Endometrial carcinomas with POLE exonuclease domain mutations have a favorable prognosis

Purpose: The aim of this study was to confirm the prognostic significance of POLE exonuclease domain mutations (EDM) in endometrial carcinoma (EC) patients. In addition, the effect of treatment on POLE mutated tumours was assessed. Experimental design: A retrospective patient cohort of 496 EC patients was identified for targeted sequencing of the POLE exonuclease domain, yielding 406 evaluable tumours. Univariable and multivariable analyses were performed to determine the effect of POLE mutation status on progression-free survival (PFS), disease-specific survival (DSS) and overall survival (OS). Combining results from eight studies in a meta-analysis, we computed pooled hazard ratios (HR) for PFS, DSS, and OS. Results: POLE EDMs were identified in 39 of 406 (9.6%) ECs. Women with POLE mutated ECs were younger, with Stage 1 (92%) tumors, grade 3 (62%), endometrioid histology (82%) and frequent (49%) lymphovascular invasion. In univariable analysis, POLE mutated ECs had significantly improved outcomes compared to patients with no EDMs for PFS, DSS and OS. In multivariable analysis, POLE EDMs were only significantly associated with improved PFS. The effect of adjuvant treatment on POLE mutated cases could not be determined conclusively, however both treated and untreated patients with POLE EDMs had good outcomes. Meta-analysis revealed an association between POLE EDMs and improved PFS and DSS with pooled HRs 0.34 (95% CI 0.15-0.73) and 0.35 (95% CI 0.13-0.92), respectively. Conclusions: POLE EDMs are prognostic markers associated with excellent outcomes for EC patients. Further investigation is needed to conclusively determine if treatment is necessary for this group of women.

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Tumor infiltrating plasma cells are associated with tertiary lymphoid structures, cytolytic T cell responses, and superior prognosis in ovarian cancer

Purpose: CD8+ tumor-infiltrating lymphoyctes (TIL) are key mediators of anti-tumor immunity and are strongly associated with survival in virtually all solid tumors. However, the prognostic effect of CD8+ TIL is markedly higher in the presence of CD20+ B cells, suggesting cooperative interactions between these lymphocyte subsets lead to more potent anti-tumor immunity. Experimental Design: We assessed the co-localization patterns, phenotypes, and gene expression profiles of tumor-associated T- and B-lineage cells in high grade serous ovarian cancer (HGSC) by multicolor immunohistochemistry, flow cytometry, and bioinformatic analysis of gene expression data from The Cancer Genome Atlas. Results: T cells and B cells co-localized in four types of lymphoid aggregate, ranging from small, diffuse clusters to large, well-organized tertiary lymphoid structures (TLS) resembling activated lymph nodes. TLS were frequently surrounded by dense infiltrates of plasma cells (PCs), which comprised up to 90% of tumor stroma. PCs expressed mature, oligoclonal immunoglobulin G transcripts, indicative of antigen-specific responses. PCs were associated with the highest levels of CD8+, CD4+ and CD20+ TIL, as well as numerous cytotoxicity-related gene products. CD8+ TIL carried prognostic benefit only in the presence of PCs and these other TIL subsets. PCs were independent of mutation load, BRCA1/2 status, and differentiation antigens but positively associated with cancer-testis antigens. Conclusions: PCs are associated with the most robust, prognostically favorable CD8+ TIL responses in HGSC. We propose that TLS facilitate coordinated anti-tumor responses involving the combined actions of cytolytic T cells and antibody-producing PCs.

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Epigenetic regulation of the homeobox gene MSX1 associates with platinum resistant disease in high grade serous epithelial ovarian cancer

Purpose: Although High Grade Serous Ovarian Cancer (HGSOC) is frequently chemo-responsive, a proportion of patients do not respond to platinum-based chemotherapy at presentation or have progression-free survival of less than 6 months. Validated predictive biomarkers of lack of response would enable alternative treatment stratification for these patients and identify novel mechanisms of intrinsic resistance. Our aim was to identify DNA methylation biomarkers of poor response to chemotherapy and demonstrate involvement of the associated gene in platinum drug cell sensitivity. Experimental Design: DNA methylation was investigated in independent tumour cohorts using Illumina HumanMethylation arrays and gene expression by Affymetrix arrays and qRT-PCR. The role of Msh homeobox 1 (MSX1) in drug sensitivity was investigated by gene reintroduction and siRNA knockdown of ovarian cancer cell lines. Results: CpG sites at contiguous genomic locations within the MSX1 gene have significantly lower levels of methylation in independent cohorts of HGSOC patients which recur by 6 months compared to after 12 months (p<0.05,q<0.05,n=78), have poor RECIST response (p<0.05,q<0.05,n=61) and are associated with progression-free survival (PFS) in an independent cohort (n=146). A decrease in methylation at these CpG sites correlates with decreased MSX1 gene expression. MSX1 expression is associated with PFS (HR 0.92, 95%CI 0.85-0.99,p=0.029,n=309)). Cisplatin resistant ovarian cancer cell lines have reduced MSX1 expression and MSX1 over-expression leads to cisplatin sensitisation, increased apoptosis and increased cisplatin-induced p21 expression. Conclusions: Hypomethylation of CpG sites within the MSX1 gene is associated with resistant HGSOC disease at presentation and identifies expression of MSX1 as conferring platinum drug sensitivity.

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Adaptation to AI therapy in breast cancer can induce dynamic alterations in ER activity resulting in estrogen independent metastatic tumours

Purpose: Acquired resistance to aromatase inhibitor therapy is a major clinical problem in the treatment of breast cancer. The detailed mechanisms of how tumour cells develop this resistance remain unclear. Here, the adapted function of ER to an estrogen-depleted environment following AI treatment is reported. Experimental Design: Global ER-ChIPseq analysis of AI resistant cells identified steroid-independent ER target genes. Matched patient tumour samples, collected before and after AI treatment, were used to assess ER activity. Results: Maintained ER activity was observed in patient tumours following neoadjuvant AI therapy. Genome-wide ER-DNA binding analysis in AI resistant cell lines identified a subset of classic ligand dependent ER target genes which develop steroid independence. Kaplan Meier analysis revealed a significant association between tumours which fail to decrease this steroid independent ER target gene set in response to neoadjuvant AI therapy, and poor disease-free and overall survival (n=72 matched patient tumour samples, p=0.00339 and 0.00155 respectively). The adaptive ER response to AI treatment was highlighted by the ER/AIB1 target gene, early growth response 3 (EGR3). Elevated levels of EGR3 were detected in endocrine resistant local disease recurrent patient tumours in comparison to matched primary tissue. However, evidence from distant metastatic tumours demonstrates that the ER signalling network may undergo further adaptations with disease progression as estrogen-independent ER target gene expression is routinely lost in established metastatic tumours. Conclusions: Overall, these data provide evidence of a dynamic ER response to endocrine treatment which may provide vital clues for overcoming the clinical issue of therapy resistance.

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Molecular Pathways: AXL, a Membrane Receptor Mediator of Resistance to Therapy

AXL is a tyrosine kinase membrane receptor that signals via the phosphatidylinositol-3-kinases (PI3K), mitogen-activated protein kinases (MAPK) and protein kinase C (PKC), among other pathways. AXL has oncogenic potential and interacts with other membrane receptors, depending on their relative abundance and availability. Increased expression of AXL in cancer is often the result of pharmacological selective pressure to a number of chemo- and targeted therapies and acts as a mechanism of acquired drug resistance. This resistance phenotype, frequently accompanied by epithelial-to-mesenchymal transition, can be reversed by AXL inhibition. In tumors with high levels of epidermal growth factor receptor (EGFR), including lung, head and neck and triple negative breast cancer, AXL dimerizes with this receptor and initiates signaling that circumvent the antitumor effects of anti-EGFR therapies. Likewise AXL overexpression and dimerization with EGFR can overcome PI3K inhibition by activating the phospholipase C-gamma (PLC)-PKC cascade that in turn sustains mammalian target of rapamycin complex 1 (mTORC1) activity. The causative role of AXL in inducing resistance drug resistance is underscored by the fact that suppression of AXL restores sensitivity to these agents. Hence, these observations indicate that AXL is selectively expressed in tumor cells refractory to therapy and that co-targeting AXL in this setting would potentially overcome drug resistance. The use of AXL inhibitors should be considered in the clinic.

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Ibrutinib for mantle cell lymphoma

Future Oncology Ahead of Print.


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[177Lu-DOTA0,Tyr3]-octreotate in the treatment of midgut neuroendocrine tumors

Future Oncology Ahead of Print.


