Endometrial sampling devices for early diagnosis of endometrial lesions

Abstract

Purpose

Endometrial carcinoma is the most common gynecologic malignancy in both developed and some developing countries. Unlike cervical cancer, for which there is routine screening, only patients symptomatic for endometrial carcinoma typically seek medical help for its diagnosis and treatment. Dilatation and curettage (D&C) has been the standard procedure for evaluating suspicious endometrial lesions. The discomfort and injury caused by the D&C procedure, however, restrict its use as a screening method for early diagnosis of endometrial lesions. High-risk endometrial cancer patients would benefit from an effective and low-cost screening test. In recent years, several endometrial devices have been developed and proposed as screening tools.

Methods

We have reviewed and evaluated the literature relating to the endometrial sampling devices in clinical use or clinical trials, with the goal of comparing devices and identifying the most appropriate ones for screening for endometrial lesions. Eligible literature was identified from systematic PubMed searches, and the relevant data were extracted. Comments, letters, unpublished data, conference proceedings, and case reports were excluded from our search. Seventy-four articles on endometrial sampling devices were obtained for this review.

Results

The main screening devices for endometrial carcinoma are aspiration devices (such as the Vabra aspirator), Pipelle, Tao Brush, and SAP-1 device. Among these devices, the Tao Brush is the most promising endometrial sampler for screening for endometrial lesions. However, its sampling insufficiency, cost, and unsuccessful insertion rate (20 % in nulliparous and 8 % in parous women) are problematic.

Conclusions

A more accurate and low-cost endometrial sampler, with improved specimen sufficiency and higher sensitivity for endometrial lesions, needs tobe developed and clinically verified.

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A comprehensive genomic characterization of esophageal squamous cell carcinoma: from prognostic analysis to in vivo assay

Abstract

Background

Esophageal squamous cell carcinoma (ESCC) is a leading cause of cancer death worldwide and is characterized by numerous genetic mutations. TNM staging is not sufficient for predicting patient outcomes. Additionally, ESCC shows poor responsiveness to chemotherapy and radiation. Thus, there is an urgent need to find efficient therapy targets. Previous ESCC high-throughput genomic studies have lacked intensive survival analysis, particularly for copy number variation (CNV) and the genes involved.

Main body

In the study "Genomic Characterization of Esophageal Squamous Cell Carcinoma Reveals Critical Genes Underlying Tumorigenesis and Poor Prognosis" recently published in the American Journal of Human Genetics, we comprehensively analyzed the effects of CNVs, mutations, and relative gene expression on patient outcomes. To validate our findings for our 67 sequencing samples, we collected a 321-patient retrospective cohort with detailed 5-year follow-up information and carried out univariate and multivariate survival analyses. In addition, the biological functions of the survival predictors in ESCC were investigated both in vitro and in vivo.

Conclusions

We found the independent ESCC survival predictors and potential therapy targets. Nevertheless, the effects of numerous low-frequency mutations need to be explored using larger sample sequencing. Overall, constructing multi-gene prognostic signatures will remain a great challenge in the future.

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Association of microRNA polymorphisms with the risk of head and neck squamous cell carcinoma in a Chinese population: a case–control study

Abstract

Background

MicroRNA (miRNA) polymorphisms may alter miRNA-related processes, and they likely contribute to cancer susceptibility. Various studies have investigated the associations between genetic variants in several key miRNAs and the risk of human cancers; however, few studies have focused on head and neck squamous cell carcinoma (HNSCC) risk. This study aimed to evaluate the associations between several key miRNA polymorphisms and HNSCC risk in a Chinese population.

Methods

In this study, we genotyped five common single-nucleotide polymorphisms (SNPs) in several key miRNAs (miR-149 rs2292832, miR-146a rs2910164, miR-605 rs2043556, miR-608 rs4919510, and miR-196a2 rs11614913) and evaluated the associations between these SNPs and HNSCC risk according to cancer site with a case–control study including 576 cases and 1552 controls, which were matched by age and sex in a Chinese population.

Results

The results revealed that miR-605 rs2043556 [dominant model: adjusted odds ratio (OR) 0.71, 95% confidence interval (CI) 0.58–0.88; additive model: adjusted OR 0.74, 95% CI 0.62–0.89] and miR-196a2 rs11614913 (dominant model: adjusted OR 1.36, 95% CI 1.08–1.72; additive model: adjusted OR 1.28, 95% CI 1.10–1.48) were significantly associated with the risk of oral squamous cell carcinoma (OSCC). Furthermore, when these two loci were evaluated together based on the number of putative risk alleles (rs2043556 A and rs11614913 G), a significant locus-dosage effect was noted on the risk of OSCC (P _trend < 0.001). However, no significant association was detected between the other three SNPs (miR-149 rs2292832, miR-146a rs2910164, and miR-608 rs4919510) and HNSCC risk.

Conclusion

Our study provided the evidence that miR-605 rs2043556 and miR-196a2 rs11614913 may have an impact on genetic susceptibility to OSCC in Chinese population.

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Targeting GPNMB in Melanoma

Purpose: To determine if BRAF and/or MEK inhibitor-induced GPNMB expression renders melanomas sensitive to CDX-011, an antibody-drug conjugate targeting GPNMB. Experimental Design: The TCGA melanoma dataset was interrogated for a panel of MITF-regulated melanosomal differentiation antigens, including GPNMB. BRAF mutant melanoma cell lines treated with BRAF or MEK inhibitors were assessed for GPNMB expression by RT-qPCR, immunoblot and FACs analyses. Transient siRNA-mediated knockdown approaches were used to determine if MITF is requirement for treatment-induced GPNMB upregulation. GPNMB expression was analyzed in serial biopsies and serum samples from melanoma patients taken before, during and after disease progression on MAPK inhibitor treatment. Sub-cutaneous injections were performed to test the efficacy of MAPK inhibitors alone, CDX-011 alone, or their combination in suppressing melanoma growth. Results: A MITF-dependent melanosomal differentiation signature is associated with poor prognosis in patients with this disease. MITF is increased following BRAF and MEK inhibitor treatment and induces the expression of melanosomal differentiation genes, including GPNMB. GPNMB is expressed at the cell surface in MAPK inhibitor-treated melanoma cells and is also elevated in on-treatment versus pre-treatment biopsies from melanoma patients receiving MAPK pathway inhibitors. Combining BRAF and/or MEK inhibitors with CDX-011, an antibody-drug-conjugate targeting GPNMB, is effective in causing melanoma regression in pre-clinical animal models and delays the recurrent melanoma growth observed with MEK or BRAF/MEK inhibitor treatment alone. Conclusions: The combination of MAPK pathway inhibitors with an antibody-drug-conjugate targeting GPNMB is an effective therapeutic option for patients with melanoma.

