distinctly different group of patients which are young and usually not in the setting of chronic liver disease. The diagnosis of FL-HCC requires the integration of clinical information, imaging studies, and histology. In terms of the treatment options, the only potentially curative treatment option for patients who have resectable disease is surgery either liver resection (LR) or liver transplantation (LT). When performed in a context of aggressive therapy, long-term outcomes after surgery, particularly liver resection for FL-HCC, were favorable. The clinical outcome of patients with unresectable disease is suboptimal with median survival of less than 12 months. The aim of this review is to update the available evidence on diagnosis, treatment options, outcome predictors, and recent developments of patients with this rare disease and to provide a summarized overview of the available literature.
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Serial transperineal sector prostate biopsies: impact on long-term erectile dysfunction
James JY Chong, Mieke Van Hemelrijck, Declan Cahill and Janette Kinsella
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Cancers, Vol. 8, Pages 52: The MYC 3′ Wnt-Responsive Element Drives Oncogenic MYC Expression in Human Colorectal Cancer Cells
Mutations in components of the Wnt/β-catenin signaling pathway drive colorectal cancer (CRC) by deregulating expression of downstream target genes including the c-MYC proto-oncogene (MYC). The critical regulatory DNA enhancer elements that control oncogenic MYC expression in CRC have yet to be fully elucidated. In previous reports, we correlated T-cell factor (TCF) and β-catenin binding to the MYC 3′ Wnt responsive DNA element (MYC 3′ WRE) with MYC expression in HCT116 cells. Here we used CRISPR/Cas9 to determine whether this element is a critical driver of MYC. We isolated a clonal population of cells that contained a deletion of a single TCF binding element (TBE) within the MYC 3′ WRE. This deletion reduced TCF/β-catenin binding to this regulatory element and decreased MYC expression. Using RNA-Seq analysis, we found altered expression of genes that regulate metabolic processes, many of which are known MYC target genes. We found that 3′ WRE-Mut cells displayed a reduced proliferative capacity, diminished clonogenic growth, and a decreased potential to form tumors in vivo. These findings indicate that the MYC 3′ WRE is a critical driver of oncogenic MYC expression and suggest that this element may serve as a therapeutic target for CRC.
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