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Table_of_Contents

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Web-based cognitive training for breast cancer survivors with cognitive complaints—a randomized controlled trial

Abstract

Background

Cognitive complaints are common amongst breast cancer survivors, and no standard treatment exists. The present study evaluates whether web-based cognitive training can alleviate subjectively reported and objectively assessed cognitive complaints in a sample of breast cancer survivors. The primary and secondary outcomes were an objective measure of working memory and a measure of perceived cognitive functioning. Additional outcomes were neuropsychological tests of memory, executive function, working memory and questionnaire-based assessment of anxiety, depression and somatization.

Methods

A total of 157 female breast cancer survivors were recruited from an existing cohort and through announcements in open access cancer-related Internet fora and randomly allocated to either web-based cognitive training (eCogT) with telephone support (n = 94) or a waitlist control (WLC) condition (n = 63). eCogT encompassed 30 training sessions over 6 weeks. Neuropsychological assessments were undertaken over the telephone, and questionnaire data was collected online. Data was collected at baseline, post-intervention and at 5-month follow-up.

Results

Mixed linear models revealed no statistically significant change in primary or secondary outcome at follow-up in either group. Statistically significant improvements (p 0.040–0.043) were found in the eCogT group for verbal learning and on a working memory test.

Conclusions

Web-based cognitive training did not result in improvements of the primary or secondary outcome. Improved performance was observed on verbal learning and working memory. These effects were observed at 5-month follow-up, indicating long-term effects of training. The intervention may be applied in a clinical setting at low cost and without risk of adverse effects. © 2016 The Authors. Psycho-Oncology Published by John Wiley & Sons Ltd.

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Correlates of self-rated attachment in patients with cancer and their caregivers: a systematic review and meta-analysis

Abstract

Background

This study aimed to evaluate the association between an anxious/avoidant attachment style and psychosocial variables in patients with cancer and their caregivers.

Methods

PsycINFO, PubMed, Google Scholar, and SCOPUS were searched for empirical studies published in peer-reviewed journals between 1994 and 2015, and unpublished data from one cohort were added. Meta-analyses synthesized results from studies investigating the correlates of attachment styles, measured with validated scales, among patients with cancer or their caregivers.

Results

Thirteen studies (k = 13) were included in the quantitative synthesis (including unpublished data from one cohort). Anxious attachment was associated with depression (r = 0.29, CI 0.19–0.38, I² = 76%), anxiety (r = 0.34, CI 0.13–0.52, I² = 69%), and social support (r = −0.39, CI −0.55–0.21, I² = 87%). Avoidant attachment was associated with depressive symptoms (r = 0.20, CI 0.15–0.25, I² = 16%), anxiety (r = 0.13, CI 0.01–0.24, I² = 4%), and social support (r = −0.28, CI −0.42–0.14, I² = 75%).

Conclusions

Patients with cancer and their caregivers showing high levels of insecure attachment are at risk of experiencing higher levels of depressive symptoms, anxiety, and poor social support. Findings suggest that clinicians' awareness of attachment styles may serve as important clinical insight to improve treatment outcomes. Large-scale studies and longitudinal studies are required to investigate distinct longitudinal pathways in cancer-related distress across different attachment styles Copyright © 2016 John Wiley & Sons, Ltd.

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Comparison of anthropometric measurements of adiposity in relation to cancer risk: a systematic review of prospective studies

Abstract

Purpose

In epidemiology, the relationship between increased adiposity and cancer risk has long been recognized. However, whether the association is the same for measures of abdominal or whole body adiposity is unclear. The aim of this systematic review is to compare cancer risk, associated with body mass index (BMI), an indicator of whole body adiposity, with indicators of abdominal adiposity in studies in which these indicators have been directly measured.

Methods

We conducted a systematic search from 1974 (EMBASE) and 1988 (PubMed) to September 2015 with keywords related to adiposity and cancer. Included studies were limited to cohort studies reporting directly measured anthropometry and performing mutually adjusted analyses.

Results

Thirteen articles were identified, with two reporting on breast cancer, three on colorectal cancer, three on endometrial cancer, two on gastro-oesophageal cancer, two on renal cancer, one on ovarian cancer, one on bladder cancer, one on liver and biliary tract cancer and one on leukaemia. Evidence suggests that abdominal adiposity is a stronger predictor than whole body adiposity for gastro-oesophageal, leukaemia and liver and biliary tract cancer in men and women and for renal cancer in women. Abdominal adiposity was a stronger predictor for bladder and colorectal cancer in women, while only BMI was a predictor in men. In contrast, BMI appears to be a stronger predictor for ovarian cancer. For breast and endometrial cancer, both measures were predictors for cancer risk in postmenopausal women.

Conclusions

Only few studies used mutually adjusted and measured anthropometric indicators when studying adiposity–cancer associations. Further research investigating cancer risk and adiposity should include more accurate non-invasive indicators of body fat deposition and focus on the understudied cancer types, namely leukaemia, ovarian, bladder and liver and biliary tract cancer.

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Lifestyle factors and risk of leukemia and non-Hodgkin’s lymphoma: a case–control study

Abstract

Purpose

Risk factors for leukemia and lymphomas in adults are largely unknown. This study was aimed at evaluating the association between lifestyle factors and the risk of hematological malignancies in an adult population.

Methods

Data were drawn from a population-based case–control study carried out in Italy and included 294 cases (199 lymphoid and 95 myeloid) and 279 controls. Analyses were performed using standard multivariable logistic regression.

Results

Hair dye use for at least 15 years was associated with a higher risk of lymphoid malignancies among females (OR 2.3, 95 % CI 1.0–4.9, p = 0.036, test for trend). Furthermore, a protective effect of a moderate to heavy tea consumption on the risk of myeloid malignancies was observed (OR 0.4, 95 % CI 0.2–0.9, p = 0.017). No association was found for the use of alcoholic beverages and tobacco smoking.

Conclusions

Our results confirm the potential carcinogenic effect of prolonged hair dye use observed in previous investigations. The excess risk could be explained by exposure to a higher concentration of toxic compounds in hair products used in the past. The protective effect of regular tea consumption observed in an area with a very high prevalence of black tea consumers deserves further investigation.

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Driving New Approaches to Cancer Prevention and Early Detection

The following is the last in a series of posts from senior NCI scientists and leaders on NCI's Annual Plan and Budget Proposal for Fiscal Year 2017, which was officially submitted to the President on September 17, 2015. The proposal provides an overview of NCI's priorities and key initiatives and the institute's funding request for the President to consider when formulating his own Fiscal Year (FY) 2017 budget proposal.

In this post, Barry Kramer, M.D., M.P.H., director of NCI's Division of Cancer Prevention (DCP), discusses a new NCI-funded research effort intended to help guide treatment decisions for people diagnosed with cancer following a screening test.

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Analysis of Ionomic Profiles of Canine Hairs Exposed to Lipopolysaccharide (LPS)-Induced Stress

Abstract

The purpose of this study was to provide a new insight on the response of canines to stress exposure; the ionomic profiles of canine hair (2.8 ± 0.3 years, 15.17 ± 2.1 kg) (n = 10) was determined before and after lipopolysaccharide (LPS) injections. LPS was intramuscularly injected to induce inflammatory stress responses which were confirmed by observing increases in the level of serum cortisol, aldosterone, and inflammatory cytokines such as IL-6, IL-1β, and TNF-α. The hair contents of 17 elements were obtained by applying analytical procedures using the inductively coupled plasma mass spectrometry (ICP-MS). The following elements: sodium(Na) and potassium(K) among macro-elements, iron(Fe) and manganese(Mn) among micro-elements, and aluminum(Al), nickel(Ni), and lead(Pb) for toxic elements, showed significant increased levels with the immunological stress. The degree of increase in toxic elements was remarkable with the stress exposure. A forty-five-fold increase seen in Al accumulation with the stress exposure was noteworthy. Although mercury(Hg) and cadmium(Cd) showed decreased levels with the stress exposure, the degree was negligible compared to the level of increase. Correlation pattern between the elements was changed with the immunological stress. Toxic elements became more correlated with macro- or micro-elements than with toxic elements themselves after the stress exposure. Principal component analysis (PCA) showed that LPS challenge shifted the overall hair mineral profiles to a consistent direction changing Al and K up, even in animals with different hair mineral profiles before LPS treatment. In conclusion, the multivariate data processing and study of element distribution patterns provided new information about the ionomic response of the canine hairs to immunological stress, i.e., the ionomic profiles of canine hairs is strongly affected by the stress induced by LPS injections.

