Ischaemic pituitary tumour apoplexy and concurrent meningitis: a diagnostic dilemma

Pituitary tumour apoplexy is a rare but potentially life threatening clinical syndrome that mostly results from haemorrhage in the pre-existent tumour. Pure ischaemic subtype of apoplexy is even rarer. The presentation can be hard to differentiate clinically from bacterial meningitis. Moreover, the presence of one does not necessarily exclude the other and early diagnosis of both conditions is imperative for timely management. We report a case of ischaemic pituitary tumour apoplexy that may have precipitated in the setting of bacterial meningitis.

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Hyperacute leucopenia associated with furosemide

A 72-year-old man presented to the hospital with exacerbation of congestive heart failure. He was given furosemide 40 mg intravenously twice at 4 hours apart. At 4 hours after the second dose of furosemide, his white blood cells (WBC) dropped acutely from 9.8 to 2.4x10⁹/L (reference range 4.1 to 9.3x10⁹/L). With the discontinuation of furosemide, the WBC trended up to 7.1x10⁹/L about 13 hours after the second dose of intravenous furosemide and remained in normal range for the next 3 days. However, when the oral furosemide was started on hospital day 4, there was a mild drop in WBC count, which returned to and maintained at baseline since the next day. The dynamic changes in the patient's WBC were coincident with the use of furosemide. The possible mechanisms of furosemide-associated transient hyperacute leucopenia were discussed.

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Giant insulinoma: an unusual cause of hypoglycaemia

Description 

A 70-year-old non-diabetic man presented to the accident and emergency department with convulsions and symptoms of hunger, anxiety and blurred vision. A non-tender epigastric mass was identified, and he was found to be hypoglycaemic, with plasma glucose levels of 1.5 mmol/L (4.4–6.1 mmol/L). C-peptide and insulin levels were both inappropriately elevated.

After stabilisation with glucose, the patient was investigated with CT, which revealed a 154 mm mass in the pancreas that displaced the stomach and encased the coeliac trunk, the superior mesenteric vein and the splenic vein (figure 1). Collaterals were found at the level of the hepatic hilum, the gastro-oesophageal junction and adjacent to the mass itself. Calcifications typical of insulinomas were evident (figure 2). No metastases were seen. Fine-needle aspiration was then performed, confirming the diagnosis (figure 3).

Figure 1

Multiplanar reconstruction identifying the 154 mm insulinoma.

...

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Severe panniculitis and polyarthritis caused by acinar cell carcinoma arising from an ectopic pancreas

The pancreatitis, panniculitis and polyarthritis (PPP) syndrome is a rare condition caused by pancreatic diseases, such as acute or chronic pancreatitis or pancreatic carcinoma. We report the first case of PPP syndrome caused by metastatic acinar cell carcinoma from an ectopic pancreas. The symptoms were successfully managed by the treatment of the metastatic carcinoma. Pancreatic cytosteatonecrosis should be always considered in a patient who is showing symptoms of panniculitis and polyarthritis.

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Retrobulbar heavy liquid discovered 5 years postvitrectomy

Description

This report of a mass in the upper eyelid resulting from long-term complications of heavy liquid tamponade therapy of retinal detachment is a good example of learning from rare cases.

Retinal detachments may be repaired by scleral buckling, vitrectomy surgery or by a combination of both techniques. Retinal detachments repaired by vitrectomy are typically tamponaded by either gas or silicone oil. In certain complex cases, heavy liquid (perfluorohexyloctane/polydimethylsiloxane) is used as a short-term tamponading agent that is subsequently replaced with gas or silicone oil.1 2

A 16-year-old woman presented with bilateral retinal detachments secondary to giant tears. The patient had no relevant ocular history and denied trauma. The left eye had a macula-sparing detachment and the right eye had a macula-off retinal detachment. Both retinas were reattached sequentially with a combination of scleral buckling and vitrectomy with heavy liquid tamponade. The heavy...

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Multilevel lumbar spine infection due to poor dentition in an immunocompetent adult: a case report

Although spinal infections have been reported following dental procedures, development of a spinal infection attributed to poor dentition without a history of a dental procedure in an immunocompetent adult has...