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Risk Stratification for Avascular Necrosis of the Femoral Head After Internal Fixation of Femoral Neck Fractures by Post-Operative Bone SPECT/CT

Abstract

Purpose

Avascular necrosis (AVN) of the femoral head is a major complication after internal fixation of a femoral neck fracture and determines the functional prognosis. We investigated postoperative bone single-photon emission computed tomography/computed tomography (SPECT/CT) for assessing the risk of femoral head AVN.

Methods

We retrospectively reviewed 53 consecutive patients who underwent bone SPECT/CT within 2 weeks of internal fixation of a femoral neck fracture and follow-up serial hip radiographs over at least 12 months.

Results

Nine patients developed femoral head AVN. In 15 patients who showed normal uptake on immediate postoperative SPECT/CT, no AVN occurred, whereas 9 of 38 patients who showed cold defects of the femoral head later developed AVN. The negative predictive value of immediate postoperative SPECT/CT for AVN was 100 %, whereas the positive predictive value was 24 %. Among 38 patients with cold defects, 1 developed AVN 3 months postoperatively. A follow-up bone SPECT/CT was performed in the other 37 patients at 2–10 months postoperatively. The follow-up bone SPECT/CT revealed completely normalized femoral head uptake in 27, partially normalized uptake in 8, and persistent cold defects in 2 patients. AVN developed in 3.7 % (1/27), 62.5 % (5/8), and 100 % (2/2) of each group, respectively.

Conclusions

According to the time point of imaging, radiotracer uptake patterns of the femoral head on postoperative bone SPECT/CT indicate the risk of AVN after internal fixation of femoral neck fractures differently. Postoperative bone SPECT/CT may help orthopedic surgeons determine the appropriate follow-up of these patients.

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An Integrated Model of RAF Inhibitor Action Predicts Inhibitor Activity against Oncogenic BRAF Signaling

Publication date: Available online 11 August 2016
Source:Cancer Cell
Author(s): Zoi Karoulia, Yang Wu, Tamer A. Ahmed, Qisheng Xin, Julien Bollard, Clemens Krepler, Xuewei Wu, Chao Zhang, Gideon Bollag, Meenhard Herlyn, James A. Fagin, Amaia Lujambio, Evripidis Gavathiotis, Poulikos I. Poulikakos
The complex biochemical effects of RAF inhibitors account for both the effectiveness and mechanisms of resistance to these drugs, but a unified mechanistic model has been lacking. Here we show that RAF inhibitors exert their effects via two distinct allosteric mechanisms. Drug resistance due to dimerization is determined by the position of the αC helix stabilized by inhibitor, whereas inhibitor-induced RAF priming and dimerization are the result of inhibitor-induced formation of the RAF/RAS-GTP complex. The biochemical effect of RAF inhibitor in cells is the combined outcome of the two mechanisms. Therapeutic strategies including αC-helix-IN inhibitors are more effective in multiple mutant BRAF-driven tumor models, including colorectal and thyroid BRAF^V600E cancers, in which first-generation RAF inhibitors have been ineffective.

Teaser

Karoulia et al. show that the biochemical effect of RAF inhibitors in cells is the combined outcome of two distinct allosteric mechanisms. These results provide a blueprint for the development of improved RAF inhibitor-based therapeutic strategies for BRAF-dependent tumors.


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Risk Factors Associated With Symptomatic Radiation Pneumonitis After Stereotactic Body Radiation Therapy for Stage I Non-Small Cell Lung Cancer

Radiation pneumonitis is the most frequent acute pulmonary toxicity following stereotactic body radiation therapy for lung cancer. Here, we investigate clinical and dosimetric factors associated with symptomatic radiation pneumonitis in patients with stage I non–small cell lung cancer treated with stereotactic body radiation therapy. A total of 67 patients with stage I non–small cell lung cancer who received stereotactic body radiation therapy at our institution were enrolled, and their clinicopathological parameters and dosimetric parameters were recorded and analyzed. The median follow-up period was 26.4 months (range: 7-48 months). In univariate analysis, tumor size (P = .041), mean lung dose (P = .028), V2.5 (P = .024), V5 (P = .014), V10 (P = .004), V20 (P = .024), V30 (P = .020), V40 (P = .040), and V50 (P = 0.040) were associated with symptomatic radiation pneumonitis. In multivariable logistic regression analysis, V10 (P = .049) was significantly associated with symptomatic radiation pneumonitis. In conclusion, this study found that tumor size, mean lung dose, and V2.5 to V50 were risk factors markedly associated with symptomatic radiation pneumonitis. Our data suggested that lung V10 was the most significant factor, and optimizing lung V10 may reduce the risk of symptomatic radiation pneumonitis. For both central and peripheral stage I lung cancer, rate of radiation pneumonitis ≥grade 2 was low after stereotactic body radiation therapy with appropriate fraction dose.

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A comprehensive genomic characterization of esophageal squamous cell carcinoma: from prognostic analysis to in vivo assay

Esophageal squamous cell carcinoma (ESCC) is a leading cause of cancer death worldwide and is characterized by numerous genetic mutations. TNM staging is not sufficient for predicting patient outcomes. Additio...

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Association of microRNA polymorphisms with the risk of head and neck squamous cell carcinoma in a Chinese population: a case–control study

MicroRNA (miRNA) polymorphisms may alter miRNA-related processes, and they likely contribute to cancer susceptibility. Various studies have investigated the associations between genetic variants in several key...

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Adolescents Who Wouldn’t Have Smoked May Be Drawn to E-Cigarettes

Some adolescents who otherwise would never have smoked are using e-cigarettes, according to a study published July 11 in the journal Pediatrics. The findings suggest that adolescents are not just using e-cigarettes as a substitute for conventional cigarettes but that e-cigarettes are attracting new users to tobacco products.

