New combination immunotherapies are displaying both efficacy and immune-related adverse events (irAEs) in humans. However, grade 3/4 irAEs occur in a high proportion, which can lead to discontinuation of treatment and can result in fatalities if not promptly treated. Prolonged T regulatory cell (Treg) depletion in tumor bearing Foxp3-DTR mice using diphtheria toxin (DT) mirrored the spectrum of anti-tumor responses and severity of irAEs that can occur in ipilimumab/nivolumab treated patients. In contrast, transient Treg depletion or anti-CTLA-4/PD-1 therapy had equivalent effects in mice, lowering the immune tolerance threshold and allowing irAEs to be more easily induced following treatment with additional immunomodulatory antibodies. Transient Treg depletion of DT in combination with anti-PD-1 or anti-TIM-3 monoclonal antibodies (mAbs) had a high therapeutic window compared to DT plus anti-CD137. In contrast, DT plus anti-CD137 treated mice ddeveloped severe irAEs similar to grade 3/4 clinical symptoms. These irAEs appeared due to an infiltration of activated proliferating effector T cells in the tissues producing IFNγ and TNF, however, TNF blockade decreased irAEs severity without impacting on tumor growth.
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Cancer Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Δευτέρα 8 Αυγούστου 2016
Assessing therapeutic window of combination immunotherapies
Gene-fusions in Barrett's-associated neoplasia
Esophageal adenocarcinoma (EAC) is a deadly cancer with increasing incidence in the U.S., but mechanisms underlying pathogenesis are still mostly elusive. In addressing this question, we assessed gene-fusion landscapes by comprehensive RNA sequencing (RNAseq) of 55 pre-treatment EAC and 49 non-malignant biopsy tissues from patients undergoing endoscopy for Barrett's esophagus. In this cohort, we identified 21 novel candidate EAC-associated fusions occurring in 3.33%-11.67% of EACs. Two candidate fusions were selected for validation by PCR and Sanger sequencing in an independent set of pre-treatment EAC (N=115) and non-malignant (N=183) biopsy tissues. In particular, we observed RPS6KB1-VMP1 gene fusion as a recurrent event occurring in ~10% of EAC cases. Notably, EAC cases harboring RPS6KB1-VMP1 fusions exhibited significantly poorer overall survival as compared to fusion-negative cases. Mechanistic investigations established that the RPS6KB1-VMP1 transcript coded for a fusion protein which significantly enhanced the growth rate of non-dysplastic Barrett's esophagus cells. Compared to the wild-type VMP1 protein, which mediates normal cellular autophagy, RPS6KB1-VMP1 fusion exhibited aberrant subcellular localization and was relatively ineffective in triggering autophagy. Overall, our findings identified RPS6KB1-VMP1 as a genetic fusion that promotes EAC by modulating autophagy-related processes, offering new insights into the molecular pathogenesis of esophageal adenocarcinomas.
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Higher Rate of Severe Toxicities in Obese Patients Receiving dose-dense (dd) Chemotherapy according to Unadjusted Body Surface Area- Results of the Prospectively Randomized GAIN study
Obese patients receiving dose-dense (dd) chemotherapy according to their real body surface area (BSA) are at higher risk for severe toxicities. However, efficacy is not influenced by relative total dose intensity. Therefore, dose adjustment of dd chemotherapy is warranted in obese patients to avoid complications.
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Prognostic value of tumor-infiltrating lymphocytes differs depending on histological type and smoking habit in completely resected non-small cell lung cancer
A lower number of CD8+ in Non AD, a higher FOXP3/CD4 ratio in smokers with AD, and a lower number of CD20+ in nonsmokers with AD were identified as independent worse prognostic factors in patients with resected NSCLC. Evaluating the influence of histological type and cigarette smoke on the immunological environment may lead to the establishment of individualized immunotherapy for patients with NSCLC.
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Towards the molecular dissection of peritoneal pseudomyxoma
In this translational study, we identified and validated KRAS mutations (but not GNAS mutations) as a poor prognostic factor in patients treated with peritonectomy and HIPEC for peritoneal pseudomyxoma.
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Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer
Final results from the randomised phase III TANIA trial in bevacizumab-pretreated metastatic breast cancer showed that although adding bevacizumab to second- and third-line chemotherapy significantly improved second-line progression-free survival (PFS) versus chemotherapy alone, third-line PFS and overall survival (secondary end points) were not significantly improved with continued bevacizumab.
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FERTILITY-SPARING SURGERY IN EPITHELIAL OVARIAN CANCER: A SYSTEMATIC REVIEW OF ONCOLOGICAL ISSUES
Conservative treatment to preserve fertility in ovarian cancer can be safely performed for stage IA and IC grade 1 and 2 disease and stage IC1 according to the new FIGO staging system. For patients with "less favourable" prognostic factors (grade 3, stage IC3 disease, clear cell tumour), the safety of FSS could not be confirmed but patients should be informed that radical treatment probably may not necessarily improve their oncological outcome. FSS should remain contraindicated for stage II/III disease (whatever the histologic subtype).
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Predictors of chemotherapy efficacy in Non-Small Cell Lung Cancer : a challenging landscape
The majority of non-small cell lung cancer (NSCLC) tumours do not present targetable driver mutations, and less than 25% of NSCLC patients derive benefit from immunotherapy. Therefore, conventional cytotoxic chemotherapy (CCC) remains the cornerstone treatment for NSCLC patients. Predictive biomarkers of CCC able to identify chemosensitive patients and select appropriate drug combinations are crucially lacking. Such biomarkers would also be helpful to limit toxicities, decrease overall costs, and hopefully improve patient outcome. A variety of biomarkers have been evaluated either in the pre-clinical or clinical setting and the most promising of them will be discussed in detail. However, despite all efforts to identify predictive biomarkers of sensitivity to CCC in NSCLC, results have been disappointing and a strikingly high attrition rate between promising pre-clinical data and negative clinical results has been observed. Not even a handful of biomarkers are still in the race, and none are ready yet for clinical practice implementation. The causes of failure (lack of standardisation along with clinical, biological, and technical challenges) will be discussed in this review. Nevertheless, recent technological developments open encouraging perspectives for performing analytical validation of candidate biomarkers of CCC efficacy. Technological innovation also drives the development of alternative types of predictive biomarkers such as DNA signatures.
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Tumor-related leukocytosis is associated with poor radiation response and clinical outcome in uterine cervical cancer patients
In this large population study of uterine cervical cancer, patients with tumor-related leukocytosis had unfavorable features, and showed poor response to radiotherapy and as well as decreased overall survival. A high neutrophil/lymphocyte ratio is also associated with poor treatment outcome. Therefore, alternative diagnostic and treatment strategies are required for these patients.
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An Online Psychological Intervention Can Improve The Sexual Satisfaction Of Men Following Treatment For Localised Prostate Cancer: Outcomes Of An Rct Evaluating My Road Ahead
Abstract
Background
Prostate cancer treatment often results in significant psycho-sexual challenges for men following treatment, however many men report difficulty in accessing appropriate care.
Methods
A randomised controlled trial was undertaken to assess the efficacy of a 10-week self-guided online psychological intervention called My Road Ahead (MRA) for men with localised prostate cancer in improving sexual satisfaction. Participants were randomised to one of three conditions My Road Ahead alone or My Road Ahead plus online forum, or forum access alone. Pre, post and follow-up assessments of overall sexual satisfaction were conducted. Mixed models and structural equation modelling were used to analyse the data.