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Procedural sedation and analgesia for adults in Europe: Safety first

No abstract available

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Neostigmine-based reversal of intermediate acting neuromuscular blocking agents to prevent postoperative residual paralysis: A systematic review

BACKGROUND Neostigmine is widely used to antagonise residual paralysis. Over the last decades, the benchmark of acceptable neuromuscular recovery has increased progressively to a train-of-four (TOF) ratio of at least 0.9. Raising this benchmark may impact on the efficacy of neostigmine. OBJECTIVE(S) The systematic review evaluates the efficacy of neostigmine to antagonise neuromuscular block to attain a TOF ratio of at least 0.9. DESIGN We performed a systematic search of the literature from January 1992 to December 2015. DATA SOURCES OR SETTING PubMed, EMBASE and the Cochrane Controlled Clinical Trials database were searched for randomised controlled human studies. Search was performed without language restrictions, using the following free text terms: 'neostigmine', 'sugammadex', 'edrophonium' or 'pyridostigmine' AND 'neuromuscular block', 'reversal' or 'reverse'. ELIGIBILITY CRITERIA Studies were accepted for inclusion if they used quantitative neuromuscular monitoring and neostigmine as the reversal agent. Selected trials were checked by two of the authors for data integrity. Trials relevant for inclusion had to report the number of patients included, the type of anaesthetic maintenance, the type of neuromuscular blocking agent used, the reversal agent and dose used, the depth of neuromuscular block when neostigmine was administered and the reversal time (time from injection of neostigmine until a TOF ratio ≥0.9 was attained). RESULTS 19 trials were eligible for quantitative analysis. In patients with deep residual block [T1 (first twitch height) 25% of baseline), or that a recovery time longer than 15 min be accepted. Correspondence to Thomas Fuchs-Buder, MD, Department of Anaesthesia and Critical Care, University Hospital of Nancy, Rue du Morvan, F-54511 Vandoeuvre-Les-Nancy, France. Cedex E-mail: t.fuchs-buder@chru-nancy.fr © 2017 European Society of Anaesthesiology

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Editorial Board

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Global impact of radiotherapy in oncology: Saving one million lives by 2035

Cancer is a group of over 200 distinct diseases with a common fatal outcome if not treated. In 2016, almost 9 million patients died of cancer, an increase of 18% in just the last ten years [1]. Moreover, in parallel with the predicted rise in worldwide cancer cases from the current 15 million to 24 million in two decades, the annual cancer deaths are expected to amount to 14.5 million by 2035 [2]. The good news is there are possibilities to bend this devastating curve: wide implementation of the current cancer prevention efforts will reduce the projected numbers of all cancers by 40–50%, while early diagnosis and advances in cancer treatment resulted in doubling of long-term survival in the past 40 years [3].

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Important ESTRO dates

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Contents

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The Biology of Cancer Exosomes: Insights and New Perspectives

Exosomes are a subclass of extracellular vesicles involved in intercellular communication that are released by all cell types, including cancer cells. Cancer exosomes carry malignant information in the form of proteins, lipids, and nucleic acids that can reprogram recipient cells. Exosomes have emerged as putative biological mediators in cancer contributing to major steps of disease progression. A leading role exists for cancer exosomes in specific aspects of tumor progression: modulation of immune response, tumor microenvironment reprogramming, and metastasis. This review will address the functions attributed to cancer exosomes in these three aspects of cancer biology, highlighting recent advances and potential limitations. Finally, we explore alternative strategies to develop better models to study cancer exosomes biology. Cancer Res; 77(23); 1–9. ©2017 AACR.

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Precision Oncology: Between Vaguely Right and Precisely Wrong

Precision Oncology seeks to identify and target the mutation that drives a tumor. Despite its straightforward rationale, concerns about its effectiveness are mounting. What is the biological explanation for the "imprecision?" First, Precision Oncology relies on indiscriminate sequencing of genomes in biopsies that barely represent the heterogeneous mix of tumor cells. Second, findings that defy the orthodoxy of oncogenic "driver mutations" are now accumulating: the ubiquitous presence of oncogenic mutations in silent premalignancies or the dynamic switching without mutations between various cell phenotypes that promote progression. Most troublesome is the observation that cancer cells that survive treatment still will have suffered cytotoxic stress and thereby enter a stem cell–like state, the seeds for recurrence. The benefit of "precision targeting" of mutations is inherently limited by this counterproductive effect. These findings confirm that there is no precise linear causal relationship between tumor genotype and phenotype, a reminder of logician Carveth Read's caution that being vaguely right may be preferable to being precisely wrong. An open-minded embrace of the latest inconvenient findings indicating nongenetic and "imprecise" phenotype dynamics of tumors as summarized in this review will be paramount if Precision Oncology is ultimately to lead to clinical benefits. Cancer Res; 77(23); 1–7. ©2017 AACR.