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Correlation Between Apparent Diffusion Coefficients and Standardized Uptake Values in Hybrid 18 F-FDG PET/MR: Preliminary Results in Rectal Cancer

Abstract

Purpose

Fluorine-18-fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography (PET) and diffusion-weighted magnetic resonance imaging (DWI) share the same role in clinical oncology and it is feasible to obtain the standardized uptake value (SUV) and apparent diffusion coefficient (ADC) simultaneously by emerging the hybrid positron emission tomography/magnetic resonance (PET/MR). This study investigated the correlation between the ADCs of rectal cancer lesions and their SUVs derived from hybrid PET/MR.

Methods

Nine patients with histologically proven rectal adenocarcinoma (5 men, 4 women; mean age, 70 ± 15.91 years) underwent torso ¹⁸F-FDG PET/CT and regional hybrid ¹⁸F-FDG PET/MR sequentially. A fixed threshold value of 40 % of maximum uptake was used to determine tumor volume of interest (VOI) on PET image; SUVmax, SUVpeak, and SUVmean were calculated automatically. A single freehand region of interest (ROI) was drawn on high b-value (b1000) DWI image and copied to corresponding ADC map to determine the ADCmean of rectal cancer lesion. Spearman's rank correlation coefficient (ρ) was calculated to determine the correlation between SUVs and ADC values.

Results

SUVmax, SUVpeak, and SUVmean derived by hybrid PET/MR were 12.35 ± 4.66 (mean ± standard deviation), 9.66 ± 3.15 and 7.41 ± 2.54, respectively. The ADCmean value of rectal cancer lesions was 1.02 ± 0.08 × 10⁻³mm²/s. ADCmean was significantly and inversely correlated with SUV values (SUVmax, ρ = −0.95, p < 0.001; SUVpeak, ρ = −0.93, p < 0.001; SUVmean, ρ = −0.91, p = 0.001).

Conclusions

This preliminary hybrid PET/MR study demonstrates a significant inverse correlation exists between metabolic activity on ¹⁸F-FDG PET and water diffusion on DWI in rectal cancer.

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Risk Factors for the Loss of Lean Body Mass After Gastrectomy for Gastric Cancer

Abstract

Background

Lean body mass loss after surgery, which decreases the compliance of adjuvant chemotherapy, is frequently observed in gastric cancer patients who undergo gastrectomy for gastric cancer. However, the risk factors for loss of lean body mass remain unclear.

Methods

The current study retrospectively examined the patients who underwent curative gastrectomy for gastric cancer between June 2010 and March 2014 at Kanagawa Cancer Center. All the patients received perioperative care for enhanced recovery after surgery. The percentage of lean body mass loss was calculated by the percentile of lean body mass 1 month after surgery to preoperative lean body mass. Severe lean body mass loss was defined as a lean body mass loss greater than 5 %. Risk factors for severe lean body mass loss were determined by both uni- and multivariate logistic regression analyses.

Results

This study examined 485 patients. The median loss of lean body mass was 4.7 %. A lean body mass loss of 5 % or more occurred for 225 patients (46.4 %). Both uni- and multivariate logistic analyses demonstrated that the significant independent risk factors for severe lean body mass loss were surgical complications with infection or fasting (odds ratio [OR] 3.576; p = 0.001), total gastrectomy (OR 2.522; p = 0.0001), and gender (OR 1.928; p = 0.001).

Conclusions

Nutritional intervention or control of surgical invasion should be tested in future clinical trials for gastric cancer patients with these risk factors to maintain lean body mass after gastrectomy.

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Solitary Lymph Node Recurrence of Esophageal Squamous Cell Carcinoma: Surgical Failure or Systemic Disease?

Abstract

Background

Post-surgical solitary lymph node recurrence (SLNR) may be a characteristic of esophageal squamous cell carcinoma (ESCC).

Methods

Among 402 patients who underwent curative resection for ESCC between 2003 and 2010, we retrospectively reviewed the cases of 148 patients who developed disease recurrence.

Results

Among the 148 reviewed cases, 24 patients (16.2 %) developed SLNR and 124 (83.8 %) developed non-SLNR. Clinicopathological background did not differ between the two groups. Five-year overall survival was 37.8 % among the 22 patients with SLNR who received local treatment (surgery or radiation) with or without systemic chemotherapy, compared with only 2.5 % among patients with non-SLNR (p = 0.0002). Among the 24 cases of SLNR, 18 were localized inside the surgical field (i.e. the standard three-field regional lymph nodes), while six occurred outside of the surgical field (abdominal para-aortic nodes in four cases and mediastinum in two cases). Notably, of the six patients with SLNR outside of the surgical field, four survived without additional recurrence after SLNR development. Among patients with SLNR, survival was not associated with tumor location, tumor size, or time to recurrence. Initial tumor stage was not associated with SLNR incidence but was identified as a predictor of long-term survival among patients with SLNR.

Conclusions

SLNR developed inside and outside of the surgical field, showing a relatively favorable prognosis with local treatment regardless of location. SLNR outside of the surgical field may actually be localized disease in ESCC.

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Evaluating the Prognostic Role of Elevated Preoperative Carcinoembryonic Antigen Levels in Colon Cancer Patients: Results from the National Cancer Database

Abstract

Objectives

Carcinoembryonic antigen (CEA) is a reliable tumor marker for the management and surveillance of colon cancer. However, limitations in previous studies have made it difficult to elucidate whether CEA should be established as a prognostic indicator. This study examines the association between elevated preoperative CEA levels and overall survival in colon cancer patients using a national population-based registry.

Methods

Stage I–III colon cancer patients were identified from the 2004–2006 National Cancer Database. A multivariable Cox proportional hazards model was used to estimate the association between elevated CEA levels and overall survival after controlling for important patient, hospital, and tumor characteristics. A Monte Carlo Markov Chain was used to impute the large degree of missing CEA data. All models controlled for the propensity score in order to account for selection bias.

Results

A total of 137,381 patients met the inclusion criteria. Overall, 34 % of patients had an elevated CEA level and 66 % had a normal CEA level, with a median survival of 70 and 100 months, respectively. Patients with an elevated CEA level had a 62 % increase in the hazard of death (HR 1.62, 95 % CI 1.53–1.74) compared with patients with a normal CEA level.

Conclusions

Preoperative CEA was an independent predictor of overall survival across all stages. The results support recommendations to include CEA levels as another high-risk feature that clinicians can use to counsel patients on adjuvant chemotherapy, especially for stage II patients.

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Optimal Percent Myxoid Component to Predict Outcome in High-Grade Myxofibrosarcoma and Undifferentiated Pleomorphic Sarcoma

Abstract

Background

Myxofibrosarcoma and undifferentiated pleomorphic sarcoma (UPS) are aggressive, genetically complex sarcomas. The minimum myxoid component used as a criterion for myxofibrosarcoma varies widely, so we determined the optimal myxoid component cutpoints for stratifying outcomes of UPS and myxofibrosarcoma. We also analyzed clinicopathologic factors associated with outcome.

Methods

Review of a prospective, single-institution database identified 197 patients with primary, high-grade extremity/truncal myxofibrosarcoma or UPS resected during 1992–2013. Histology was reviewed and percent myxoid component determined for each tumor. Disease-specific survival (DSS) and distant recurrence-free survival (DRFS) were analyzed using the Kaplan–Meier method, log-rank test, and Cox regression.

Results

Median follow-up for survivors was 6.4 years. In minimum p value analysis of myxoid component, the best cutpoint for both DSS and DRFS was 5 % (adjusted p ≤ 0.001), followed by 70 %. Therefore, sarcomas with <5 % myxoid component (n = 69) were classified as UPS and those with ≥5 % myxoid component (n = 128) as myxofibrosarcoma. Five-year DRFS was 24 % for UPS, 51 % for 5–69 % myxoid component myxofibrosarcoma, and 65 % for ≥70 % myxoid component myxofibrosarcoma. Myxoid component, tumor size, and age were independently associated with DSS; myxoid component and tumor size were associated with DRFS. Only tumor site was associated with local recurrence.

Conclusions

Percent myxoid component and tumor size are the two most important predictors of DSS and DRFS in high-grade myxofibrosarcoma and UPS. A 5 % myxoid component cutpoint is an improved criterion for classifying myxofibrosarcoma. Myxoid component-based classification improves stratification of patient outcome and will aid in selection of patients for systemic therapy and clinical trials.