Results
142 participants (mean age 61 years; SD = 7) participated. The majority of participants had undergone radical prostatectomy (88%) and all men had received treatment for localised prostate cancer. Significant differences were obtained for the three groups (p = .026) and a significant improvement in total sexual satisfaction was observed only for participants who were allocated to MRA + Forum with a large effect size (p = .004, partial η2 = .256). Structural equation modelling indicated that increases in sexual function, masculine self esteem and sexual confidence contributed significantly to overall sexual satisfaction for the MRA + Forum plus forum condition.
Conclusions
This study is the first, to our knowledge, that has evaluated a self-guided online psychological intervention tailored to the specific needs of men with prostate cancer. The findings indicate the potential for MRA to deliver support that men may not otherwise receive and also highlight the importance of psychological intervention to facilitate improved sexual outcomes.
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Post-traumatic growth in breast cancer: How and when do distress and stress contribute?
Abstract
Objective
While several theoretical models provide explanation for the genesis and development of post traumatic growth (PTG) in the aftermath of stressful events, empirical evidence regarding the predictors and consequences of PTG in breast cancer patients in active treatment and early survivorship is inconclusive. This study, therefore, examines the role of distress and stress, as predictors and outcomes of post-traumatic growth in women with breast cancer over an 18-month period.
Methods
These effects are tested in two structural equation models that track pathways of PTG in a sample of 253 recently diagnosed women. Questionnaires were completed at diagnosis and at 4 follow up time points assessing cancer-specific stress (IES), global stress (PSS), depression and anxiety (HADS). Post-traumatic growth (SLQ -38) was assessed at follow up time points.
Results
Cancer-specific stress was related to higher PTG concurrently and longitudinally. Anxiety was related concurrently to higher PTG but overall general distress had minimal impact on post-traumatic growth. Global stress was inversely related to PTG. Positive growth at six months was associated with subsequent reduction in stress.
Conclusions
This study showing that early stage higher cancer-specific stress and anxiety were related to positive growth supports the idea that struggle with a challenging illness may be instrumental in facilitating PTG and findings show positive implications of PTG for subsequent adjustment. This article is protected by copyright. All rights reserved.
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Oncologist, Patient and Companion Questions during Pre-Treatment Consultations About Adjuvant Cancer Treatment: A Shared Decision-Making Perspective
Abstract
Objectives
To assess the occurrence of questions that foster shared decision-making, in particular cancer patients' understanding of treatment decisions and oncologists' understanding of patients' priorities, during consultations in which preference-sensitive decisions are discussed. Specifically, regarding a) patient understanding, do oncologists ask about patients' pre-existing knowledge, information preferences, and understanding; do patients and companions ask about the disease and treatment; b) patient priorities, do oncologists ask about patients' treatment- and decision-related preferences; do patients and companions ask about the decision.
Methods
Audiotaped pre-treatment consultations of 100 cancer patients with 32 oncologists about (neo-)adjuvant treatment were coded and analysed to document question type, topic, and initiative.
Results
The oncologists ascertained prior knowledge in 50 patients, asked 24 about preferred (probability) information, and invited questions from 56 patients. The oncologists asked 32 patients about treatment preferences and/or for consent. Respectively one-third and one-fifth of patients and companions asked about treatment benefits compared to three-quarter of them who asked about treatment harms and/or procedures.
Conclusions
It would be helpful to patients if oncologists more often assessed patients' existing knowledge to tailor their information provision. Also, patients could receive treatment recommendations that better fit their personal situation if oncologists collected information on patients' views about treatments. Moreover, by educating patients to ask about treatment alternatives, benefits and harms, patients may gain a better understanding of the choice they have. This article is protected by copyright. All rights reserved.
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Real-world implementation of electronic patient-reported outcomes in outpatient pediatric cancer care
Abstract
Objective
The KLIK method is an online tool to monitor and discuss electronic patient-reported outcomes (ePROs), which has been shown to enhance outcomes. This study aimed to (1) determine the fidelity (i.e., extent to which used as intended) of the KLIK method as implemented in outpatient pediatric cancer care, and (2) study healthcare professional (HCP)-reported barriers and facilitators for implementation.
Methods
Two hundred and five children with newly-diagnosed cancer (enrollment rate 85%) participated. At one (T1), three (T2) and six (T3) months post-diagnosis, patients (8–18 years) or parents (of patients 0–7 years) completed health-related quality of life (HRQoL) questionnaires, which were transformed into an ePROfile and discussed by their HCP during consultations. Fidelity was determined by: percentage of website registrations, HRQoL-questionnaires completed, and ePROfiles discussed. Implementation determinants were assessed with HCPs after the final T3 with the Measurement Instrument for Determinants of Innovations.
Results
Depending on time point (T1-T3), fidelity was 86-89% for website registration, 66-85% for completed HRQoL-questionnaires, and 56-62% for ePROfile discussion. Barriers were mainly related to organizational issues (e.g. organizational change) and less frequently to users (e.g. motivation to comply) or the intervention (compatibility). Facilitators were related to the user (e.g. positive outcome expectations) and intervention (simplicity), but not to the organization.
Conclusions
When implementing ePROs in outpatient pediatric oncology practice, HCPs report determinants that influence ePRO integration. To improve implementation and outcomes, tailored organizational (e.g. formal ratification by management, time) and specific local (e.g. individualized assessments) strategies should be developed to achieve optimal ePRO discussion. This article is protected by copyright. All rights reserved.
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Processus du traitement par irradiation
Source:Cancer/Radiothérapie
Author(s): I. Barillot, B. Chauvet, J.M. Hannoun Lévi, A. Lisbona, T. Leroy, M.A. Mahé
Le but de cet article est de décrire le contexte réglementaire de l'exercice de la radiothérapie en France, les processus de radiothérapie externe et de curiethérapie et les recommandations du suivi des patients.The purpose of this article is to describe the regulatory framework of the radiotherapy practice in France, the external irradiation and brachytherapy process and the guidelines for patient follow-up.
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Radiothérapie des cancers de l’enfant
Source:Cancer/Radiothérapie
Author(s): A. Laprie, L. Padovani, V. Bernier, S. Supiot, A. Huchet, A. Ducassou, L. Claude
Le but de cet article est de décrire les spécificités de la radiothérapie pédiatrique : types de cancers, indications, techniques, organisation et réglementation.The purpose of this article is to describe the specificities of paediatric radiation oncology: cancer types, radiotherapy indications, techniques, organisation and reglementary framework.
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Délinéation des organes à risque et contraintes dosimétriques
Source:Cancer/Radiothérapie
Author(s): G. Noël, D. Antoni, I. Barillot, B. Chauvet
À partir d'une revue de la littérature, cet article définit les limites de délinéation pour les organes critiques, puis les contraintes de dose sur ces derniers lorsque la radiothérapie est délivrée selon un étalement et fractionnement classiques ou en hypofractionnement, tel qu'utilisé dans la radiothérapie en conditions stéréotaxiques.From a review of literature, the objective of this paper is to define limits for delineation of organs at risk and dose constraints in this latter when radiotherapy is delivered with conventional fractionation or with hypofractionation as for stereotactic body radiation therapy.
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Radiothérapie des cancers primitifs du poumon
Source:Cancer/Radiothérapie
Author(s): P. Giraud, T. Lacornerie, F. Mornex
Les indications, doses, techniques de radiothérapie, association à une chimiothérapie concomitante, des cancers primitifs du poumon sont présentées. Les recommandations de délinéation des volumes cibles et organes à risques sont détaillées.Indication, doses, technique of radiotherapy and concomitant chemotherapy, for primary lung carcinoma are presented. The recommendations for delineation of the target volumes and organs at risk are detailed.