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The Biology of Cancer Exosomes: Insights and New Perspectives

Exosomes are a subclass of extracellular vesicles involved in intercellular communication that are released by all cell types, including cancer cells. Cancer exosomes carry malignant information in the form of proteins, lipids, and nucleic acids that can reprogram recipient cells. Exosomes have emerged as putative biological mediators in cancer contributing to major steps of disease progression. A leading role exists for cancer exosomes in specific aspects of tumor progression: modulation of immune response, tumor microenvironment reprogramming, and metastasis. This review will address the functions attributed to cancer exosomes in these three aspects of cancer biology, highlighting recent advances and potential limitations. Finally, we explore alternative strategies to develop better models to study cancer exosomes biology. Cancer Res; 77(23); 1–9. ©2017 AACR.

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Precision Oncology: Between Vaguely Right and Precisely Wrong

Precision Oncology seeks to identify and target the mutation that drives a tumor. Despite its straightforward rationale, concerns about its effectiveness are mounting. What is the biological explanation for the "imprecision?" First, Precision Oncology relies on indiscriminate sequencing of genomes in biopsies that barely represent the heterogeneous mix of tumor cells. Second, findings that defy the orthodoxy of oncogenic "driver mutations" are now accumulating: the ubiquitous presence of oncogenic mutations in silent premalignancies or the dynamic switching without mutations between various cell phenotypes that promote progression. Most troublesome is the observation that cancer cells that survive treatment still will have suffered cytotoxic stress and thereby enter a stem cell–like state, the seeds for recurrence. The benefit of "precision targeting" of mutations is inherently limited by this counterproductive effect. These findings confirm that there is no precise linear causal relationship between tumor genotype and phenotype, a reminder of logician Carveth Read's caution that being vaguely right may be preferable to being precisely wrong. An open-minded embrace of the latest inconvenient findings indicating nongenetic and "imprecise" phenotype dynamics of tumors as summarized in this review will be paramount if Precision Oncology is ultimately to lead to clinical benefits. Cancer Res; 77(23); 1–7. ©2017 AACR.

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Poziotinib Shows Promise for Rare Lung Cancer [News in Brief]

Good responses seen in patients with exon 20 mutations, for which approved EGFR inhibitors are largely ineffective.

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FOXF1 defines the core-regulatory circuitry in gastrointestinal stromal tumor (GIST) [Research Articles]

The cellular context that integrates upstream signaling and downstream nuclear response dictates the oncogenic behaviour and shapes treatment responses in distinct cancer types. Here, we uncover that in GIST, the forkhead family member, FOXF1, directly controls the transcription of two master regulators, KIT and ETV1, both required for GIST precursor-interstitial cells of Cajal (ICC) lineage-specification and GIST tumorigenesis. Further, FOXF1 co-localizes with ETV1 at enhancers and functions as a pioneer factor that regulates the ETV1-dependent GIST-lineage specific transcriptome through modulation of the local chromatin context, including chromatin accessibility, enhancer maintenance and ETV1 binding. Functionally, FOXF1 is required for human GIST cell growth in vitro and murine GIST tumor growth and maintenance in vivo. The simultaneous control of the upstream signaling and nuclear response sets up a unique regulatory paradigm and highlights the critical role of FOXF1 in enforcing the GIST cellular context for highly lineage-restricted clinical behaviour and treatment response.

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NKG2D-dependent anti-tumor effects of chemotherapy and radiotherapy against glioblastoma

Purpose: NKG2D is a potent activating immune cell receptor and glioma cells express the cognate ligands (NKG2DL). These ligands are inducible by cellular stress and temozolomide (TMZ) or irradiation (IR), the standard treatment of glioblastoma, could affect their expression. However, a role of NKG2DL for the efficacy of TMZ and IR has never been addressed. Experimental Design:We assessed the effect of TMZ and IR on NKG2DL in vitro and in vivo in a variety of murine and human glioblastoma models including glioma-initiating cells and a cohort of paired glioblastoma samples from patients before and after therapy. Functional effects were studied with immune cell assays. The relevance of the NKG2D system for the efficacy of TMZ and IR was assessed in vivo in syngeneic orthotopic glioblastoma models with blocking antibodies and NKG2D knockout mice. Results:TMZ or IR induced NKG2DL in vitro and in vivo in all glioblastoma models and glioblastoma patient samples had increased levels of NKG2DL after therapy with TMZ and IR. This enhanced the immunogenicity of glioma cells in a NGK2D-dependent manner, was independent from cytotoxic or growth inhibitory effects, attenuated by O6-methylguanine-DNA-methyltransferase (MGMT) and required the DNA damage response. The survival benefit afforded by TMZ or IR relied on an intact NKG2D system and was decreased upon inhibition of the NKG2D pathway. Conclusions: The immune system may influence the activity of convential cancer treatments with particular importance of the NKG2D pathway in glioblastoma. Our data provide a rationale to combine NKG2D-based immunotherapies with TMZ and IR.