E-cigarettes are electronic devices that create an aerosol by heating a liquid solution that often contains nicotine and flavorings, as well as other chemicals. They allow users to simulate smoking conventional cigarettes by inhaling the aerosol, which mimics combustible cigarette smoking. The Food and Drug Administration recently finalized a rule extending its regulation of tobacco products to include e-cigarettes. The rule went into effect this week.

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Gastric biomarkers: a global review

Abstract

Background

Gastric cancer is an aggressive disease with a poor 5-year survival and large global burden of disease. The disease is biologically and genetically heterogeneous with a poorly understood carcinogenesis at the molecular level. Despite the many prognostic, predictive, and therapeutic biomarkers investigated to date, gastric cancer continues to be detected at an advanced stage with resultant poor clinical outcomes.

Main body

This is a global review of gastric biomarkers with an emphasis on HER2, E-cadherin, fibroblast growth factor receptor, mammalian target of rapamycin, and hepatocyte growth factor receptor as well as sections on microRNAs, long noncoding RNAs, matrix metalloproteinases, PD-L1, TP53, and microsatellite instability.

Conclusion

A deeper understanding of the pathogenesis and biological features of gastric cancer, including the identification and characterization of diagnostic, prognostic, predictive, and therapeutic biomarkers, hopefully will provide improved clinical outcomes.

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The interaction of Wnt-11 and signalling cascades in prostate cancer

Abstract

Prostate cancer (PCa) is the second most common cancer among the male population. Conventional therapies target androgen signalling, which drives tumour growth; however, they provide limited survival benefits for patients. It is essential, therefore, to develop a more specific biomarker than the current gold standard, PSA testing. The Wnt signalling pathway induces expression of target genes through cell surface receptors. A non-canonical member of this family, Wnt-11, is evolutionarily highly conserved and is normally expressed by various cells in the developing embryo, as well as in the heart, liver and skeletal muscle of adult humans. We comprehensively review several cell signalling pathways to explain how they interact with Wnt-11, demonstrating its use as a potential biomarker for PCa. Several studies have shown that the expression of Wnt-11 is associated with gastric, renal and colorectal adenocarcinomas and PCa. Moreover, Wnt-11 affects extracellular matrix composition and cytoskeletal rearrangement, and it is required for proliferation and/or survival during cell differentiation. It was found that PCa cell lines express high levels of Wnt-11, which allows differentiation of the epithelial prostate tumour cells to neuron-like (NE) cells. The NE cells produce additional factors that can cause regression after treatment. Accumulating evidence shows that Wnt-11 could be a potential biomarker in diagnosing PCa. Many studies have shown both non-canonical and canonical Wnts interact with several signalling cascades such as PKC, JNK, NF-κB, Rho, PKA and PI3K. In particular, evidence demonstrates Wnt-11 is involved in the progression of PCa, thus it could have the potential to become both a specific disease marker and an important therapeutic target.

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Anti-EGFR Agents: Current Status, Forecasts and Future Directions

Abstract

The epidermal growth factor receptor (EGFR) is one of the most important and attractive targets for specific anticancer therapies. It is a robust regulator of pathways involved in cancer pathogenesis and progression. Thus far, clinical trials have demonstrated the benefits of monoclonal antibodies and synthetic tyrosine kinase inhibitors in targeting this receptor; however, novel strategies are still being developed. This article reviews the current state of efforts in targeting the EGFR in cancer therapy. Following a brief characterization of EGFR, we will present a complete list of anti-EGFR agents that are already approved, and available in clinical practice. Aside from the indications, we will present the sales forecasts and expiry dates of product patents for the selected agents. Finally, we discuss the novel anti-EGFR strategies that are currently in preclinical development.

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The role of adipose stem cells in inflammatory bowel disease: From biology to novel therapeutic strategies

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STK33 potentiates the malignancy of hypopharyngeal squamous carcinoma: Possible relation to calcium

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Role of targeted agents in neuroendocrine tumors: Results from a meta-analysis

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Decursinol angelate inhibits PGE2-induced survival of the human leukemia HL-60 cell line via regulation of the EP2 receptor and NFκB pathway

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Analysis of circulating tumor cells in colorectal cancer liver metastasis patients before and after cryosurgery

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Association of BRCA1 Mutations with Impaired Ovarian Reserve: Connection Between Infertility and Breast/Ovarian Cancer Risk

Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.


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AKT1 E17K mutation profiling in breast cancer: prevalence, concurrent oncogenic alterations, and blood-based detection

Abstract

Background

The single hotspot mutation AKT1 [G49A:E17K] has been described in several cancers, with the highest incidence observed in breast cancer. However, its precise role in disease etiology remains unknown.

Methods

We analyzed more than 600 breast cancer tumor samples and circulating tumor DNA for AKT1 ^E17K and alterations in other cancer-associated genes using Beads, Emulsions, Amplification, and Magnetics digital polymerase chain reaction technology and targeted exome sequencing.

Results

Overall AKT1 ^E17K mutation prevalence was 6.3 % and not correlated with age or menopausal stage. AKT1 ^E17K mutation frequency tended to be lower in patients with grade 3 disease (1.9 %) compared with those with grade 1 (11.1 %) or grade 2 (6 %) disease. In two cohorts of patients with advanced metastatic disease, 98.0 % (n = 50) and 97.1 % (n = 35) concordance was obtained between tissue and blood samples for the AKT1 ^E17K mutation, and mutation capture rates of 66.7 % (2/3) and 85.7 % (6/7) in blood versus tissue samples were observed. Although AKT1-mutant tumor specimens were often found to harbor concurrent alterations in other driver genes, a subset of specimens harboring AKT1 ^E17K as the only known driver alteration was also identified. Initial follow-up survival data suggest that AKT1 ^E17K could be associated with increased mortality. These findings warrant additional long-term follow-up.

Conclusions

The data suggest that AKT1 ^E17K is the most likely disease driver in certain breast cancer patients. Blood-based mutation detection is achievable in advanced-stage disease. These findings underpin the need for a further enhanced-precision medicine paradigm in the treatment of breast cancer.