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Radiothérapie externe des cancers prostatiques
Source:Cancer/Radiothérapie
Author(s): R. de Crevoisier, P. Pommier, I. Latorzeff, O. Chapet, B. Chauvet, C. Hennequin
Les techniques de radiothérapie externe prostatique sont décrites, tant en cas d'irradiation de la prostate en place qu'après prostatectomie, incluant ou non les aires ganglionnaires pelviennes. Les points suivants sont présentés : indications d'irradiation, dose totale et fractionnement, acquisition des images scanographiques de planification, délinéation des volumes d'intérêt (volumes cibles et organes à risque) et définition des marges, planifications par de la radiothérapie conformationnelle avec modulation d'intensité (RCMI) et contraintes de dose associées et finalement la radiothérapie guidée par l'image.The prostate external beam radiotherapy techniques are described, when irradiating the prostate or after prostatectomy, with and without pelvic lymph nodes. The following parts are presented: indications of radiotherapy, total dose and fractionation, planning CT image acquisition, volume of interest delineation (target volumes and organs at risk) and margins, Intensity modulated radiotherapy planning and corresponding dose–volume constraints, and finally Image guided radiotherapy
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Modification of tumor cell exosome content by transfection with wt-p53 and microRNA-125b expressing plasmid DNA and its effect on macrophage polarization
Modification of tumor cell exosome content by transfection with wt-p53 and microRNA-125b expressing plasmid DNA and its effect on macrophage polarization
Oncogenesis 5, e250 (August 2016). doi:10.1038/oncsis.2016.52
Authors: M Trivedi, M Talekar, P Shah, Q Ouyang & M Amiji
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Combination gemcitabine/cisplatin therapy and ERCC1 expression for resected pancreatic adenocarcinoma: Results of a Phase II prospective trial
Background
Standard adjuvant treatment for pancreatic adenocarcinoma (PDAC) is gemcitabine [Gem(CONKO-001: Gem vs. placebo DFS:13.4 vs. 6.7 mo; P < 0.001; OS:22.8 vs. 20.2 mo; P = 0.01)]. Addition of cisplatin (Cis) to Gem has resulted in increased PFS for advanced and metastatic disease, which may be predicted by low expression of excision repair cross-complementing group–1 (ERCC1), the key enzyme in nucleotide excision repair. This Phase II prospective trial assesses outcomes of patients treated with adjuvant Gem/Cis, stratifying results by tumor ERCC1 expression.
Methods
Patients with resected PDAC were enrolled (2010–2013) and received Gem(1,000 mg/m2)/Cis(50 mg/m2). Tumor ERCC1 expression was evaluated by immunohistochemistry and dichotomized into low or high expression. Primary outcomes were recurrence-free and overall survival (RFS/OS).
Results
Of 22 pts, 16(73%) were Stage IIB, 5(23%) Stage IIA, and 1(4%) Stage IA. Grade 3/4 toxicity occurred in 13 pts (59%); neutropenia was most common (n = 9;41%). Median follow-up was 37.5 months. Median RFS was 16.7 mo; OS was 35.5 mo. Low ERCC1 (n = 15;75%) compared to high ERCC1 (n = 5;25%) was not associated with improved RFS (12.4 vs. 16.7 mo; P = 0.68) or OS (Median not reached vs. 21.6 mo; P = 0.22).
Conclusions
Adjuvant Gem/Cis is feasible in patients with resected pancreatic adenocarcinoma. RFS and OS for Gem/Cis appear promising compared to historic control. Tumor ERCC1 expression can be reliably evaluated, and low expression is present in most patients. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.
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Dosimetric verification of dental stent efficacy in head and neck radiation therapy using modern radiation therapy techniques: quality of life and treatment compliance implications
Abstract
Objective
During radiotherapy to the head and neck, metallic dental restorations produce secondary electrons that increase dose to nearby tissue causing painful ulcers that contribute to morbidity during treatment and lead to breaks in therapy. Various protective measures have been tested with simplified phantoms and beam arrangements. Our objective was to quantitatively assess electron scatter using an anatomical phantom and modern beam configurations.
Methods
A tissue-equivalent phantom was created to simulate the oral cavity with gold crowns on opposing molars. Four-millimeter ethylene copolymer dosimetric dental stents were produced. The phantom was placed in a water bath to simulate soft tissue. Radiation was delivered in opposed lateral, nine-field intensity-modulated radiation therapy (IMRT), and volumetric modulated arc therapy (VMAT) configurations. A GafChromic EBT3 film was used to simulate the mucosal surfaces of the tongue and the buccal mucosa. The film readings were then converted to isodose plots using DoseLab.
Results
With opposed beams, a 32 % reduction in maximum dose was measured in the occlusal plane with the use of stents. In the nine-field IMRT and VMAT plans, maximum dose to the adjacent film was reduced by approximately 40 % with the use of the dental stent.
Conclusions
This approximately 40 % dose reduction implies that patients' oral mucosae adjacent to dental fixtures could receive more than 100 Gy during a course of definitive radiotherapy to the head and neck without dental stents. In this era of increasing IMRT/VMAT utilization, our results emphasize the value of stent use to improve morbidity and reduce treatment breaks for patients undergoing head and neck radiotherapy.
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Does smoking influence the physical activity and lung cancer relation? A systematic review and meta-analysis
Abstract
Research suggests an inverse association between physical activity and lung cancer. However, whether the relation is modified by degree of smoking adjustment has not been summarized. We conducted a meta-analysis of physical activity and lung cancer focusing on evaluating whether smoking status and the degree of smoking adjustment influenced the association. Comparing high versus low physical activity levels from 25 observational studies yielded a lung cancer summary relative risk (RR) of 0.79 [95 % confidence interval (CI) = 0.72–0.87], with RRs of 0.87 (95 % CI = 0.80–0.94) for cohort studies and 0.57 (95 % CI = 0.46–0.71) for case–control studies. In further analyses restricted to cohort studies, physical activity was inversely related to lung cancer among former smokers (RR = 0.68, 95 % CI = 0.51–0.90) and current smokers (RR = 0.80, 95 % CI = 0.70–0.90), whereas the association was null among never smokers (RR = 1.05, 95 % CI = 0.78–1.40, p interaction = 0.26). The degree of smoking adjustment did not modify the association (p interaction = 0.73). Physical activity was unrelated to lung cancer among never smokers but it was inversely associated with lung cancer among former and current smokers. Although the physical activity and lung cancer relation was not modified by smoking status or degree of smoking adjustment, residual confounding by smoking remains a possible explanation for the relations observed.
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Non-invasive urine testing of EGFR activating mutation and T790M resistance mutation in non-small cell lung cancer
Abstract
Background
The increasing understanding of non-small cell lung cancer (NSCLC) biology over the last two decades has led to the identification of multiple molecular targets. This led to the development of multiple targeted therapies in the primary and secondary resistance setting and the epidermal growth factor receptor (EGFR) gene remains the most frequently observed molecular target in NSCLC. Tissue biopsies remain the standard for the identification of such EGFR mutations. Obtaining serial tissue biopsies, especially in the secondary resistance setting is associated with multiple medical and logistical challenges. Utilizing circulating tumor DNA (ctDNA) fragments for molecular analysis can overcome these challenges and aid in therapeutic decision-making.
Case presentation
Here we present a present a 72-year-old Korean woman with metastatic, EGFR L858R mutated bronchogenic adenocarcinoma. She developed skeletal progression on treatment with first and second generation tyrosine kinase inhibitors (TKIs). Repeated biopsies failed to provide informative molecular test results. A novel urine ctDNA assay was utilized and confirmed T790M positive status. The patient was started on a third generation TKI, which led to a measurable clinical response.