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NKG2D-dependent anti-tumor effects of chemotherapy and radiotherapy against glioblastoma

Purpose: NKG2D is a potent activating immune cell receptor and glioma cells express the cognate ligands (NKG2DL). These ligands are inducible by cellular stress and temozolomide (TMZ) or irradiation (IR), the standard treatment of glioblastoma, could affect their expression. However, a role of NKG2DL for the efficacy of TMZ and IR has never been addressed. Experimental Design:We assessed the effect of TMZ and IR on NKG2DL in vitro and in vivo in a variety of murine and human glioblastoma models including glioma-initiating cells and a cohort of paired glioblastoma samples from patients before and after therapy. Functional effects were studied with immune cell assays. The relevance of the NKG2D system for the efficacy of TMZ and IR was assessed in vivo in syngeneic orthotopic glioblastoma models with blocking antibodies and NKG2D knockout mice. Results:TMZ or IR induced NKG2DL in vitro and in vivo in all glioblastoma models and glioblastoma patient samples had increased levels of NKG2DL after therapy with TMZ and IR. This enhanced the immunogenicity of glioma cells in a NGK2D-dependent manner, was independent from cytotoxic or growth inhibitory effects, attenuated by O6-methylguanine-DNA-methyltransferase (MGMT) and required the DNA damage response. The survival benefit afforded by TMZ or IR relied on an intact NKG2D system and was decreased upon inhibition of the NKG2D pathway. Conclusions: The immune system may influence the activity of convential cancer treatments with particular importance of the NKG2D pathway in glioblastoma. Our data provide a rationale to combine NKG2D-based immunotherapies with TMZ and IR.

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“HEATPAC” - a phase II randomized study of concurrent thermochemoradiotherapy versus chemoradiotherapy alone in locally advanced pancreatic cancer

Pancreatic cancer has a dismal prognosis with 5-year overall survival rate of around 5%. Although surgery is still the best option in operable cases, majority of the patients who present in locally advanced st...

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“HEATPAC” - a phase II randomized study of concurrent thermochemoradiotherapy versus chemoradiotherapy alone in locally advanced pancreatic cancer

Pancreatic cancer has a dismal prognosis with 5-year overall survival rate of around 5%. Although surgery is still the best option in operable cases, majority of the patients who present in locally advanced st...

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Crystal structure of the coxsackievirus A16 RNA-dependent RNA polymerase elongation complex reveals novel features in motif A dynamics

Abstract

The RNA-dependent RNA polymerases (RdRPs) encoded by RNA viruses represent a unique class of nucleic acid polymerases. Unlike other classes of single-subunit polymerases, viral RdRPs have evolved a unique conformational change in their palm domain to close the active site during catalysis. The hallmark of this conformational change is the backbone shift of the polymerase motif A from an "open" state to a "closed" state, allowing two universally conserved aspartic acid residues to orient toward each other for divalent metal binding and catalysis. The "closed" motif A conformation was only observed upon the binding of correct NTP in RdRP catalytic complexes or under rare conditions such as induced by a bound lutetium ion or a bound glutamate molecule. By solving the crystal structure of the catalytic elongation complex of the coxsackievirus RdRP, we in this work observed for the first time the "closed" motif A conformation in the absence of an NTP substrate or other conformational-change-inducing factors. This observation emphasizes the intrinsic dynamic features of viral RdRP motif A, and solidifies the structural basis for how this important structural element participates in catalytic events of the RdRPs.