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Metronomic cyclophosphamide activation of anti-tumor immunity: tumor model, mouse host, and drug schedule dependence of gene responses and their upstream regulators

Abstract

Background

Cyclophosphamide (CPA) can activate immunogenic tumor cell death, which induces immune-based tumor ablation and long-term anti-tumor immunity in a syngeneic C57BL/6 (B6) mouse GL261 glioma model when CPA is given on a 6-day repeating metronomic schedule (CPA/6d). In contrast, we find that two other syngeneic B6 mouse tumors, LLC lung carcinoma and B16F10 melanoma, do not exhibit these drug-induced immune responses despite their intrinsic sensitivity to CPA cytotoxicity.

Methods

To elucidate underlying mechanisms, we investigated gene expression and molecular pathway changes associated with the disparate immune responsiveness of these tumors to CPA/6d treatment.

Results

Global transcriptome analysis indicated substantial elevation of basal GL261 immune infiltration and strong CPA/6d activation of GL261 immune stimulatory pathways and their upstream regulators, but without preferential depletion of negative immune regulators compared to LLC and B16F10 tumors. In LLC tumors, where CPA/6d treatment is shown to be anti-angiogenic, CPA/6d suppressed VEGFA target genes and down regulated cell adhesion and leukocyte transendothelial migration genes. In GL261 tumors implanted in adaptive immune-deficient scid mice, where CPA/6d-induced GL261 regression is incomplete and late tumor growth rebound can occur, T cell receptor signaling and certain cytokine-cytokine receptor responses seen in B6 mice were deficient. Extending the CPA treatment interval from 6 to 9 days (CPA/9d) − which results in a strong but transient natural killer cell response followed by early tumor growth rebound − induced fewer cytokines and increased expression of drug metabolism genes.

Conclusions

These findings elucidate molecular response pathways activated by intermittent metronomic CPA treatment and identify deficiencies that characterize immune-unresponsive tumor models and drug schedules.

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An evaluation in vitro of PARP-1 inhibitors, rucaparib and olaparib, as radiosensitisers for the treatment of neuroblastoma

Abstract

Background

The radiopharmaceutical ¹³¹I-meta-iodobenzylguanidine (¹³¹I-MIBG) is an effective treatment for neuroblastoma. However, maximal therapeutic benefit from ¹³¹I-MIBG is likely to be obtained by its combination with chemotherapy. We previously reported enhanced antitumour efficacy of ¹³¹I-MIBG by inhibition of the poly(ADP-ribose) polymerase-1 (PARP-1) DNA repair pathway using the phenanthridinone derivative PJ34. Recently developed alternative PARP-1 inhibitors have greater target specificity and are expected to be associated with reduced toxicity to normal tissue. Therefore, our purpose was to determine whether the more specific PARP-1 inhibitors rucaparib and olaparib enhanced the efficacy of X-radiation or ¹³¹I-MIBG.

Methods

Radiosensitisation of SK-N-BE(2c) neuroblastoma cells or noradrenaline transporter gene-transfected glioma cells (UVW/NAT) was investigated using clonogenic assay. Propidium iodide staining and flow cytometry was used to analyse cell cycle progression. DNA damage was quantified by the phosphorylation of H2AX (γH2AX).

Results

By combining PARP-1 inhibition with radiation treatment, it was possible to reduce the X-radiation dose or ¹³¹I-MIBG activity concentration required to achieve 50 % cell kill by approximately 50 %. Rucaparib and olaparib were equally effective inhibitors of PARP-1 activity. X-radiation-induced DNA damage was significantly increased 2 h after irradiation by combination with PARP-1 inhibitors (10-fold greater DNA damage compared to untreated controls; p < 0.01). Moreover, combination treatment (i) prevented the restitution of DNA, exemplified by the persistence of 3-fold greater DNA damage after 24 h, compared to untreated controls (p < 0.01) and (ii) induced greater G₂/M arrest (p < 0.05) than either single agent alone.

Conclusion

Rucaparib and olaparib sensitise cancer cells to X-radiation or ¹³¹I-MIBG treatment. It is likely that the mechanism of radiosensitisation entails the accumulation of unrepaired radiation-induced DNA damage. Our findings suggest that the administration of PARP-1 inhibitors and ¹³¹I-MIBG to high risk neuroblastoma patients may be beneficial.

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Over-expression of long noncoding RNA BANCR inhibits malignant phenotypes of human bladder cancer

Abstract

Background

Accumulating evidences indicated that lncRNAs play crucial regulatory roles in oncogenesis and progression of cancers. BRAF activated non-coding RNA (BANCR) has been identified to contribute to the progression of some human cancers. However, the relationship between BANCR and bladder cancer (BC) is largely unclear.

Methods

BANCR expression levels in BC, paired non-cancer tissues and BC cell lines were detected by real-time quantitative RT-PCR (qRT-PCR). The relationships between BANCR expression levels and the clinical characteristics were evaluated. BANCR expression was enhanced by transfecting a pcDNA-BANCR vector. We used both CCK-8 assay and Edu assay to detect cell proliferation. We also detect cell apoptosis and migration by using ELISA assay, Flow cytometry and transwell assay, respectively. All statistical analyses were executed by using the SPSS 20.0 software.

Results

BANCR expression levels were remarkably decreased in BC tissues compared with adjacent noncancerous tissues. BANCR expression levels in two BC cell lines were also significantly down-regulated. Clinicopathologic analysis revealed that low BANCR expression was positively correlated with TNM stage, but not associated with other clinicopathological characteristics. BANCR has been successfully overexpressed in BC cell lines (T24 and SW780) by transfecting a pcDNA-BANCR vector. Cell proliferation inhibition, apoptosis induction and migration suppression were also observed in pCDNA-BANCR-transfected T24 and SW780 cells.

Conclusions

These data suggested that BANCR represents a tumor suppressor player in bladder cancer, contributes to tumor proliferation, apoptosis and migration, and may serve as a new candidate biomarker and a potential therapeutic target for patients with BC.

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Heregulin-1ß and HER3 in hepatocellular carcinoma: status and regulation by insulin

Abstract

Background

The heregulin-1ß/HER3-driven pathway is implicated in several epithelial malignancies and its blockade is currently undergoing clinical investigation. Paradoxically, the status and the regulation of this pathway is poorly known in hepatocellular carcinoma (HCC).