Conclusions
Utilization of urine liquid biopsies for EGFR diagnostics are feasible and provided critical clinical information in this patient's case. Urine liquid biopsy represents a viable alternative to tissue biopsy, particularly in the secondary resistance setting, when tissue is not available for molecular testing.
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Novel melanoma therapy
Abstract
With the rapid succession of new effective agents for melanoma in the recent years, the paradigm for treatment of metastatic melanoma is changing. The success of combining multiple effective agents compared with outcomes of monotherapy also brings increasing complexity in the treatment algorithm for various subsets of metastatic melanoma patients. We reviewed the recent reports on novel melanoma therapy to shed light on rational decision-making in treating these patients.
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Oral Squamous Carcinoma Cells Express B7-H1 and B7-DC Receptors in Vivo
Abstract
B7-H1 and B7-DC ligands are members of the B7 family with important regulatory functions in cell-mediated immune response. Both receptors are ligands of the programmed death receptor PD-1. B7-H1 expression has been detected in the majority of human carcinomas in vivo. B7-H1 mediated signals are able to negatively regulate activated T cell functions and survival, and enable tumor cells to overcome host response. The aim of this study was to investigate the expression of B7-H1 and B7-DC proteins in oral squamous cell carcinomas (OSCC) in vivo. Tissues from 15 samples were cryo-sected and following histological routine staining (HE), incubated with antibodies against human B7-H1 and B7-DC. Immuno-staining of pan-cytokeratin was performed to ascertain the epithelial origin of the tissue and CK 19 to demonstrate the proliferating stage. Confocal laser scanning microscopy confirmed the presence of both B7-H1 and B7-DC in all 15 OSCC. The B7-H1 and B7-DC staining was located in areas of the tissue that were identified as cancerous lesions in the previously stained HE sections before. Staining with Pan-CK and CK19 provided evidence for the epithelial origin and the proliferating stage of the tissue. The in vivo expression of the B7-H1 and B7-DC receptors in oral squamous cell carcinomas suggest that general mechanisms for immune evasion of tumors are also found in OSCC.
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Clinical and Pathological Significance of ER Stress Marker (BiP/GRP78 and PERK) Expression in Malignant Melanoma
Abstract
Glucose-regulated protein of 78 kD (GRP78) also referred to as immunoglobulin heavy chain binding protein (BiP/GRP78) plays an important role in the endoplasmic reticulum (ER) stress. The level of BiP/GRP78 is highly elevated in various human cancers. The purpose of this study is to examine the prognostic significance of BiP/GRP78 expression in patients with malignant melanoma. A total of 133 malignant melanoma patients were analyzed, and tumor specimens were stained by immunohistochemistry for BiP/GRP78, PKR-like endoplasmic reticulum kinase (PERK), Ki-67, p53 and microvessel density (MVD) determined by CD34. BiP/GRP78 and PERK were highly expressed in 40 % (53/133) and 78 % (104/133), respectively. BiP/GRP78 disclosed a significant relationship with PERK expression, thickness, T factor, N factor, disease staging, cell proliferation (Ki-67) and MVD (CD34). By multivariate analysis, the high expression of BiP/GRP78 was identified as an independent prognostic factor for predicting poor survival against malignant melanoma. The increased BiP/GRP78 expression was clarified as an independent prognostic marker for predicting worse outcome. ER stress marker, BiP/GRP78 could be a powerful molecular target for the treatment of malignant melanoma.
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The development of an automatically produced cholangiography procedure using the reconstruction of portal-phase multidetector-row computed tomography images: preliminary experience
Abstract
Purpose
Fusion angiography using reconstructed multidetector-row computed tomography (MDCT) images, and cholangiography using reconstructed images from MDCT with a cholangiographic agent include an anatomical gap due to the different periods of MDCT scanning. To conquer such gaps, we attempted to develop a cholangiography procedure that automatically reconstructs a cholangiogram from portal-phase MDCT images.
Methods
The automatically produced cholangiography procedure utilized an original software program that was developed by the Graduate School of Information Science, Nagoya University. This program structured 5 candidate biliary tracts, and automatically selected one as the candidate for cholangiography. The clinical value of the automatically produced cholangiography procedure was estimated based on a comparison with manually produced cholangiography.
Results
Automatically produced cholangiograms were reconstructed for 20 patients who underwent MDCT scanning before biliary drainage for distal biliary obstruction. The procedure showed the ability to extract the 5 main biliary branches and the 21 subsegmental biliary branches in 55 and 25 % of the cases, respectively. The extent of aberrant connections and aberrant extractions outside the biliary tract was acceptable. Among all of the cholangiograms, 5 were clinically applied with no correction, 8 were applied with modest improvements, and 3 produced a correct cholangiography before automatic selection.
Conclusions
Although our procedure requires further improvement based on the analysis of additional patient data, it may represent an alternative to direct cholangiography in the future.
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Clinical factors that affect the outcomes after anatomical versus non-anatomical resection for hepatocellular carcinoma
Abstract
Purpose
For hepatocellular carcinoma (HCC), the superiority of anatomical resection (AR) over non-anatomical resection (NR) is still controversial. In this study, we assessed the potential benefits of AR for HCC.
Methods
We enrolled 173 consecutive patients with HCC who underwent hepatectomy in our hospital from August 2003 to May 2013 and compared the outcomes for the AR group (n = 125) with those for the NR group (n = 48).
Results
The median observational period was 790 days. The 1- and 2-year overall survival (OS) rates were 92.1 and 85.8 %, respectively; the 1- and 2-year disease-free survival (DFS) rates were 78.2 and 63.0 %, respectively. The AR and NR groups did not significantly differ in the OS or DFS. However, the 2-year DFS was significantly better for the AR group than the NR group among HCV patients (68.2 vs. 32.2 %; P = 0.004) and patients with alpha-fetoprotein (AFP) within the normal range (<20 ng/ml; 76.7 vs. 60.9 %; P = 0.031), total bilirubin <0.8 mg/dl (70.8 vs. 47.0 %; P = 0.034), and tumors 2–5 cm in diameter (82.0 vs. 62.5 %; P = 0.025).
Conclusions
If a patient is HCV-negative, has low AFP, low total bilirubin, or a tumor diameter of 2–5 cm, AR is recommended.
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Severe tricuspid regurgitation after mitral valve surgery: the risk factors and results of the aggressive application of prophylactic tricuspid valve repair
Abstract
Purpose
This study aimed to examine the risk factors for severe postoperative tricuspid regurgitation (TR) in patients undergoing mitral valve surgery. We also studied the effects of prophylactic tricuspid valve repair (TVR) on severe postoperative TR.
Methods
We retrospectively studied 125 patients without severe TR who underwent mitral valve surgery from 1987 to 2006. Patients did not undergo TVR before 1998 (the early period, n = 54). In 1998 (the late period, n = 71), patients with a preoperative tricuspid annular diameter of ≥35 mm underwent TVR using an annuloplasty ring (n = 52).
Results
In the analysis of the early period, the rates of freedom from severe TR at 10 and 20 years after surgery were 76 and 59 %, respectively. A multivariate analysis identified moderate preoperative TR as a significant risk factor for severe TR. In the late period, none of the 52 patients who underwent TVR developed severe TR. However, 4/19 patients who did not undergo TVR developed severe TR, and all of these four patients had a preoperative tricuspid annular diameter of ≤35 mm.
Conclusions
Moderate preoperative TR is a significant risk factor for severe postoperative TR in patients undergoing mitral valve surgery. The aggressive application of TVR can prevent severe postoperative TR; however, tricuspid annular dilatation might not be a good indicator for TVR.