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The effects of antiepileptic drugs on the growth of glioblastoma cell lines

Abstract

To determine the effects of antiepileptic drug compounds on glioblastoma cellular growth, we exposed glioblastoma cell lines to select antiepileptic drugs. The effects of selected antiepileptic drugs on glioblastoma cells were measured by MTT assay. For compounds showing significant inhibition, cell cycle analysis was performed. Statistical analysis was performed using SPSS. The antiepileptic compounds selected for screening included carbamazepine, ethosuximide, gabapentin, lamotrigine, levetiracetam, magnesium sulfate, oxcarbazepine, phenytoin, primidone, tiagabine, topiramate, valproic acid, and vigabatrin. Dexamethasone and temozolomide were used as a negative and positive control respectively. Our results showed temozolomide and oxcarbazepine significantly inhibited glioblastoma cell growth and reached IC₅₀ at therapeutic concentrations. The other antiepileptic drugs screened were unable to reach IC₅₀ at therapeutic concentrations. The metabolites of oxcarbazepine were also unable to reach IC_50. Dexamethasone, ethosuximide, levetiracetam, and vigabatrin showed some growth enhancement though they did not reach statistical significance. The growth enhancement effects of ethosuximide, levetiracetam, and vigabatrin found in the study may indicate that these compounds should not be used for prophylaxis or short term treatment of epilepsy in glioblastoma. While valproic acid and oxcarbazepine were effective, the required dose of valproic acid was far above that used for the treatment of epilepsy and the metabolites of oxcarbazepine failed to reach significant growth inhibition ruling out the use of oral oxcarbazepine or valproic acid as monotherapy in glioblastoma. The possibility of using these compounds as local treatment is a future area of study.

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The leukemogenic fusion gene MLL-AF9 alters microRNA expression pattern and inhibits monoblastic differentiation via miR-511 repression

Abstract

Background

In this study we explored the role of microRNAs (miRNAs) as mediators of leukemogenic effects of the fusion gene MLL-AF9, which results from a frequent chromosomal translocation in infant and monoblastic acute myeloid leukemia (AML).

Methods

We performed a specific and efficient knockdown of endogenous MLL-AF9 in the human monoblastic AML cell line THP1.

Results

The knockdown associated miRNA expression profile revealed 21 MLL-AF9 dependently expressed miRNAs. Gene ontology analyses of target genes suggested an impact of these miRNAs on downstream gene regulation via targeting of transcriptional modulators as well as involvement in many functions important for leukemia maintenance as e.g. myeloid differentiation, cell cycle and stem cell maintenance. Furthermore, we identified one of the most intensely repressed miRNAs, miR-511, to raise CCL2 expression (a chemokine ligand important for immunosurveillance), directly target cyclin D1, inhibit cell cycle progression, increase cellular migration and promote monoblastic differentiation. With these effects, miR-511 may have a therapeutic potential as a pro-differentiation agent as well as in leukemia vaccination approaches.

Conclusions

Our study provides new insights into the understanding of miRNAs as functional mediators of the leukemogenic fusion gene MLL-AF9 and opens new opportunities to further investigate specific therapeutic options for AML via the miRNA level.

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The human RNA surveillance factor UPF1 regulates tumorigenesis by targeting Smad7 in hepatocellular carcinoma

Abstract

Background

In spite of progress in diagnostics and treatment of Hepatocellular Carcinoma (HCC), its prognosis remains poor, and improved treatment strategies for HCC require detailed understanding of the underlying mechanism. In this investigation we studied the role of Up-frameshift 1 (UPF1) in the tumorigenesis of HCC.

Methods

We determined the expression level of UPF1 in HCC tissues with quantitative real-time PCR and western blotting and then studied its clinical significance. Sodium bisulfite sequencing was used to investigate the regulation of UPF1. We explored the biological significance of UPF1 with gain-and-loss-of-function analyses both in vitro and in vivo. The relationship between UPF1 and SMAD7 was also investigated by western blotting and immunofluorescence.

Results

A great downregulation of UPF1 due to promoter hypermethylation was observed in tumor tissues compared to their adjacent normal tissues. Meanwhile, patients with low UPF1 expression have significantly poorer prognosis than those with high expression. Functionally, UPF1 regulated HCC tumorigenesis both in vitro and in vivo. Moreover, the decreased UPF1 level in HCC reduces NMD efficiency and leads to up-regulation of Smad7, then affects the TGF-β pathway.

Conclusion

Our findings revealed that UPF1 is a potential tumor suppressive gene and may be a potential therapeutic target for HCC.

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MiR-548c impairs migration and invasion of endometrial and ovarian cancer cells via downregulation of Twist

Abstract

Background

MicroRNAs (miRNAs) are a class of small non-coding RNAs, which post-transcriptionally repress the expression of genes involved in cancer initiation and progression. Although some miRNAs that target many signaling pathways (also called universe miRNAs) are supposed to play a global role in diverse human tumors, their regulatory functions in gynecological cancers remain largely unknown. We investigated the biological role and underlying mechanism of miR-548c (one universe miRNA) in endometrial and ovarian cancer.

Methods

The effects of miR-548c overexpression on cell proliferation, migration and invasion were studied in endometrial and ovarian cancer cells. TWIST1 (Twist) was identified as a direct miR-548c target by western blot analysis and luciferase activity assay. The expression of miR-548c and Twist were examined by qRT-PCR in endometrial and ovarian cancer tissues.

Results

Here, we report that miR-548c is down-regulated in endometrial and ovarian cancer tissues when compared to normal tissues, and our meta-analysis reveal that decreased miR-548c expression correlates with poor prognosis in endometrial cancer patients. We show that in endometrial and ovarian cancer cells, ectopic expression of miR-548c significantly inhibits whereas knockdown of miR-548c dramatically induces cancer cell proliferation, migration and invasion. By using luciferase reporter assay, we demonstrate that Twist, a known oncogene in endometrial and ovarian cancers, is a direct target of miR-548c. Furthermore, the expression of Twist partially abrogates the tumor suppressive effects of miR-548c on cell migration and invasion.

Conclusion

These findings suggest that miR-548c directly downregulates Twist, and provide a novel mechanism for Twist upregulation in both endometrial and ovarian cancers. The use of miR-548c may hold therapeutic potential for the treatment of Twist-overexpressing tumors.

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Inhibition of carbonic anhydrase potentiates bevacizumab treatment in cholangiocarcinoma

Abstract

Cholangiocarcinoma (CCA) is a unique liver cancer subtype with an increasing incidence globally. The lack of specific symptoms and definite diagnostic markers results in a delayed diagnosis and disease progression. Systemic chemotherapy is commonly selected for advanced CCA even though its advantages remain unknown. Targeted therapy, especially anti-vascular endothelial growth factor (VEGF) therapy, is promising for CCA; however, improvements in the therapeutic regimen are necessary to overcome subsequent resistance. We demonstrated VEGF expression was higher in CCA cell lines than in other liver cancer cells. Secreted VEGFs played roles in the induction of peri- and intra-tumoral vascularization. VEGF neutralization by bevacizumab effectively reduced tumor growth, mainly through the suppression of angiogenesis; however, increases in the expression of hypoxia-inducible factor 1α (HIF1α) and HIF1α-responsive genes (such as VEGF, VEGFR1, VEGFR2, carbonic anhydrase (CA) IX and CAXII) indicated the potential for subsequent therapeutic resistance. Supplementation with a carbonic anhydrase inhibitor, acetazolamide, enhanced the anti-CCA effects of bevacizumab. Anti-angiogenesis and anti-proliferation were observed with the combination treatment. These results suggested a novel treatment strategy to overcome anti-angiogenesis resistance and the importance of "induced essentiality" in the treatment of CCA.

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Pretreatment lymphocyte to monocyte ratio as a predictor of prognosis in patients with early-stage triple-negative breast cancer

Abstract

Recent studies have shown that the lymphocyte to monocyte ratio (LMR) is a useful prognostic factor in various cancers. The purpose of the current study was to investigate the association between pretreatment LMR, disease-free survival (DFS), and overall survival (OS) in patients with early-stage (I to III) triple-negative breast cancer (TNBC). Pretreatment LMR with corresponding clinical features from 230 TNBC patients was noted. A receiver operating characteristic (ROC) curve for survival prediction was plotted to verify the optimal cutoff values for LMR, lymphocyte, and monocyte counts. The difference between variables was calculated using chi-square tests. The Kaplan–Meier method and univariate and multivariate Cox regression models were applied to assess OS and DFS. Based on the ROC analysis, the optimal cutoff point for LMR was 4.7. Associations between high LMR (≥4.7) and significantly small tumor size (P = 0.005) and TNM stage (P = 0.013) were found, although there was no significant association for other clinical pathological factors. In the multivariate analysis, LMR was a significant predictive factor for both OS (hazard ratio [HR] = 0.42; 95 % confidence interval [CI], 0.19–0.95; P < 0.001) and DFS (HR = 0.40; 95 % CI, 0.20–0.79; P < 0.001). In addition, the predictive values of the OS and DFS were also observed for absolute counts of lymphocytes (P < 0.001) and monocytes (P < 0.001). Our study suggests that pretreatment LMR may be a predictive factor for long-term survival in patients with early-stage TNBC.