Methods

Using 85 HCC obtained after tumour resection, heregulin-1ß and HER3 expression was evaluated by real-time RT-PCR, ELISA and/or immunohistochemistry. Statistics were performed to analyze associations between gene expression and clinicopathological parameters. The effects of insulin on the heregulin-1ß/HER3 pathway was investigated in four HCC cell lines.

Results

HER3 mRNA was upregulated in 52 % of tumours, while heregulin-1ß mRNA was downregulated in 82 %. Hepatitis B and C viral infections were respectively associated with high and low HER3 mRNA expression. No association was seen between neither HER3 or heregulin-1ß mRNA and prognostic factors, survival or recurrence. Immunohistochemistry showed predominant cytoplasmic staining of HER3 in tumours but the staining was nonreproducible. HER3 mRNA and protein levels were not correlated in liver tissues. In HCC cells, insulin promoted HER3 proteasomal degradation and inhibited heregulin-1ß stimulation of cell migration. HER3 and insulin receptor co-immunoprecipitated in these cells. The loss of insulin receptor expression by RNA interference sensitized cells to heregulin-1ß-induced AKT phosphorylation.

Conclusions

Autocrine heregulin-1ß loop is uncommon in HCC and HER3 mRNA expression is differentially influenced by hepatitis viruses. Insulin is a negative regulator of HER3 protein expression and function in HCC cells. Altogether these data may explain why HER3 and heregulin-1ß expression have no prognostic value and suggest that HCC patients are unlikely to derive benefit from HER3-targeted monotherapies.

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Radiothérapie des cancers du col et de l’endomètre

Publication date: Available online 11 August 2016
Source:Cancer/Radiothérapie
Author(s): I. Barillot, C. Haie-Méder, C. Charra Brunaud, K. Peignaux, C. Kerr, L. Thomas
La radiothérapie externe et la curiethérapie gardent une place prépondérante dans la prise en charge des cancers du col utérin et de l'endomètre. Cette revue présente les recommandations françaises en termes de préparation et de choix des techniques d'irradiation de ces cancers gynécologiques.External irradiation and brachytherapy still have a major place in the treatment of cervix and endometrial carcinoma. This review presents the French guidelines in terms of preparation and choice of irradiation techniques of these gynecological malignancies.



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Prévention des cancers radio-induits

Publication date: Available online 11 August 2016
Source:Cancer/Radiothérapie
Author(s): J.-M. Cosset, C. Chargari, C. Demoor, P. Giraud, S. Helfre, F. Mornex, A. Mazal
L'article traite de la prévention des seuls cancers liés directement à une irradiation thérapeutique qui sont à distinguer des « cancers secondaires ». La prise en compte du risque de cancers radio-induits après irradiation thérapeutique, même s'il s'agit d'évènements heureusement rares, est devenue incontournable aujourd'hui. Avec une revue de la littérature, sont détaillés les différents paramètres en cause. L'âge du patient irradié est l'un des paramètres principaux. L'impact de la dose est également discuté en fonction du modèle utilisé, et d'après les données cliniques. Les autres paramètres définissant un traitement de radiothérapie sont discutés les uns après les autres : l'importance du volume irradié, avec l'exemple de la maladie de Hodgkin, le type de rayonnement et la participation des neutrons secondaires, l'étalement et le fractionnement. L'ensemble de ces paramètres étant à discuter en fonction de chaque organe dont la sensibilité diffère. L'article conclut par une liste de recommandations pour limiter le risque de cancers secondaires. Même avec l'avènement de la radiothérapie conformationnelle, de la modulation d'intensité, de l'arcthérapie volumétrique modulée, et le développement de machines spécifiques pour la stéréotaxie extracranienne, le radiothérapeute doit considérer ce risque et utiliser de façon raisonnable et justifiée l'imagerie de contrôle. Même s'ils ne constituent qu'un faible pourcentage des cancers survenant secondairement après une première tumeur maligne, les cancers radio-induits ne peuvent ni ne doivent être occultés ou ignorés et justifient un suivi régulier sur le long terme, précisément adapté aux paramètres précédemment décrits.The article deals with the prevention of cancers only directly related to therapeutic radiation which are distinguished from "secondary cancer". The consideration of the risk of radiation-induced cancers after radiation therapy, although it is fortunately rare events, has become indispensable today. With a review of the literature, are detailed the various involved parameters. The age of the irradiated patient is one of the main parameters. The impact of the dose is also discussed based on the model used, and based on clinical data. Other parameters defining a radiation treatment are discussed one after the other: field with the example of Hodgkin's disease, the type of radiation and the participation of secondary neutrons, spreading and splitting. All these parameters are discussed according to each organ whose sensitivity is different. The article concludes with a list of recommendations to reduce the risk of radio-induced cancers. Even with the advent of conformal radiotherapy, intensity modulation, the modulated volume arctherapy, and the development of specific machinery for the extra-cranial stereotactic, the radiation therapist must consider this risk and use of reasonable and justified control imaging. Although they constitute a small percentage of cancers that occur secondarily after a first malignant tumor, radiation-induced cancers, can not and must not be concealed or ignored and justify regular monitoring over the long term, precisely adapted on the described parameters.



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Radiothérapie des cancers du nasopharynx

Publication date: Available online 11 August 2016
Source:Cancer/Radiothérapie
Author(s): P. Maingon, P. Blanchard, F. Bidault, L. Calmels
Les cancers du nasopharynx constituent une entité rare. Le diagnostic clinique de la maladie est très souvent obtenu devant une tumeur évoluée. Celles localisées, classées T1 T2 N0 sont de pronostic favorable et sont contrôlées localement dans plus de 90 % des cas par la radiothérapie seule. Le traitement standard est une chimioradiothérapie avec du cisplatine dans les formes localement évoluées. Une vigilance particulière de la fonte des ganglions nombreux et souvent volumineux en cours de traitement, parfois associés à un amaigrissement du patient, peut conduire à une adaptation dosimétrique. Le traitement des récidives locales a une importance particulière. La place de la chirurgie est limitée mais peut être discutée en réunion de concertation pluridisciplinaire lorsqu'elle est possible. Un curage ganglionnaire doit être proposé pour une récidive ganglionnaire, en alternative à une ré-irradiation. Enfin, une ré-irradiation est proposée lorsque techniquement possible.Nasapharyngeal carcinoma is a rare disease. Oftenly, the diagnostic is made for advanced disease. Localized tumors, T1 or T2 NO observed a good prognosis and are locally controlled in more than 90 % of the cases by radiotherapy alone. The standard treatment of locally advanced disease is combined chemoradiation. A special vigilance of fast decrease of the volume of the pathological lymph nodes, sometimes associated to loss of weight might indicate an adaptive dosimetric revision. The treatment of recurrent disease is of great importance. Surgical indications are limited but should be discussed in multidisciplinary tumor board when possible. Surgical nodal sampling has to be proposed for nodal recurrence as well as reirradiation, which could be indicated according to the technical issues.