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Metrics for monitoring cancer inequities: residential segregation, the Index of Concentration at the Extremes (ICE), and breast cancer estrogen receptor status (USA, 1992–2012)
Abstract
Purpose
To address the paucity of evidence on residential segregation and cancer, we explored their relationship using a new metric: the Index of Concentration at the Extremes (ICE). We focused on breast cancer estrogen receptor (ER) status, a biomarker associated with survival and, etiologically, with social and economic privilege.
Methods
We obtained data from the 13 registry group of US Surveillance, Epidemiology, and End Results (SEER) program for 1992–2012 on all women aged 25–84 who were diagnosed with primary invasive breast cancer (n = 516,382). We appended to each case's record her annual county median household income quintile and the quintile for her annual county value for ICE measures for income (≤20th vs. ≥80th household income quintile), race/ethnicity (black vs. white), and income plus race/ethnicity (low-income black vs. high-income white). The odds of being ER+ versus ER− were estimated in relation to the county-level income and ICE measures, adjusting for relevant covariates.
Results
Women in the most privileged versus deprived county quintile for household income and for all three ICE measures had a 1.1- to 1.3-fold increased odds (95 % confidence intervals excluding 1) of having an ER+ tumor. These results were robust to adjustment for age at diagnosis, cancer registry, tumor characteristics (tumor stage, size, histology, grade), and race/ethnicity.
Conclusion
A focus on segregation offers news possibilities for understanding how inequitable group relations contribute to cancer inequities. The utility of employing the ICE for monitoring cancer inequities should be investigated in relation to other cancer outcomes.
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The role of periodic serum CA19-9 test in surveillance after colorectal cancer surgery
Abstract
Background
The serum carcinoembryonic antigen (CEA) test is mainly used for postoperative surveillance of colorectal cancer patients in Western and Japanese guidelines, but evidence to support the use of CA19-9 is scarce.
Methods
We analyzed the cohort data from 22 institutions of the Japanese Study Group for Postoperative Follow-up of Colorectal Cancer. Patients who had undergone curative surgery for primary colorectal cancer (pathological stage I–III) between 1997 and 2006 were eligible for analysis. Sensitivities of CEA and CA19-9 at the time of recurrence and the contribution of CA19-9 to detecting recurrences were assessed.
Results
A total of 17,833 patients were eligible, and the overall recurrence rate was 18 %. The sensitivity of CA19-9 in detecting recurrence was lower than that of CEA (29 vs. 57 %). Among patients with recurrence, recurrences were first suspected in 96 % using standard surveillance modalities (CEA elevation, CT scan, clinic visit, and colonoscopy), whereas recurrences were suspected because of CA19-9 elevation in an estimated 1.3 % of patients. With regard to prognosis after recurrences, the sensitivity of CA19-9 was lower than that of CEA in the detection of surgically treatable recurrences (22 vs. 49 %). In terms of overall survival after recurrences, CA19-9 and CEA had almost comparable hazard ratios (1.66 and 1.48, respectively).
Conclusions
Our data suggested that the sensitivity of serum CA19-9 test is low, and that adding it to the current standard surveillance strategies is not beneficial.
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Reconstruct the proximal radius with iliac graft and elastic intramedullary nail fixation after tumor resection
Abstract
Background
This study aims to introduce a novel technique in treating benign bone tumors of the proximal radius by elastic intramedullary nail fixation and iliac graft after tumor resection.
Method
In this retrospective case series, the treatment outcomes of 17 patients with benign bone tumor involving the proximal radius were reported from January 2010 to August 2014. All the patients received reconstruction surgery with iliac graft and elastic intramedullary nail fixation after tumor resection. Pain scoring was assessed using the 0 to 10 numerical rating scale. The quality of life scoring was assessed using the SF-30 scoring system. In addition, functional outcome was assessed with the Musculoskeletal Tumor Society score and the Disabilities of the Arm, Shoulder, and Hand score.
Results
The mean follow-up was 16 months (range, 10–22). The average bone consolidate time was 19.2 weeks (range, 16–24 weeks). The pre- and postoperative pain scores were 5.47 ± 1.58 and 1.18 ± 0.39, respectively. The pain symptom was significantly ameliorated after the operation (t = 13.50, p < 0.01). The pre- and postoperative and the quality of life scores were 48.29 ± 6.58 and 77.47 ± 5.89, respectively; the quality of life score was dramatically improved (t = −20.11, p < 0.01). The mean Musculoskeletal Tumor Society score was 83.41 % (range, 63–93 %) and the mean Disabilities of the Arm, Shoulder, and Hand score was 14.1 (range, 5.8–38.3).
Conclusion
Taken together, the application of iliac graft and elastic intramedullary nail fixation after excision of lesions might be associated to a significant reduction of the pain and improvement of QOL (quality of life) and limb function of patients with benign bone tumors of proximal radius.
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Postoperative chemoradiotherapy versus chemotherapy for R0 resected gastric cancer with D2 lymph node dissection: an up-to-date meta-analysis
Abstract
Background
This meta-analysis aims to provide more evidence on the role of postoperative chemoradiotherapy (CRT) for gastric cancer (GC) patients in Asian countries where D2 lymphadenectomy is prevalent.
Methods
We conducted a systematic review of randomized controlled trials (RCTs), extracted data of survival and toxicities, and pooled data to evaluate the efficacy and toxicities of CRT compared with chemotherapy (CT) after D2 lymphadenectomy.
Results
A total of 960 patients from four RCTs were selected. The results showed that postoperative CRT significantly reduced loco-regional recurrence rate (LRRR: RR = 0.50, 95 % CI = 0.34–0.74, P = 0.0005) and improved disease-free survival (DFS: HR = 0.73, 95 % CI = 0.60–0.89, P = 0.002). However, CRT did not affect distant metastasis rate (DMR: RR = 0.81, 95 % CI = 0.60–1.08, P = 0.15) and overall survival (OS: HR = 0.91, 95 % CI = 0.74–1.11, P = 0.34). The main grade 3–4 toxicities manifested no significant differences between the two groups.
Conclusions
Overall, CRT after D2 lymphadenectomy may reduce LRRR and prolong DFS. The role of postoperative CRT should be further investigated in the population with high risk of loco-regional recurrence.
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Violacein induces death of RAS-mutated metastatic melanoma by impairing autophagy process
Abstract
Treatment of metastatic melanoma still remains a challenge, since in advanced stage it is refractory to conventional treatments. Most patients with melanoma have either B-RAF or N-RAS mutations, and these oncogenes lead to activation of the RAS-RAF-MEK-ERK and AKT signal pathway, keeping active the proliferation and survival pathways in the cell. Therefore, the identification of small molecules that block metastatic cell proliferation and induce cell death is needed. Violacein, a pigment produced by Chromobacterium violaceum found in Amazon River, has been used by our group as a biotool for scrutinizing signaling pathways associated with proliferation, survival, aggressiveness, and resistance of cancer cells. In the present study, we demonstrate that violacein diminished the viability of RAS- and RAF-mutated melanoma cells (IC50 value ∼500 nM), and more important, this effect was not abolished after treatment medium removal. Furthermore, violacein was able to reduce significantly the invasion capacity of metastatic melanoma cells in 3D culture. In the molecular context, we have shown for the first time that violacein causes a strong drop on histone deacetylase 6 expression, a proliferating activator, in melanoma cells. Besides, an inhibition of AXL and AKT was detected. All these molecular events propitiate an inhibition of autophagy, and consequently, melanoma cell death by apoptosis.