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MEF2D/Wnt/β-catenin pathway regulates the proliferation of gastric cancer cells and is regulated by microRNA-19

Abstract

The underlying molecular pathogenesis in gastric cancer remains poorly unknown. The transcription factor myocyte enhancer factor 2D (MEF2D) participates in the initiation and development of many human cancers. However, its potential roles in gastric cancer have surprisingly not been studied. In present study, we first explored MEF2's expression in gastric cancer, finding that only MEF2D rather than MEF2A, 2B, or 2C was elevated in gastric cancer clinical specimens. Furthermore, immunohistochemical analysis on the tissue samples obtained from 260 patients with gastric cancer revealed that MEF2D expression was significantly associated with the clinical stage, vascular invasion, metastasis, and tumor size. Gastric cancer patients with MEF2D expression showed a significantly shorter overall survival time compared with that of patients lacking of MEF2D. Multivariate analysis revealed that MEF2D expression was an independent prognostic factor for overall survival. These results indicated that MEF2D was a prognostic marker for gastric cancer. Notably, MEF2D silencing was able to reduce the proliferation and survival of gastric cancer cells. Further study revealed that MEF2D suppression significantly inactivated the oncogenic Wnt/β-catenin pathway. Downregulation of MEF2D inhibited the tumorigenesis of gastric cancer cells in nude mice. Finally, MEF2D is a direct target of miR-19, which was found to be decreased in gastric cancer clinical specimens. Collectively, we found that miR-19/MEF2D/Wnt/β-catenin regulatory network contributes to the growth of gastric cancer, hinting a new promising target for gastric cancer treatment.

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Secretome profiling of oral squamous cell carcinoma-associated fibroblasts reveals organization and disassembly of extracellular matrix and collagen metabolic process signatures

Abstract

An important role has been attributed to cancer-associated fibroblasts (CAFs) in the tumorigenesis of oral squamous cell carcinoma (OSCC), the most common tumor of the oral cavity. Previous studies demonstrated that CAF-secreted molecules promote the proliferation and invasion of OSCC cells, inducing a more aggressive phenotype. In this study, we searched for differences in the secretome of CAFs and normal oral fibroblasts (NOF) using mass spectrometry-based proteomics and biological network analysis. Comparison of the secretome profiles revealed that upregulated proteins involved mainly in extracellular matrix organization and disassembly and collagen metabolism. Among the upregulated proteins were fibronectin type III domain-containing 1 (FNDC1), serpin peptidase inhibitor type 1 (SERPINE1), and stanniocalcin 2 (STC2), the upregulation of which was validated by quantitative PCR and ELISA in an independent set of CAF cell lines. The transition of transforming growth factor beta 1 (TGF-β1)-mediating NOFs into CAFs was accompanied by significant upregulation of FNDC1, SERPINE1, and STC2, confirming the participation of these proteins in the CAF-derived secretome. Type I collagen, the main constituent of the connective tissue, was also associated with several upregulated biological processes. The immunoexpression of type I collagen N-terminal propeptide (PINP) was significantly correlated in vivo with CAFs in the tumor front and was associated with significantly shortened survival of OSCC patients. Presence of CAFs in the tumor stroma was also an independent prognostic factor for OSCC disease-free survival. These results demonstrate the value of secretome profiling for evaluating the role of CAFs in the tumor microenvironment and identify potential novel therapeutic targets such as FNDC1, SERPINE1, and STC2. Furthermore, type I collagen expression by CAFs, represented by PINP levels, may be a prognostic marker of OSCC outcome.

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Prognostic value of high FoxC2 expression in resectable non-small cell lung cancer, alone or in combination with E-cadherin expression

Abstract

Background

FoxC2 is an epithelial–mesenchymal transition (EMT) regulator which induces metastasis. The purpose of this study is to assess the prognostic value of FoxC2 expression in non-small cell lung cancer (NSCLC), alone or in combination with E-cadherin expression.

Methods

A retrospective study was conducted using immunohistochemistry to investigate FoxC2 and E-cadherin expression in a cohort of 309 patients with surgically resected NSCLCs. The prognostic value of FoxC2 and E-cadherin on overall survival (OS) and recurrence-free survival (RFS) was determined by Kaplan-Meier analysis and Cox proportional hazard models.

Results

High FoxC2 expression was detected in 26.5 % of tumors, and significantly correlated with tobacco use (p = 0.047), adenocarcinoma (p = 0.008) and nodal involvement (p < 0.001). Univariate analysis revealed its association with OS (p = 0.036) and RFS (p = 0.011). By multivariate analysis, high FoxC2 expression lost its significance as an independent predictor of recurrence (p = 0.077), while TNM stage, nodal status and the presence of high FoxC2 and impaired E-cadherin expression retained independent prognostic significance in relation to both OS and RFS. Subset analyses indicated that high FoxC2 expression was significantly associated with disease outcome in node-positive, but not in node-negative patients.

Conclusion

Evaluation of FoxC2 expression, alone or in combination with E-cadherin expression, may help to stratify NSCLC patients for risk of disease progression, pointing to this EMT regulator as a potential prognostic marker.

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CD133+ liver cancer stem cells resist interferon-gamma-induced autophagy

Abstract

Background

Hepatocellular carcinoma (HCC) is one of the most fatal malignancies worldwide, and CD133 is a popular cancer stem cell (CSC) marker for HCC. CD133⁺ CSCs have been reported to resist conventional chemo- and radiotherapy, but little is known about their response to immune surveillance. Interferon-gamma (IFN-γ) is one of key cytokines that the immune system produce to eradicate cancer cells, so we investigated the function of IFN-γ on CD133+ HCC CSCs in this study.

Methods

The response of CD133⁺ cells to IFN-γ was performed with functional assays (cell proliferation assay and tumor formation in nude mice), flow cytometry, immunofluorescence staining and RNA interference.

Results

We found that IFN-γ inhibited the proliferation of cell lines with low percentage of CD133⁺ cells (wild-type human cells, BEL7402, QGY7701) but it did not affect the proliferation of cell lines with high percentage of CD133⁺ cells (wild-type human cells, Huh7, PLC8024) in vivo and in vitro (nude mice). Flow cytometry analysis demonstrated that the percentage of CD133+ cells increased after IFN-γ treatment of low CD133⁺ cell lines. Furthermore, IFN-γ induced the autophagy of low CD133⁺ cell lines to decrease proliferation.

Conclusion

CD133⁺ HCC CSCs resisted IFN-γ-induced autophagy, which might also be a mechanism through which CSCs resist immune eradication.

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Novel polymorphisms in caspase-8 are associated with breast cancer risk in the California Teachers Study

Abstract

Background

The ability of tamoxifen and raloxifene to decrease breast cancer risk varies among different breast cancer subtypes. It is important to determine one's subtype-specific breast cancer risk when considering chemoprevention. A number of single nucleotide polymorphisms (SNPs), including one in caspase-8 (CASP8), have been previously associated with risk of developing breast cancer. Because caspase-8 is an important protein involved in receptor-mediated apoptosis whose activity is affected by estrogen, we hypothesized that additional SNPs in CASP8 could be associated with breast cancer risk, perhaps in a subtype-specific manner.

Methods

Twelve tagging SNPs of CASP8 were analyzed in a nested case control study (1,353 cases and 1,384 controls) of non-Hispanic white women participating in the California Teachers Study. Odds ratios (ORs) and 95 % confidence intervals (CIs) were calculated for each SNP using all, estrogen receptor (ER)-positive, ER-negative, human epidermal growth factor receptor 2 (HER2)-positive, and HER2-negative breast cancers as separate outcomes.

Results

Several SNPs were associated with all, ER-positive, and HER2-positive breast cancers; however, after correcting for multiple comparisons (i.e., p < 0.0008), only rs2293554 was statistically significantly associated with HER2-positive breast cancer (OR = 1.98, 95 % CI 1.34-2.92, uncorrected p = 0.0005).

Conclusions

While our results for CASP8 SNPs should be validated in other cohorts with subtype-specific information, we conclude that some SNPs in CASP8 are associated with subtype-specific breast cancer risk. This study contributes to our understanding of CASP8 SNPs and breast cancer risk by subtype.

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Ligation of lymph vessels for the treatment of recurrent inguinal lymphoceles following lymphadenectomy

Abstract

Background

Recurrent lymphocele following groin dissection is generally a self-limiting condition, but in a few cases, the lymphocele persists and for this, there are not many options. Few reports have proposed the efficacy of lymph vessel ligation with patent blue as a vessel locator. We have used this technique since 2007 in our very severe cases and herein present our results.