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Radiothérapie des métastases intrapulmonaires

Publication date: Available online 11 August 2016
Source:Cancer/Radiothérapie
Author(s): P. Giraud, T. Lacornerie, F. Mornex
Les indications, doses et techniques de radiothérapie des métastases intrapulmonaires sont présentées. Les recommandations de délinéation des volumes cibles et organes à risques sont détaillées.Indication, doses, and technique of radiotherapy, for intrathoracic metastases are presented. The recommendations for delineation of the target volumes and organs at risk are detailed.



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Implications de la pose de matériel « inerte » dans l’organisme humain sur la qualité de la radiothérapie

Publication date: Available online 10 August 2016
Source:Cancer/Radiothérapie
Author(s): C. Le Fèvre, E. Buffard, D. Antoni, D. Chaussemy, V. Matter-Parrat, G. Noël
La prescription de dose, la délinéation, le calcul dosimétrique sont clairement plus compliqués quand un patient est porteur d'un matériel prothétique. La connaissance des caractéristiques de ce matériel est nécessaire afin de diminuer les incertitudes de calcul. Des recommandations pour chaque étape sont données dans cet article, permettant une optimisation de la sécurité des traitements.Dose prescription, delineation and dose calculation are clearly complicated when a patient have been operated on with insertion of prosthesis. Knowledge of the physical and material characteristics is needed to decrease incertitude of calculations. Recommendations for each step of treatments are proposed in this article allowing to optimization of the treatment safety.



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Radiothérapie des métastases osseuses

Publication date: Available online 11 August 2016
Source:Cancer/Radiothérapie
Author(s): S. Thureau, M.-H. Vieillard, S. Supiot, J.-L. Lagrange
La radiothérapie garde une place majeure dans la prise en charge des métastases osseuses. Elle est principalement utilisée dans un but palliatif à visée antalgique ou décompressive. De façon plus récente, les développements de la radiothérapie stéréotaxique et de la radiothérapie conformationnelle avec modulation d'intensité laissent entrevoir son utilisation à dose curative dans la maladie oligométastatique. L'objectif de cet article est de rapporter les indications et les modalités de la radiothérapie dans ces différentes situations.Radiotherapy plays a major role in palliative treatment of bone metastases. Recent developments of stereotactic radiotherapy and intensity modulated radiation therapy give the possibility to treat oligometastatic diseases. The objective of this paper is to report indications and treatment modalities of radiotherapy in these situations.



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Radiothérapie des cancers cutanés

Publication date: Available online 10 August 2016
Source:Cancer/Radiothérapie
Author(s): C. Hennequin, E. Rio, M.-A. Mahé
Le rôle de la radiothérapie dans les cancers cutanés est difficile à préciser, car il y a peu d'essais randomisés ou de séries prospectives. Dans les carcinomes basocellulaires, la radiothérapie permet un bon taux de contrôle local, mais dans un essai randomisé elle est apparue moins efficace et plus morbide que la chirurgie. Elle doit être réservée aux contre-indications de celle-ci, chez les patients de plus de 60ans, pour des lésions non sclérodermiformes et dans des zones non sensibles. Pour les carcinomes épidermoïdes, une radiothérapie adjuvante doit être proposée en cas de facteurs de pronostic défavorable. Des doses de 60 à 70Gy ou équivalent sont nécessaires et fonction de la taille tumorale. Les mélanomes desmoplastiques bénéficient d'une radiothérapie adjuvante, mais cela n'a pas été démontré pour les autres formes histologiques. L'irradiation prophylactique des aires ganglionnaires (45 à 50Gy), pour des formes évoluées (atteinte ganglionnaire massive), diminue le taux de récidive locorégionale mais sans modifier la survie. Pour les tumeurs de Merckel, une méta-analyse et une large étude épidémiologique ont montré que la radiothérapie adjuvante (50 à 56Gy) améliorait le taux de contrôle local. Elle doit inclure les aires ganglionnaires, en l'absence d'exploration chirurgicale de celles-ci (ganglion sentinelle). Les tumeurs de Kaposi sont très radiosensibles et peuvent être traitées par irradiation à doses relativement modérées (24 à 30Gy). De même, les lymphomes cutanés sont très radiosensibles : les lymphomes B sont une indication élective de l'irradiation à visée curative. Pour les lymphomes T, l'électronthérapie cutanée totale garde quelques indications ; sinon, à visée palliative, l'irradiation des nodules cutanés apparaît très efficace.The indications of radiotherapy for skin cancers are not clearly defined because of the lack of randomised trials or prospective studies. For basal cell carcinomas, radiotherapy frequently offers a good local control, but a randomized trial showed that surgery is more efficient and less toxic. Indications of radiotherapy are contra-indications of surgery for patients older than 60, non-sclerodermiform histology and occurring in non-sensitive areas. Adjuvant radiotherapy could be proposed to squamous cell carcinomas, in case of poor prognostic factors. Dose of 60 to 70Gy are usually required, and must be modulated to the size of the lesions. Adjuvant radiotherapy seems beneficial for desmoplastic melanomas but not for the other histological types. Prophylactic nodal irradiation (45 to 50Gy), for locally advanced tumours (massive nodal involvement), decreases the locoregional failure rate but do not increase survival. Adjuvant radiotherapy (50 to 56Gy) for Merckel cell carcinomas increases also the local control rate, as demonstrated by meta-analysis and a large epidemiological study. Nodal areas must be included, if there is no surgical exploration (sentinel lymph node dissection). Kaposi sarcomas are radiosensitive and could be treated with relatively low doses (24 to 30Gy). Also, cutaneous lymphomas are good indications for radiotherapy: B lymphomas are electively treated with limited fields. The role of total skin electron therapy for T-lymphomas is still discussed; but palliative radiotherapy is very efficient in case of cutaneous nodules.