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Neonatal encephalocardiomyopathy caused by mutations in VARS2
Abstract
VARS2 encodes a mitochondrial aminoacyl-tRNA-synthetase. Mutations in VARS2 have recently been identified as a cause of mitochondrial encephalomyopathy in three individuals. However, clinical information remained scarce. Exome sequencing lead us to identify compound heterozygous pathogenic VARS2 variants in a boy presenting with severe lactic acidosis, hypertrophic cardiomyopathy, epilepsy, and abnormalities on brain imaging including hypoplasia of corpus callosum and cerebellum as well as a massive lactate peak on MR-spectroscopy. Studies in patient-derived fibroblasts confirmed the functional relevance of the identified VARS2 variants. Our report expands the phenotypic spectrum associated with this rare mitochondrial defect, in that VARS2 deficiency may also cause severe neonatal presentations with cardiac involvement and structural brain abnormalities.
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The serum zinc concentration as a potential biological marker in patients with major depressive disorder
Abstract
Despite many clinical trials assessing the role of zinc in major depressive disorder (MDD), the conclusions still remain ambiguous. The aim of the present clinical study was to determine and comparison the zinc concentration in the blood of MDD patients (active stage or remission) and healthy volunteers (controls), as well as to discuss its potential clinical usefulness as a biomarker of the disease. In this study 69 patients with current depressive episode, 45 patients in remission and 50 controls were enrolled. The zinc concentration was measured by electrothermal atomic absorption spectrometry (ET AAS). The obtained results revealed, that the zinc concentration in depressed phase were statistically lower than in the healthy volunteers [0.89 vs. 1.06 mg/L, respectively], while the zinc level in patients achieve remission was not significantly different from the controls [1.07 vs. 1.06 mg/L, respectively]. Additionally, among the patients achieve remission a significant differences in zinc concentration between group with and without presence of drug-resistance in the previous episode of depression were observed. Also, patients in remission demonstrated correlation between zinc level and the average number of depressive episodes in the last year. Serum zinc concentration was not dependent on atypical features of depression, presence of psychotic symptoms or melancholic syndrome, age, age of onset or duration of disease, number of episodes in the life time, duration of the episode/remission and severity of depression measured by the Hamilton Rating Scale for Depression (HDRS), and the Montgomery-Asberg Depression Rating Scale (MADRS). Concluding, our findings confirm the correlation between zinc deficit present in the depressive episode, and are consistent with the majority of previous studies. These results may also indicate that serum zinc concentration might be considered as a potential biological marker of MDD.
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Antiviral therapy improves overall survival in hepatitis C virus-infected patients who develop diffuse large B-cell lymphoma
ABSTRACT
Chronic Hepatitis C virus (HCV) infection is associated with increased incidence of non-Hodgkin lymphoma. Several studies have demonstrated regression of indolent lymphoma with antiviral therapy (AVT) alone. However, the role of AVT in HCV-infected patients with diffuse large B-cell lymphoma (DLBCL) is unclear. We therefore analyzed AVT's impact on oncologic outcomes of HCV-infected patients (cases) who developed DLBCL. Cases seen at our institution (June 2004-May 2014) were matched with uninfected counterparts (controls) and then divided according to prior AVT consisting of interferon-based regimens. We studied 304 patients (76 cases and 228 controls). More cases than controls had extranodal (79% v 72%; p=0.07) and upper gastrointestinal (GI; 42% v 24%; p=0.004) involvement. Cases never given AVT had DLBCL more refractory to first-line chemotherapy than that in the controls (33% v 17%; p=0.05) and exhibited a trend toward more progressive lymphoma at last examination compared to controls (50% v 32%; p=0.09) or cases given AVT (50% v 27%; p=0.06). Cases never given AVT had worse 5-year overall survival (OS) rates than did the controls (HR, 2.3 [95% CI, 1.01-5.3]; p=0.04). Furthermore, AVT improved 5-year OS rates among cases in both univariate (median [Interquartile range]: 39 [26-56] v 16 [6-41] months, p=0.02) and multivariate analyses (HR=0.21 [95% CI, 0.06-0.69]; p=0.01). This study highlights the negative impact of chronic HCV on survival of DLBCL patients and shows that treatment of HCV infection is associated with a better cancer response to chemotherapy and improves 5-year OS. This article is protected by copyright. All rights reserved.
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Anti-tumor Activity of the ATR Inhibitor AZD6738 in HER2 positive Breast Cancer Cells
ABSTRACT
Ataxia telangiectasia and Rad3-related (ATR) proteins are sensors of DNA damage, which induces homologous recombination (HR)-dependent repair. ATR is a master regulator of DNA damage repair (DDR), signaling to control DNA replication, DNA repair, and apoptosis. Therefore, the ATR pathway might be an attractive target for developing new drugs. This study was designed to investigate the antitumor effects of the ATR inhibitor, AZD6738 and its underlying mechanism in human breast cancer cells. Growth inhibitory effects of AZD6738 against human breast cancer cell lines were studied using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (methyl thiazolyl tetrazolium, MTT) assay. Cell cycle analysis, Western blotting, immunofluorescence, and comet assays were also performed to elucidate underlying mechanisms of AZD6738 action. Anti-proliferative and DDR inhibitory effects of AZD6738 were demonstrated in human breast cancer cell lines. Among 13 cell lines, the IC50 values of 9 cell lines were less than 1 μmol/L using MTT assay. Two cell lines, SK-BR-3 and BT-474, were chosen for further evaluation focused on human epidermal growth factor receptor 2 (HER2)-positive breast cancer cells. Sensitive SK-BR-3 but not the less sensitive BT-474 breast cancer cells showed increased level of apoptosis and S phase arrest and reduced expression levels of phosphorylated check-point kinase 1 (CHK1) and other repair markers. Decreased functional CHK1 expression induced DNA damage accumulation due to HR inactivation. AZD6738 showed synergistic activity with cisplatin. Understanding the antitumor activity and mechanisms of AZD6738 in HER2-positive breast cancer cells creates the possibility for future clinical trials targeting DDR in HER2-positive breast cancer treatment. This article is protected by copyright. All rights reserved.
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Comparison of methods using paraffin-embedded tissues and exfoliated cervical cells to evaluate HPV genotype attribution
Summary
Monitoring the attribution of human papillomavirus (HPV) genotypes to cervical precancerous lesions is essential in assessing the efficacy of HPV vaccines. To resolve the lack of studies comparing the HPV genotyping procedures used to estimate HPV genotype attribution, we performed a retrospective cross-sectional study to determine the appropriate genotyping procedures for evaluating the potential efficacy of HPV vaccines. Three procedures, including two different genotyping methods, Clinichip® HPV test (Chip) and modified GP5+/6+ PCR coupled to fluorescent bead sorter detection (MGP), and in exfoliated cervical cells (C-Chip and C-MGP, respectively) or formalin-fixed paraffin-embedded tissues (F-MGP), were compared. The overall agreement in detecting high-risk HPV was 88.5%–92.1% among the three procedures, and genotype-specific agreement was 83.9%–100% for all pairwise comparisons. In cervical intraepithelial neoplasia grade 2/3 specimens, HPV16/18 attribution estimated with the hierarchical attribution method was consistent among the procedures: 52.3% (45/86) for C-Chip, 54.7% (47/86) for C-MGP, and 52.3% (45/86) for F-MGP (p = 0.81). HPV16/18/31/33/45/52/58 hierarchical attribution was 88.4% (76/86) with C-Chip, 86.0% (74/86) with C-MGP, and 83.7% (72/86) with F-MGP (p = 0.49). In CIN3 specimens, the corresponding hierarchical attribution was 96.4% (53/55) with C-Chip, 89.1% (49/55) with C-MGP, and 94.5% (52/55) with F-MGP (p = 0.27). Although F-MGP is theoretically a reliable method for determining HPV genotype attribution, it is acceptable to use C-Chip or C-MGP, coupled to the hierarchical attribution formula to correct the bias of multiple infections. These approaches using exfoliated cervical cells are practical for monitoring the efficacy of HPV vaccines.