Methods

The study was a retrospective case series in a university hospital setting. All patients who had this procedure performed were included from the first procedure performed in 2007 until August 2015, and their data was retrieved from electronic patient records.

Results

In total, eight patients had this procedure performed for a total of ten inguinal regions. In all regions, leaking lymph vessels were easily found by the blue color and a median of 3 (range 1–5 vessels) vessels per region were ligated using titanium clips. For two patients, there was still a need for puncture which lasted 13–37 days postoperatively. For the remaining patients, there was an immediate stop in lymphocele formation but one patient developed a lymphatic malformation which after removal resulted in the recurrence of lymphocele and had the procedure performed again with immediate effect.

Conclusions

Ligation of lymph vessels for the treatment of recurrent inguinal lymphoceles appears to be an appropriate treatment modality that is both quick and easy to perform with minimum risk, and in most cases, it results in immediate complete stop in the lymphocele formation.

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MiR-548c impairs migration and invasion of endometrial and ovarian cancer cells via downregulation of Twist

MicroRNAs (miRNAs) are a class of small non-coding RNAs, which post-transcriptionally repress the expression of genes involved in cancer initiation and progression. Although some miRNAs that target many signal...

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The leukemogenic fusion gene MLL-AF9 alters microRNA expression pattern and inhibits monoblastic differentiation via miR-511 repression

In this study we explored the role of microRNAs (miRNAs) as mediators of leukemogenic effects of the fusion gene MLL-AF9, which results from a frequent chromosomal translocation in infant and monoblastic acute my...

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The human RNA surveillance factor UPF1 regulates tumorigenesis by targeting Smad7 in hepatocellular carcinoma

In spite of progress in diagnostics and treatment of Hepatocellular Carcinoma (HCC), its prognosis remains poor, and improved treatment strategies for HCC require detailed understanding of the underlying mecha...

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Impaired mitochondrial function is abrogated by dexrazoxane in doxorubicin-treated childhood acute lymphoblastic leukemia survivors

BACKGROUND

Impaired cardiac function in doxorubicin-treated childhood cancer survivors is partly mediated by the disruption of mitochondrial energy production. Doxorubicin intercalates into mitochondrial DNA (mtDNA) and disrupts genes encoding for polypeptides that make adenosine triphosphate.

METHODS

This cross-sectional study examined mtDNA copy numbers per cell and oxidative phosphorylation (OXPHOS) in peripheral blood mononuclear cells (PBMCs) in 64 childhood survivors of high-risk acute lymphoblastic leukemia (ALL) who had been treated on Dana-Farber Cancer Institute childhood ALL protocols and had received doxorubicin alone (42%) or doxorubicin with the cardioprotectant dexrazoxane (58%). The number of mtDNA copies per cell and the OXPHOS enzyme activity of nicotinamide adenine dinucleotide dehydrogenase (complex I [CI]) and cytochrome c oxidase (complex IV [CIV]) were measured with quantitative real-time polymerase chain reaction immunoassays and thin-layer chromatography, respectively.

RESULTS

At a median follow-up of 7.8 years after treatment, the median number of mtDNA copies per cell for patients treated with doxorubicin alone (1106.3) was significantly higher than the median number for those who had also received dexrazoxane (310.5; P = .001). No significant differences were detected between the groups for CI or CIV activity.

CONCLUSIONS

Doxorubicin-treated survivors had an increased number of PBMC mtDNA copies per cell, and concomitant use of dexrazoxane was associated with a lower number of mtDNA copies per cell. Because of a possible compensatory increase in mtDNA copies per cell to maintain mitochondrial function in the setting of mitochondrial dysfunction, overall OXPHOS activity was not different between the groups. The long-term sustainability of this compensatory response in these survivors at risk for cardiac dysfunction over their lifespan is concerning. Cancer 2016. © 2016 American Cancer Society.

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Assessment of Breast Cancer Risk and Belief in Breast Cancer Screening Among the Primary Healthcare Nurses

Abstract

Breast cancer is the most frequently diagnosed cancer in women. Early detection of breast cancer is known to increase survival rates significantly after diagnosis. This research was carried out to determine the level of breast cancer risk among primary healthcare nurses and their belief in breast cancer screening. In this descriptive research, the data were collected in face-to-face interviews with the participants. The researchers contacted all primary healthcare nurses currently working in the province. The data collection tools included a questionnaire form on sociodemographic characteristics, breast cancer risk assessment form, and Champion's Health Belief Model Scale (CHBMS) for breast cancer screening. In data analysis, descriptive statistics, t test, and analysis of variance (ANOVA) were used. The mean age of nurses was 35 ± 3.6. The mean score for the breast cancer risk assessment form was calculated as 82.9 ± 18.7. The subscale scores for the CHBMS for breast cancer screening were as follows: susceptibility 7.3 ± 1.8, seriousness 19.5 ± 4.1, benefits of breast self-exam 15.5 ± 2.6, barriers to breast self-exam 15.1 ± 2.8, self-efficacy 40.3 ± 7.0, and motivation 19.5 ± 4.1. The risk of breast cancer was found to be low in the study group. The analysis of the subscale scores for the CHBMS for breast cancer screening revealed that nurses had a below-average susceptibility perception, a somewhat lower perception of seriousness, an above-average mean score for perceived benefits, a moderate barrier perception, a relatively high perceived self-efficacy, and motivation above average.

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Radiothérapie des chloromes ou sarcomes granulocytiques : revue de la littérature

Publication date: Available online 13 January 2016
Source:Cancer/Radiothérapie
Author(s): S. Yossi, S. de Talhouet, S. Ducastelle-Leprêtre, A. Hassouni, G. Pigné, I. Selmaji, H. Samlali, M. Ginoux, I. Caraivan, A. d'Hombres
Le chlorome, ou sarcome granulocytique, est une entité clinique rare, le plus souvent associée à une hémopathie, notamment une leucémie aiguë myéloïde. Les stratégies de prise en charge reposent sur l'association d'un traitement systémique et d'un traitement local (chirurgie ou radiothérapie). Les données concernant la dose de radiothérapie à délivrer sont issues d'études rétrospectives et de cas cliniques. Nous avons effectué une revue de la littérature à partir du moteur de recherche Pubmed, afin de préciser les modalités et les indications de la radiothérapie des chloromes.Granulocytic sarcoma, or chloroma, is a rare clinical entity, usually associated with a blood disease, including acute myeloid leukemia. Management strategies are based on the combination of systemic therapy and local therapy (surgery or radiation). Data for radiotherapy dose are derived from retrospective studies and case reports. We conducted a literature review using the Pubmed search engine to clarify the terms and indications for radiotherapy of chloromas.



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Bénéfices de la radiothérapie avec asservissement respiratoire dans le traitement du cancer du sein