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Radiothérapie et grossesse

Publication date: Available online 10 August 2016
Source:Cancer/Radiothérapie
Author(s): R. Mazeron, I. Barillot, F. Mornex, P. Giraud
La découverte d'un cancer en cours de grossesse est une situation rare et délicate. Les développements de l'embryon et du fœtus humain étant extrêmement sensibles aux radiations ionisantes, la prise en charge de ces tumeurs doit être discutée. Les études, précliniques et cliniques, basées le plus souvent sur des accidents d'exposition, montrent que des irradiations sus-diaphragmatiques sont réalisables pendant la grossesse. Lorsqu'une radiothérapie est retenue, une estimation sur fantôme de la dose délivrée au fœtus, confirmée par une mesure in vivo, est recommandée. Les techniques d'irradiation et d'imagerie de recalage doivent être aménagées par minorer au maximum la dose délivrée au fœtus et la maintenir sous le seuil de 0,1Gy.The diagnostic of cancer during pregnancy is a rare and delicate situation. As the developments of the embryo and the human fetus are extremely sensitive to ionizing radiations, the treatment of these tumors should be discussed. The studies – preclinical and clinical – based mostly on exposure accidents show that subdiaphragmatic treatments are possible during pregnancy. When radiotherapy is used, phantom estimations of the dose to the fetus, confirmed by in vivo measurements are required. Irradiation and imaging techniques should be arranged to decrease as much as possible the dose delivered to the fetus and hold below the threshold of 0.1Gy.



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Radiothérapie du cancer du sein

Publication date: Available online 10 August 2016
Source:Cancer/Radiothérapie
Author(s): C. Hennequin, I. Barillot, D. Azria, Y. Belkacémi, M. Bollet, B. Chauvet, D. Cowen, B. Cutuli, A. Fourquet, J.M. Hannoun-Lévi, M. Leblanc, M.A. Mahé
Dans le cancer du sein, la radiothérapie est un élément essentiel de la prise en charge. Après traitement conservateur pour un carcinome infiltrant, l'irradiation complémentaire doit être systématique, quelles que soient les caractéristiques de la patiente, car elle diminue le taux de rechute locale et améliore par-là la survie. L'irradiation partielle n'est pas une technique de routine mais peut être proposée à des patientes sélectionnées et dûment informées. Pour les carcinomes canalaires in situ, l'irradiation doit également être systématique après tumorectomie. Après mastectomie, une irradiation pariétale complémentaire s'impose pour les patientes atteintes d'une tumeur classée pT3–T4, envahissant ou non les ganglions, quel que soit le nombre de ganglions atteints. Après chimiothérapie néo-adjuvante et mastectomie, et en l'absence d'atteinte ganglionnaire durant l'intervention, l'irradiation est préconisée s'il existait une lésion classée T3–T4 ou une atteinte ganglionnaire clinique ou radiologique avant la chimiothérapie. L'irradiation axillaire n'est, la plupart du temps, pas indiquée après curage chirurgical ; elle se discute en cas de ganglion sentinelle atteint et en l'absence de curage. L'irradiation des aires sus- et sous-claviculaires est préconisée en cas d'atteinte histologique axillaire. L'irradiation mammaire interne se discute au cas par cas, en évaluant le rapport bénéfice-risque (toxicité cardiaque). Une dose de 45–50 Gy est délivrée dans la totalité du sein en fractionnement classique. Un complément de dose (boost) dans le lit tumoral doit être délivré chez les patientes de moins de 60ans après traitement conservateur. Des modalités d'hypofractionnement sont possibles après tumorectomie, si les aires ganglionnaires ne nécessitent pas d'irradiation (42,5 Gy en 16 fractions, ou 41,6 Gy en 13 ou 40 Gy en 15). La délinéation du sein, de la paroi et des aires ganglionnaires repose à la fois sur des données cliniques et radiologiques. La technique usuelle reste l'irradiation conformationnelle tridimensionnelle, la radiothérapie en modulation d'intensité n'ayant que des indications limitées. L'asservissement respiratoire pourrait être utile en cas de dose reçue par le cœur excessive. L'administration concomitante de la chimiothérapie adjuvante est déconseillée. En revanche, l'hormonothérapie peut être débutée en même temps que l'irradiation.In breast cancer, radiotherapy is an essential component of the treatment. After conservative surgery for an infiltrating carcinoma, radiotherapy must be systematically performed, regardless of the characteristics of the disease, because it decreases the rate of local recurrence and by this way, specific mortality. Partial breast irradiation could not be proposed routinely but only in very selected and informed patients. For ductal carcinoma in situ, adjuvant radiotherapy must be also systematically performed after lumpectomy. After mastectomy, chest wall irradiation is required for pT3–T4 tumours and if there is an axillary nodal involvement, whatever the number of involved lymph nodes. After neo-adjuvant chemotherapy and mastectomy, in case of pN0 disease, chest wall irradiation is recommended if there is a clinically or radiologically T3–T4 or node positive disease before chemotherapy. Axillary irradiation is recommended only if there is no axillary surgical dissection and a positive sentinel lymph node. Supra and infra-clavicular irradiation is advised in case of positive axillary nodes. Internal mammary irradiation must be discussed case by case, according to the benefit/risk ratio (cardiac toxicity). Dose to the chest wall or the breast must be between 45–50Gy with a conventional fractionation. A boost dose over the tumour bed is required if the patient is younger than 60 years old. Hypofractionation (42.5 Gy in 16 fractions, or 41.6 Gy en 13 or 40 Gy en 15) is possible after tumorectomy and if a nodal irradiation is not mandatory. Delineation of the breast, the chest wall and the nodal areas are based on clinical and radiological evaluations. 3D-conformal irradiation is the recommended technique, intensity-modulated radiotherapy must be proposed only in case of specific clinical situations. Respiratory gating could be useful to decrease the cardiac dose. Concomitant administration of chemotherapy in unadvised, but hormonal treatment could be start with radiotherapy.