This article is protected by copyright. All rights reserved.
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Peperomin E reactivates silenced tumor suppressor genes in lung cancer cells via inhibition of DNA methyltransferase
Summary
Advanced lung cancer has poor prognosis owing to its low sensitivity to current chemotherapy agents. Therefore, discovery of new therapeutic agents is urgently needed. In this study, we investigated the antitumor effects of peperomin E, a secolignan isolated from Peperomia dindygulensis, a frequently used Chinese folk medicine for lung cancer treatment. The results indicate that peperomin E exhibits antiproliferative effects, promoting apoptosis and cell-cycle arrest in non-small cell lung cancer (NSCLC) cell lines in a dose-dependent manner, while demonstrating lower toxicity against normal human lung epidermal cells. Peperomin E inhibited tumor growth in A549 xenograft BALB/c nude mice without significant secondary adverse effects, indicating that it may be safely used to treat NSCLC. Furthermore, the mechanisms underlying the anticancer effects of peperomin E have been investigated. Using an in silico target fishing method, we observed that peperomin E directly interacts with the active domain of DNA methyltransferase 1 (DNMT1), potentially affecting its genome methylation activity. Subsequent experiments verified that peperomin E decreased DNMT1 activity and expression, thereby decreasing global methylation and reactivating the epigenetically silenced tumor suppressor genes (TSGs) including RASSF1A, APC, RUNX3 and p16INK4, which in turn activates their mediated pro-apoptotic and cell-cycle regulate signaling pathways in lung cancer cells. The observations herein report for the first time that peperomin E is a potential chemotherapeutic agent for NSCLC. The anticancer effects of peperomin E may be partly attributable to its ability to demethylate and reactivate methylation-silenced TSGs through direct inhibition of the activity and expression of DNMT1.
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Do perfusion and diffusion MRI predict glioblastoma relapse sites following chemoradiation?
Abstract
To assess the value of T2* dynamic-susceptibility contrast MRI (DSC-MRI) and diffusion-weighted imaging (DWI) to predict the glioblastoma relapse sites after chemoradiation. From a cohort of 44 patients, primarily treated with radiotherapy (60 Gy) and concomitant temozolomide for glioblastoma, who were included in the reference arm of a prospective clinical trial (NCT01507506), 15 patients relapsed and their imaging data were analyzed. All patients underwent anatomical MRI, DSC-MRI and DWI before radiotherapy and every 2 months thereafter until relapse. Voxels within the sites of relapse were correlated with their perfusion and/or diffusion abnormality (PDA) pretreatment status after rigid co-registration. The relative cerebral blood volume (rCBV) and apparent diffusion coefficient (ADC) were used as biomarkers. Several PDA areas were thresholded: hyperperfused voxels using a 1.75 fixed rCBV threshold (HPt); hypoperfused (hPg) and hyperperfused (HPg) voxels using a histogram-based Gaussian method; diffusion-restricted voxels (DRg); and HPg voxels with diffusion restriction (HPg&DRg). Two sets of voxels (2,459,483 and 2,073,880) were analyzed according to these thresholding methods. Positive predictive values (PPV) of PDA voxels were low (between 9.5 and 31.9 %). The best PPV was obtained with HPg&DRg voxels within the FLAIR hyperintensity, as 18.3 % of voxels without initial PDA were within relapse sites, versus 31.9 % with initial PDA (p < 0.0001). This prospective study suggests that DSC and/or DWI-MRI do not predict the glioblastoma relapse sites. However, further investigations with new methodological approaches are needed to better understand the role of these modalities in the prediction of glioblastoma relapse sites.
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Insurance status and disparities in disease presentation, treatment, and outcomes for men with germ cell tumors
BACKGROUND
People aged 26 to 34 years represent the greatest proportion of the uninsured, and they have the highest incidence of testicular cancers. The aim of this study was to investigate the association between insurance status and cancer outcomes in men diagnosed with germ cell tumors.
METHODS
The Surveillance, Epidemiology, and End Results database was used to identify 10,211 men diagnosed with germ cell gonadal neoplasms from 2007 to 2011. Associations between insurance status and characteristics at diagnosis and receipt of treatment were examined with log-binomial regression. The association between insurance status and mortality was assessed with Cox proportional hazards regression.
RESULTS
Uninsured patients had an increased risk of metastatic disease at diagnosis (relative risk [RR], 1.26; 95% confidence interval [CI], 1.15-1.38) in comparison with insured patients, as did Medicaid patients (RR, 1.62; 95% CI, 1.51-1.74). Among men with metastatic disease, uninsured and Medicaid patients were more likely to be diagnosed with intermediate/poor-risk disease (RR for uninsured patients, 1.22; 95% CI, 1.04-1.44; RR for Medicaid patients, 1.39; 95% CI, 1.23-1.57) and were less likely to undergo lymph node dissection (RR for uninsured patients, 0.74; 95% CI, 0.57-0.94; RR for Medicaid patients, 0.76; 95% CI, 0.63-0.92) in comparison with insured patients. Men without insurance were more likely to die of their disease (hazard ratio [HR], 1.88; 95% CI, 1.29-2.75) in comparison with insured men, as were those with Medicaid (HR, 1.58; 95% CI, 1.16-2.15).
CONCLUSIONS
Patients without insurance and patients with Medicaid have an increased risk of presenting with advanced disease and dying of the disease in comparison with those who have insurance. Future studies should examine whether implementation of the Patient Protection and Affordable Care Act reduces these disparities. Cancer 2016. © 2016 American Cancer Society.
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Insurance status, health equity, and the cancer care continuum
As illustrated in two studies published in this issue of Cancer, an individual's sociodemographic characteristics including type of health insurance can decrease access to receiving high-quality and timely cancer care and result in adverse outcomes. Understanding the factors that create cancer health care disparities can help researchers, clinicians, and policy makers develop strategies and interventions to reduce them. See also pages.
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Influence of insurance status on survival of adults with glioblastoma multiforme: A population-based study
BACKGROUND
To the authors' knowledge, the impact of insurance status on the survival time of patients with glioblastoma multiforme (GBM) has not been fully understood. The objective of the current study was to clarify the association between insurance status and survival of patients with GBM by analyzing population-based data.
METHODS
The authors performed a cohort study using data from the Surveillance, Epidemiology, and End Results program. They included adult patients (aged ≥18 years) with GBM as their primary diagnosis from the years 2007 to 2012. Patients without information regarding insurance status were excluded. A survival analysis between insurance status and GBM-related death was performed using an accelerated failure time model. Demographic and clinical variables were included to adjust for confounding effects.
RESULTS
Among the 13,665 adult patients in the study cohort, 558 (4.1%) were uninsured, 1516 (11.1%) had Medicaid coverage, and 11,591 (84.8%) had non-Medicaid insurance. Compared with patients who were uninsured, insured patients were more likely to be older, female, white, married, and with a smaller tumor size at diagnosis. Accelerated failure time analysis demonstrated that older age (hazard ratio [HR], 1.04; P<.001), male sex (HR, 1.08; P<.001), large tumor size at the time of diagnosis (HR, 1.26; P<.001), uninsured status (HR, 1.14; P =.018), and Medicaid insurance (HR, 1.10; P =.006) were independent risk factors for shorter survival among patients with GBM, whereas radiotherapy (HR, 0.40; P<.001) and married status (HR, 0.86; P<.001) indicated a better outcome. The authors discovered an overall yearly progressive improvement in survival in patients with non-Medicaid insurance who were diagnosed from 2007 through 2011 (P =.015), but not in uninsured or Medicaid-insured patients.