Publication date: Available online 13 January 2016
Source:Cancer/Radiothérapie
Author(s): S. Vourch, P. Miglierini, O. Miranda, J.-P. Malhaire, N. Boussion, O. Pradier, U. Schick
Objectif de l'étudeNous avons comparé rétrospectivement, pour des cas de cancer du sein gauche, les doses délivrées au volume cible prévisionnel, au poumon gauche, au cœur et à l'artère coronaire descendante antérieure gauche lors d'une radiothérapie conformationnelle en respiration libre et d'une radiothérapie asservie à la respiration.Patientes et méthodesSeize patientes ont bénéficié d'une scanographie de simulation tridimensionnelle et d'une scanographie quadridimensionnelle réalisée à l'aide d'une ceinture abdominale. Pour chaque patiente, cinq dosimétries ont été générées : respiration libre, inspiration maximale, expiration maximale, et deux plans optimisés résultant de la réduction de 3mm des limites postérieures tangentiels pour créer un plan d'inspiration maximale optimisée et d'expiration maximale optimisée. Les histogrammes dose–volume du volume cible prévisionnel, du poumon homolatéral, du cœur et de l'artère coronaire descendante antérieure gauche ont été analysés et comparés.RésultatsLa couverture du volume cible prévisionnel par l'isodose 95 % était similaire quel que soit le plan dosimétrique concerné (p=0,49). L'inspiration maximale permettait de délivrer moins de dose que la respiration libre au poumon homolatéral, au cœur et à l'artère coronaire descendante antérieure gauche. L'inspiration maximale optimisée était plus avantageuse que celle non optimisée (p<0,05), avec moins de dose au poumon homolatéral, au cœur et à l'artère coronaire descendante antérieure gauche. Comparés à ceux de l'expiration maximale, les résultats obtenus avec l'inspiration maximale étaient similaires pour ce qui concerne la dose reçue par le poumon et l'artère coronaire descendante antérieure gauche, et meilleurs concernant la dose au cœur.ConclusionLa radiothérapie asservie à la respiration permettait, tout en conservant la même couverture du volume cible prévisionnel, une réduction de la dose aux organes à risque (poumon gauche, cœur et artère coronaire descendante antérieure gauche) du fait de la diminution des marges autour des volumes cibles. Son utilisation en phase inspiratoire permettait de plus une expansion pulmonaire donc une réduction proportionnelle du volume pulmonaire irradié et éloignait le cœur des faisceaux, ce que ne permettait pas l'expiration, moins avantageuse. Il s'agit d'une option intéressante pour le traitement du cancer du sein gauche.PurposeThe purpose of this study was to compare free-breathing radiotherapy, end-expiration gating and end-inspiration gating for left breast cancer, with respect to the target volume coverage and dose to organs at risk.Patients and methodsSixteen patients underwent 3D and 4D simulation CT. For each patient, five dosimetric plans were compared: free breathing, end-inspiration gating, end-expiration gating, and two optimised plans with a 3mm reduction of the posterior field edge to create optimised end-inspiration and end-expiration plans. Dose–volume parameters, including planning target volume coverage and dose to lung, heart and left anterior descending coronary artery were analysed.ResultsPlanning target volume coverage was adequate and similar in the five dosimetric plans (P=0.49). Significant advantage was found for end-inspiration gating in sparing the ipsilateral lung, heart and left anterior descending coronary artery compared to free-breathing 3D radiotherapy. Optimised end-inspiration was even more favourable than end-inspiration gating (P<0.05), with less dose delivered to the ipsilateral lung, heart and left anterior descending coronary artery. When compared to end-expiration gating, end-inspiration gating dosimetric outcomes were similar regarding lung and left anterior descending coronary artery doses, but the heart dose was inferior on the end-inspiration gating compared to end-expiration gating.ConclusionBreathing-adapted radiation therapy allowed for dose reduction to organs at risk (left lung, heart and left anterior descending coronary artery), while keeping the same planning target volume coverage. Therefore it can be considered as an interesting option for left breast cancer radiation treatment.



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Identification of the murine H-2D b and human HLA-A*0201 MHC class I-restricted HPV6 E7-specific cytotoxic T lymphocyte epitopes

Abstract

Recurrent respiratory papillomatosis is caused by human papillomavirus (HPV) infection, most commonly types 6 (HPV-6) and 11 (HPV-11). Due to failed host immune responses, HPV is unable to be cleared from the host, resulting in recurrent growth of HPV-related lesions that can obstruct the lumen of the airway within the upper aerodigestive tract. In our murine model, the HPV-6b and HPV-11 E7 antigens are not innately immunogenic. In order to enhance the host immune responses against the HPV E7 antigen, we linked calreticulin (CRT) to HPV-6b E7 and found that vaccinating C57BL/6 mice with the HPV-6b CRT/E7 DNA vaccine is able to induce a CD8⁺ T cell response that recognizes an H-2D^b-restricted E7aa21-29 epitope. Additionally, vaccination of HLA-A*0201 transgenic mice with HPV-6b CRT/E7 DNA generated a CD8⁺ T cell response against the E7aa82-90 epitope that was not observed in the wild-type C57BL/6 mice, indicating this T cell response is restricted to HLA-A*0201. In vivo cytotoxic T cell killing assays demonstrated that the vaccine-induced CD8⁺ T cells are able to efficiently kill target cells. Interestingly, the H-2D^b-restricted E7aa21-29 sequence and the HLA-A*0201-restricted E7aa82-90 sequence are conserved between HPV-6b and HPV-11 and may represent shared immunogenic epitopes. The identification of the HPV-6b/HPV-11 CD8⁺ T cell epitopes facilitates the evaluation of various immunomodulatory strategies in preclinical models. More importantly, the identified HLA-A*0201-restricted T cell epitope may serve as a peptide vaccination strategy, as well as facilitate the monitoring of vaccine-induced HPV-specific immunologic responses in future human clinical trials.

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Identification of the murine H-2D b and human HLA-A*0201 MHC class I-restricted HPV6 E7-specific cytotoxic T lymphocyte epitopes

Abstract

Recurrent respiratory papillomatosis is caused by human papillomavirus (HPV) infection, most commonly types 6 (HPV-6) and 11 (HPV-11). Due to failed host immune responses, HPV is unable to be cleared from the host, resulting in recurrent growth of HPV-related lesions that can obstruct the lumen of the airway within the upper aerodigestive tract. In our murine model, the HPV-6b and HPV-11 E7 antigens are not innately immunogenic. In order to enhance the host immune responses against the HPV E7 antigen, we linked calreticulin (CRT) to HPV-6b E7 and found that vaccinating C57BL/6 mice with the HPV-6b CRT/E7 DNA vaccine is able to induce a CD8⁺ T cell response that recognizes an H-2D^b-restricted E7aa21-29 epitope. Additionally, vaccination of HLA-A*0201 transgenic mice with HPV-6b CRT/E7 DNA generated a CD8⁺ T cell response against the E7aa82-90 epitope that was not observed in the wild-type C57BL/6 mice, indicating this T cell response is restricted to HLA-A*0201. In vivo cytotoxic T cell killing assays demonstrated that the vaccine-induced CD8⁺ T cells are able to efficiently kill target cells. Interestingly, the H-2D^b-restricted E7aa21-29 sequence and the HLA-A*0201-restricted E7aa82-90 sequence are conserved between HPV-6b and HPV-11 and may represent shared immunogenic epitopes. The identification of the HPV-6b/HPV-11 CD8⁺ T cell epitopes facilitates the evaluation of various immunomodulatory strategies in preclinical models. More importantly, the identified HLA-A*0201-restricted T cell epitope may serve as a peptide vaccination strategy, as well as facilitate the monitoring of vaccine-induced HPV-specific immunologic responses in future human clinical trials.

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A novel PI3K axis selective molecule exhibits potent tumor inhibition in colorectal carcinogenesis

Phosphatidylinositol-3-kinase (PI3K) pathway deregulation is responsible for initiation, chemo-resistance, and poor prognosis of colorectal cancer (CRC). Therefore, PI3K pathway inhibition can provide a plausible way of attaining CRC treatment. We report PI3K target specific synthesis and selection of a potent molecule, that is, 2,3-dihydro-2-(naphthalene-1-yl) quinazolin-4(1H)-one (DHNQ) from quinazolinone series based on the structural activity relationship after evaluation in diverse cancers. This molecule inhibited the PI3K enzyme activity and transcriptional as well as translational expression levels in colorectal cancer (CRC) models. This was associated with subsequent decrease in phosphorylation of its downstream effector proteins, that is, p-Akt^(Ser-473) and p-mTORC1^(Ser-2448) and decreased ERK signaling. Furthermore, DHNQ decreased expression of cyclins that caused G₁ arrest and decreased Bcl-2/Bax ratio after mitochondrial membrane potential loss, reactive oxygen species generation, and an increase in cytosolic Ca²⁺ loads that is responsible for the decreased CRC cell proliferation and survival. These biochemical changes triggered apoptotic cell death with altered autophagic Beclin-1 and LC3β expression. It seemed that the PI3K-Akt signaling regulated apoptosis and autophagy through different mechanisms but mTORC1 mediated autophagy appeared not to be involved in the cell death induction by DHNQ. The molecule also showed significant anticancer efficacy in in vivo tumor models without any mortality indicating its non-toxic nature with possible clinical significance. Overall, the selective elucidation of DHNQ molecular mechanism will provide the possible strategies for the clinical development in CRC that may respond to this specific, potent and novel P13K inhibitor. © 2016 Wiley Periodicals, Inc.

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Remembering Ellen Stovall, Cancer Survivor Advocate

By Otis W. Brawley, MD, FACP

Ellen Stovall, a long-time cancer survivor advocate, died of heart failure last week.  She was 69 years old.  As is the case these days, word of her death spread through email.  We at the American Cancer Society were saddened to hear of her death, but for me and for many others this one was extremely personal.

I first met Ellen more than 25 years ago when I was a young oncologist at the National Cancer Institute. She would become a good friend.  Over the years, she would encourage me.  She often gave me emotional and intellectual support especially when I took unpopular stances on issues.

Shortly after I first met Ellen she founded the National Coalition for Cancer Survivorship.  She and some other courageous survivors would demand that consumers be included in medical and scientific research decision-making and they would get a seat at the table.

In a world where people come and go, Ellen stayed pertinent for more than 25 years.  Ellen was disruptive.  She was quiet and polite, but effective. She was not a politician, but she was the consummate insider.