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Radiothérapie des cancers de l’hypopharynx

Publication date: Available online 10 August 2016
Source:Cancer/Radiothérapie
Author(s): Y. Pointreau, C. Lafond, P. Trémolières, F. Legouté, S. Servagi-Vernat, P. Giraud, P. Maingon, G. Calais, M. Lapeyre
La radiothérapie conformationnelle avec modulation d'intensité est la technique de référence dans le traitement des cancers de l'hypopharynx. Les tumeurs localisées de stade T1 et T2 peuvent être traitées soit par irradiation externe (exclusive), soit par chirurgie conservatrice. Pour les tumeurs nécessitant une pharyngolaryngectomie totale (de stade T2 ou T3), une chimiothérapie d'induction suivie d'une radiothérapie externe exclusive ou une chimioradiothérapie concomitante exclusive d'emblée peut être proposée. Pour les tumeurs de stade T4, une chirurgie est conseillée. La prise en charge des aires ganglionnaires est le plus souvent fonction du traitement initial de la tumeur primitive. En cas de tumeur en place, les doses seront de 70Gy, les doses prophylactiques de 50Gy, en irradiation classique à raison de 2Gy par fraction ou avec boost intégré (70Gy en fractions de 2Gy et 56Gy en fractions de 1,8Gy ou 70Gy en fractions de 2,12Gy). Après chirurgie, l'indication est retenue pour les tumeurs évoluées avec des niveaux de doses fonction des critères anatomopathologiques (66Gy en cas de résection R1, 50 à 54Gy en cas de résection complète). La définition des volumes tumoraux et ganglionnaires repose sur des recommandations.The intensity-modulated radiotherapy is the gold standard in the treatment of hypopharynx cancers. Early T1 and T2 tumours could be treated by exclusive radiotherapy or surgery. For tumours requiring total pharyngolaryngectomy (T2 or T3), induction chemotherapy followed by exclusive radiotherapy or concurrent chemoradiotherapy are possible. For T4 tumours, surgery must be proposed. The treatment of lymph nodes is based on the initial treatment of the primary tumour. In non-surgical procedure, in case of sequential radiotherapy, curative dose is 70Gy and prophylactic dose is 50Gy. An integrated simultaneous boost radiotherapy is allowed (70Gy in 2Gy per fraction and 56Gy in 1.8Gy per fraction or 70Gy in 2.12Gy per fraction). Postoperatively, radiotherapy is used for locally advanced cancers with dose levels based on pathologic criteria (66Gy for R1 resection, 50 to 54Gy for complete resection). Volume delineation is based on guidelines.



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Patients porteurs d’un stimulateur cardiaque ou d’un défibrillateur implantable

Publication date: Available online 10 August 2016
Source:Cancer/Radiothérapie
Author(s): I. Barillot, R. Mazeron, F. Mornex, P. Giraud
Les patients porteurs de stimulateur cardiaque ou de défibrillateur ont une contre-indication relative à la radiothérapie. Cette revue présente les précautions publiées par l'Agence nationale de sécurité du médicament et des produits de santé (ANSM).Patients with pacemakers or defibrillators have a relative contra-indication for radiotherapy. This review presents the precautions issued by the French agency for drug safety (ANSM).



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Patient-oncologist Alliance and Psychosocial Well-being in Chinese Society Strongly Affect Cancer Management Adherence with Cancer of Unknown Primary

Abstract

Background

Patient-oncologist alliance and psychosocial well-being have strong associations with adherence to cancer management. For patients with cancer of unknown primary (CUP), adherence is crucial to treatment or occult primary screening plans. There has been no study investigating the relationship between alliance, psychosocial factors and adherence in such patients or in Chinese socio-cultural settings.

Methods

The measures of alliance, psychosocial well-being and adherence willingness were administered to 368 patients with CUP, with a mean age of 58.33 ± 11.24 years, comprising 126 males and 142 females. Multiple linear regression models were applied to investigate the independent relationship between alliance and adherence by controlling for socioeconomic and psychosocial confounders.

Results

Alliance was found independently and positively associated with greater adherence willingness and adherence to treatment and follow-up screening after controlling for significant confounders, including medical conditions, psychosocial well-being variables, and socioeconomic factors.

Conclusion

Stronger patient-oncologist alliance may foster enhanced adherence to treatment and follow-up screening in patients with CUP. Patient-oncologist alliance seems affected by socioeconomic factors and psychosocial well-being in the Chinese sociocultural settings. This article is protected by copyright. All rights reserved.

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Targeting of the P2X7 receptor in pancreatic cancer and stellate cells

Abstract

The ATP-gated receptor P2X7 (P2X7R) is involved in regulation of cell survival and has been of interest in cancer field. Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer and new markers and therapeutic targets are needed. PDAC is characterized by a complex tumour microenvironment, which includes cancer and pancreatic stellate cells (PSCs), and potentially high nucleotide/side turnover. Our aim was to determine P2X7R expression and function in human pancreatic cancer cells in vitro as well as to perform in vivo efficacy study applying P2X7R inhibitor in an orthotopic xenograft mouse model of PDAC. In the in vitro studies we show that human PDAC cells with luciferase gene (PancTu-1 Luc cells) express high levels of P2X7R protein. Allosteric P2X7R antagonist AZ10606120 inhibited cell proliferation in basal conditions, indicating that P2X7R was tonically active. Extracellular ATP and BzATP, to which the P2X7R is more sensitive, further affected cell survival and confirmed complex functionality of P2X7R. PancTu-1 Luc migration and invasion was reduced by AZ10606120, and it was stimulated by PSCs, but not by PSCs from P2X7^-/- animals. PancTu-1 Luc cells were orthotopically transplanted into nude mice and tumour growth was followed non-invasively by bioluminescence imaging. AZ10606120-treated mice showed reduced bioluminescence compared to saline-treated mice. Immunohistochemical analysis confirmed P2X7R expression in cancer and PSC cells, and in metaplastic/neoplastic acinar and duct structures. PSCs number/activity and collagen deposition was reduced in AZ10606120 treated tumours. This article is protected by copyright. All rights reserved.

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