CONCLUSIONS
Variations existed in insurance status within the GBM population. Uninsured status and Medicaid insurance suggested shorter survival compared with non-Medicaid insurance among a population of patients with GBM. Cancer 2016. © 2016 American Cancer Society.
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Telomeres and telomerase in head and neck squamous cell carcinoma: from pathogenesis to clinical implications
Abstract
Strongly associated with tobacco use, heavy alcohol consumption, and with high-risk human papillomavirus (HPV) infection, head and neck squamous cell carcinoma (HNSCC) is a frequently lethal, heterogeneous disease whose pathogenesis is a multistep and multifactorial process involving genetic and epigenetic events. The majority of HNSCC patients present with locoregional advanced stage disease and are treated with combined modality strategies that can markedly impair quality of life and elicit unpredictable results. A large fraction of those who undergo locoregional treatment and achieve a complete response later develop locoregional recurrences or second field tumors. Biomarkers that are thus able to stratify risk and enable clinicians to tailor treatment plans and to personalize post-therapeutic surveillance strategies are highly desirable. To date, only HPV status is considered a reliable independent predictor of treatment response and survival in patients with HNSCC arising from the oropharyngeal site. Recent studies suggest that telomere attrition, which may be an early event in human carcinogenesis, and telomerase activation, which is detected in up to 90 % of malignancies, could be potential markers of cancer risk and disease outcome. This review examines the current state of knowledge on and discusses the implications linked to telomere dysfunction and telomerase activation in the development and clinical outcome of HNSCC.
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The Role of Molecular Diagnostics in the Management of Patients with Gliomas
Opinion statement
The revised World Health Organization (WHO) classification of tumors of the central nervous system of 2016 combines biology-driven molecular marker diagnostics with classical histological cancer diagnosis. Reclassification of gliomas by molecular similarity beyond histological boundaries improves outcome prediction and will increasingly guide treatment decisions. This change in paradigms implies more personalized and eventually more efficient therapeutic approaches, but the era of molecular targeted therapies for gliomas is yet at its onset. Promising results of molecularly targeted therapies in genetically less complex gliomas with circumscribed growth such as subependymal giant cell astrocytoma or pilocytic astrocytoma support further development of molecularly targeted therapies. In diffuse gliomas, several molecular markers that predict benefit from alkylating agent chemotherapy have been identified in recent years. For example, co-deletion of chromosome arms 1p and 19q predicts benefit from polychemotherapy with procarbazine, CCNU (lomustine), and vincristine (PCV) in patients with anaplastic oligodendroglioma, and the presence of 1p/19q co-deletion was integrated as a defining feature of oligodendroglial tumors in the revised WHO classification. However, the tremendous increase in knowledge of molecular drivers of diffuse gliomas on genomic, epigenetic, and gene expression levels has not yet translated into effective molecular targeted therapies. Multiple reasons account for the failure of early clinical trials of molecularly targeted therapies in diffuse gliomas, including the lack of molecular entry controls as well as pharmacokinetic and pharmacodynamics issues, but the key challenge of specifically targeting the molecular backbone of diffuse gliomas is probably extensive clonal heterogeneity. A more profound understanding of clonal selection, alternative activation of oncogenic signaling pathways, and genomic instability is warranted to identify effective combination treatments and ultimately improve survival.
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Improving Prognostic Modeling in Myelodysplastic Syndromes
Abstract
Myelodysplastic syndromes (MDSs) are a heterogeneous group of disorders characterized by the accumulation of complex genetic alterations that drive disease pathogenesis and outcome. Several prognostic models have been developed over the last two decades to risk stratify patients with MDS. These models mainly used clinical variables including blast percentage, cytopenias, cytogenetics, transfusion dependency, and age. Recently, somatic mutations in specific genes have been shown to impact overall survival in MDS and can be incorporated into established prognostic models to improve their predictive abilities. Here, we review the advantages and disadvantages of established prognostic models in MDS and the impact of emerging data regarding the incorporation of somatic mutations in risk stratification.
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Treatment of Childhood Acute Lymphoblastic Leukemia: Prognostic Factors and Clinical Advances
Abstract
While the majority of children and adolescents with newly diagnosed childhood acute lymphoblastic leukemia (ALL) will be cured, as many as 20 % of patients will experience relapse. On current treatment regimens, the intensity of upfront treatment is stratified based upon prognostic factors with the aim of improving cure rates (for those at the highest risk of relapse) and minimizing treatment-related morbidity (for lower-risk patients). Here we review advances in the understanding of prognostic factors and their application. We also highlight novel treatment approaches aimed at improving outcomes in childhood ALL.
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TMPRSS2-ERG gene fusion is rare compared to PTEN deletions in stage T1a prostate cancer
Abstract
T1a prostate cancers (cancer found incidentally in transurethral resection, <5% of the tissue) are indolent tumors of the transition zone. The overexpression of ERG and the inactivation of PTEN have been shown to be important drivers of carcinogenesis in large series of prostate cancer, but the genetics of transition zone tumors have not been well characterized. We evaluated the status of ERG and PTEN in formalin-fixed paraffin-embedded tissue using immunohistochemical and FISH analysis in 54 T1a transition zone tumors. The protein expression of ERG was determined using a rabbit monoclonal antibody and nuclear staining was scored as positive or negative. The genomic status of ERG was determined using 3 colored FISH using an ERG-TMPRSS2 tri-color probe set. The protein expression of PTEN was determined using a rabbit monoclonal antibody and cytoplasmic and nuclear staining was scored as positive or negative. The genomic status of PTEN was determined using dual color FISH with a PTEN probe and a CEP10 probe. We found ERG rearrangement in 2 of 54 tumors (4%), one with protein overexpression by immunohistochemistry. PTEN inactivation was seen in 13 of 54 tumors (24%). Nine of the 13 PTEN alleles were inactivated by hemizygous deletion. No homozygous PTEN deletion was observed. PTEN deletion and ERG rearrangement were mutually exclusive. ERG rearrangement was rare compared to peripheral zone tumors and to PTEN inactivation in T1a transition zone tumors. This article is protected by copyright. All rights reserved
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Loss of MiR-424-3p, not miR-424-5p, confers chemoresistance through targeting YAP1 in non-small cell lung cancer
Abstract
MiR-424 has been discovered to be involved in the chemoresistance of lung cancer. However, the underlying mechanism by which miR-424 played role in chemoresistance has been unknown. Here, in our study, to investigate the role of miR-424 in non-small cell lung cancer (NSCLC), we've detected the expression of miR-424-3p and -5p in NSCLC tissues and paired normal control. Moreover, to explore the role of miR-424-3p in NSCLC cells, miR-424-3p and -5p were both re-expressed and knocked down using transient transfection with their respective mimics and inhibitors. Cell viability, migration and invasion were evaluated using MTT, wound-healing and Transwell assays, respectively. It was found that down-regulation of miR-424-3p was pronouncedly associated with NSCLC progression and overall prognosis; and that both miR-424-3p and miR-424-5p were markedly capable of preventing the proliferation, migration and invasion in NSCLC cells. Additionally, it is miR-424-3p but not miR-424-5p that enhances the chemo- sensitivity of NSCLC cells through targeting YAP1. Mechanistically, YAP1 was identified as down-stream target of miR-424-3p. Together, it was for the first time in our study found that it is loss of miR-424-3p not miR-424-5p that enables chemoresistance through targeting YAP1 in NSCLC, supporting that miR-424-3p could be used as therapeutic target in the curing of NSCLC with chemoresistance. This article is protected by copyright. All rights reserved
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