Ellen would eventually define and get us all to accept that a person is a cancer survivor as soon as they are diagnosed with cancer. She would help make cancer survivorship an academic discipline. She effectively pushed a national agenda for programs to study survivorship and programs to support survivors.

I knew Ellen was important to me and important in the development of my career, but as I talked to colleagues about Ellen, I found out how many others she influenced in the oncology space.  Every one of them told me how she made them feel special, empowered, and wiser. There are so many professionals of numerous disciplines who she influenced: a dozen or more of us at the ACS and even more at NCI, ASCO, AACR, NCCN, NBCC and a bunch of other organizations.

Ellen Stovall is a true hero, an example of how one person can make a difference and every person should try.   She was a three-time cancer survivor.  She died of cardiac complications caused by the radiation and chemotherapy she had received four decades ago. Ellen died of the cure.  Her death serves as a reminder of the importance of the very discipline she championed.  Even in dying Ellen teaches us lessons about survivorship.

Dr. Brawley is the chief medical officer of the American Cancer Society.

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Mechanisms of navigating goals after testicular cancer: meaning and emotion regulation

Abstract

Objective

The navigation of major life goals can be challenging to cancer survivors, particularly during young adulthood. This study examined the relationships of goal navigation skills (e.g., goal identification, goal clarification, and goal adjustment) with having a sense of life meaning, emotion regulation coping processes, and physical and psychological health indicators in young adult survivors of testicular cancer.

Methods

Men ages 18 to 29 years (N = 171; M age = 25.2, SD = 3.32) with a history of testicular cancer were recruited via the California State Cancer Registry and completed questionnaire measures including assessments of goal navigation, sense of meaning, emotional approach coping, and indicators of physical and psychological well-being.

Results

Goal navigation skills were negatively related to depressive symptoms (r = −0.41, p < 0.01) and positively related to physical functioning (r = 0.28, p < 0.01). Controlling for participant age and months since diagnosis, mediation models revealed significant indirect effects of sense of meaning on depressive symptoms (−0.50, p < 0.05) and physical functioning (0.34, p < 0.05). Similarly, emotion-regulating coping had significant indirect effects on depressive symptoms (−0.08, p < 0.05) and physical functioning (0.11, p < 0.05)

Conclusions

Consistent with a self-regulation framework, goal navigation skill is related to physical and psychological well-being via its association with maintenance of a sense of meaning as well as successful attempts at regulation of emotions. The study provides preliminary evidence that these skill-based processes relate to adjustment to cancer in young adults. Copyright © 2016 John Wiley & Sons, Ltd.

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Influence of different treatment techniques and clinical factors over the intrafraction variation on lung stereotactic body radiotherapy

Abstract

Purpose

In the present study we compared three different Stereotactic body radiation therapy (SBRT) treatment delivery techniques in terms of treatment time (TT) and their relation with intrafraction variation (IFV). Besides that, we analyzed if different clinical factors could have an influence on IFV. Finally, we appreciated the soundness of our margins.

Materials and methods

Forty-five patients undergoing SBRT for stage I lung cancer or lung metastases up to 5 cm were included in the study. All underwent 4DCT scan to create an internal target volume (ITV) and a 5 mm margin was added to establish the planning target volume (PTV). Cone-beam CTs (CBCTs) were acquired before and after each treatment to quantify the IFV. Three different treatment delivery techniques were employed: fixed fields (FF), dynamically collimated arcs (AA) or a combination of both (FA). We studied if TT was different among these modalities of SBRT and whether TT and IFV were correlated. Clinical data related to patients and tumors were recorded as potential influential factors over the IFV.

Results

A total of 52 lesions and 147 fractions were analyzed. Mean IFV for x-, y- and z-axis were 1 ± 1.16 mm, 1.29 ± 1.38 mm and 1.17 ± 1.08 mm, respectively. Displacements were encompassed by the 5 mm margin in 96.1 % of fractions. TT was significantly longer in FF therapy (24.76 ± 5.4 min), when compared with AA (15.30 ± 3.68 min) or FA (17.79 ± 3.52 min) (p < 0.001). Unexpectedly, IFV did not change significantly between them (p = 0.471). Age (p = 0.003) and left vs. right location (p = 0.005) were related to 3D shift ≥2 mm. In the multivariate analysis only age showed a significant impact on the IFV (OR = 1.07, p = 0.007).

Conclusions

The choice of AA, FF or FA does not impact on IFV although FF treatment takes significantly longer treatment time. Our immobilization device offers enough accuracy and the 5 mm margin may be considered acceptable as it accounts for more than 95 % of tumor shifts. Age is the only clinical factor that influenced IFV significantly in our analysis.

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A premature proposal for new liver cancer seromarkers

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miR-143 inhibits tumor progression by targeting FAM83F in esophageal squamous cell carcinoma

Abstract

Family with sequence similarity 83 (FAM83) members play important roles in carcinogenesis and tumor progression in several tumor types. However, the mechanism by which cancer cells regulate FAM83F still remains unclear. In this study, we found that the FAM84F protein and messenger RNA (mRNA) levels were consistently upregulated in esophageal squamous cell carcinoma (ESCC) tissues, which suggests that a post-transcriptional mechanism may be involved in the regulation of FAM83F. Since microRNAs (miRNAs) are powerful post-transcriptional regulators of gene expression, we performed bioinformatic analyses to search for miRNAs that could potentially target FAM83F. We identified the specific targeting site of miR-143 in the 3′-untranslated region (3′-UTR) of FAM83F and confirmed the inverse correlation between the levels of miR-143 and FAM83F protein and mRNA in ESCC tissue samples. By overexpressing or silencing miR-143 in ESCC cells, we experimentally validated that miR-143 directly binds to the 3′-UTR of the FAM83F transcript and degrades the FAM83F mRNA to regulate FAM83F expression. Furthermore, the biological consequences that miR-143 mediated by targeting FAM83F were examined using in vitro cell proliferation, apoptosis, migration, and invasion assays. We demonstrate that miR-143 exerted a tumor-suppressing effect by inhibiting the proliferation, migration, and invasion and inducing G1/G0 phase arrest of ESCC cells via the negative regulation of FAM83F expression. Taken together, our findings provide important evidence which supports the role of miR-143 as a tumor suppressor in ESCC via the inhibition of FAM83F expression.

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Reply to letter that comments on ‘Intraventricular methotrexate as part of primary therapy for children with infant and/or metastatic medulloblastoma: Feasibility, acute toxicity and evidence for efficacy’

Publication date: Available online 13 January 2016
Source:European Journal of Cancer
Author(s): R.S. Pompe, A.O. von Bueren, M. Mynarek, K. von Hoff, S. Rutkowski




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Neuroblastoma messenger RNA is frequently detected in bone marrow at diagnosis of localised neuroblastoma patients

Publication date: February 2016
Source:European Journal of Cancer, Volume 54
Author(s): Esther M. van Wezel, Boris Decarolis, Janine Stutterheim, Lily Zappeij-Kannegieter, Frank Berthold, Roswitha Schumacher-Kuckelkorn, Thorsten Simon, Marta Fiocco, Max M. van Noesel, Huib N. Caron, C. Ellen van der Schoot, Barbara Hero, Godelieve A.M. Tytgat
IntroductionThe clinical importance of the detection of neuroblastoma messenger RNA (mRNA) in bone marrow (BM) of localised neuroblastoma patients at diagnosis remains unclear. In this prospective multicentre study, BM samples of a large cohort, were studied using real-time quantitative polymerase chain reaction (qPCR).MethodsBM samples at diagnosis from 160 patients with localised neuroblastoma were prospectively collected at Dutch and German centres between 2009 and 2013. qPCR was performed using five neuroblastoma specific markers. The association with other biological factors and the prognostic impact of BM positivity and clinical response was assessed.ResultsIn 58 out of 160 patients neuroblastoma mRNA was detected in BM. In 47 of the 58 positive samples only one marker was found positive. BM positivity was significantly associated with MYCN amplification (p = 0.02) and deletion of chromosome 1p (p = 0.04). In total 31 patients had an event, of which only five patients had progression to stage IV. BM positivity was not associated with an unfavourable outcome. However, the detection of more than one marker was associated with an unfavourable outcome (systemic or local relapse) (event free survival 48% versus 85%; p = 0.03) in the whole cohort and in the observation group.ConclusionsBM positivity was associated with unfavourable biological factors and might represent more aggressive tumours. Patients with qPCR positive BM should not be upstaged, because of very few systemic events in the cohort. However, for patients with more than one marker positive a more careful follow-up is advisable. These results need to be verified in a very large cohort of localised patients.



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