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The combined activation of KCa3.1 and inhibition of Kv11.1/hERG1 currents contribute to overcome Cisplatin resistance in colorectal cancer cells

The combined activation of K_Ca3.1 and inhibition of K_v11.1/hERG1 currents contribute to overcome Cisplatin resistance in colorectal cancer cells

The combined activation of K_Ca3.1 and inhibition of K_v11.1/hERG1 currents contribute to overcome Cisplatin resistance in colorectal cancer cells, Published online: 21 November 2017; doi:10.1038/bjc.2017.392

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The impact of folate intake on the risk of head and neck cancer in the prostate, lung, colorectal, and ovarian cancer screening trial (PLCO) cohort

The impact of folate intake on the risk of head and neck cancer in the prostate, lung, colorectal, and ovarian cancer screening trial (PLCO) cohort

The impact of folate intake on the risk of head and neck cancer in the prostate, lung, colorectal, and ovarian cancer screening trial (PLCO) cohort, Published online: 21 November 2017; doi:10.1038/bjc.2017.383

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Rapid nodal staging of head and neck cancer surgical specimens with flow cytometric analysis

Rapid nodal staging of head and neck cancer surgical specimens with flow cytometric analysis

Rapid nodal staging of head and neck cancer surgical specimens with flow cytometric analysis, Published online: 21 November 2017; doi:10.1038/bjc.2017.408

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Cadherin-1 and cadherin-3 cooperation determines the aggressiveness of pancreatic ductal adenocarcinoma

Cadherin-1 and cadherin-3 cooperation determines the aggressiveness of pancreatic ductal adenocarcinoma

Cadherin-1 and cadherin-3 cooperation determines the aggressiveness of pancreatic ductal adenocarcinoma, Published online: 21 November 2017; doi:10.1038/bjc.2017.411

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Determination of an optimal response cut-off able to predict progression-free survival in patients with well-differentiated advanced pancreatic neuroendocrine tumours treated with sunitinib: an alternative to the current RECIST-defined response

Determination of an optimal response cut-off able to predict progression-free survival in patients with well-differentiated advanced pancreatic neuroendocrine tumours treated with sunitinib: an alternative to the current RECIST-defined response

Determination of an optimal response cut-off able to predict progression-free survival in patients with well-differentiated advanced pancreatic neuroendocrine tumours treated with sunitinib: an alternative to the current RECIST-defined response, Published online: 21 November 2017; doi:10.1038/bjc.2017.402

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Crystal structure of the coxsackievirus A16 RNA-dependent RNA polymerase elongation complex reveals novel features in motif A dynamics

Abstract

The RNA-dependent RNA polymerases (RdRPs) encoded by RNA viruses represent a unique class of nucleic acid polymerases. Unlike other classes of single-subunit polymerases, viral RdRPs have evolved a unique conformational change in their palm domain to close the active site during catalysis. The hallmark of this conformational change is the backbone shift of the polymerase motif A from an "open" state to a "closed" state, allowing two universally conserved aspartic acid residues to orient toward each other for divalent metal binding and catalysis. The "closed" motif A conformation was only observed upon the binding of correct NTP in RdRP catalytic complexes or under rare conditions such as induced by a bound lutetium ion or a bound glutamate molecule. By solving the crystal structure of the catalytic elongation complex of the coxsackievirus RdRP, we in this work observed for the first time the "closed" motif A conformation in the absence of an NTP substrate or other conformational-change-inducing factors. This observation emphasizes the intrinsic dynamic features of viral RdRP motif A, and solidifies the structural basis for how this important structural element participates in catalytic events of the RdRPs.

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The combined activation of KCa3.1 and inhibition of Kv11.1/hERG1 currents contribute to overcome Cisplatin resistance in colorectal cancer cells

The combined activation of K_Ca3.1 and inhibition of K_v11.1/hERG1 currents contribute to overcome Cisplatin resistance in colorectal cancer cells

The combined activation of K_Ca3.1 and inhibition of K_v11.1/hERG1 currents contribute to overcome Cisplatin resistance in colorectal cancer cells, Published online: 21 November 2017; doi:10.1038/bjc.2017.392

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The impact of folate intake on the risk of head and neck cancer in the prostate, lung, colorectal, and ovarian cancer screening trial (PLCO) cohort

The impact of folate intake on the risk of head and neck cancer in the prostate, lung, colorectal, and ovarian cancer screening trial (PLCO) cohort

The impact of folate intake on the risk of head and neck cancer in the prostate, lung, colorectal, and ovarian cancer screening trial (PLCO) cohort, Published online: 21 November 2017; doi:10.1038/bjc.2017.383

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Rapid nodal staging of head and neck cancer surgical specimens with flow cytometric analysis

Rapid nodal staging of head and neck cancer surgical specimens with flow cytometric analysis

Rapid nodal staging of head and neck cancer surgical specimens with flow cytometric analysis, Published online: 21 November 2017; doi:10.1038/bjc.2017.408

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Cadherin-1 and cadherin-3 cooperation determines the aggressiveness of pancreatic ductal adenocarcinoma

Cadherin-1 and cadherin-3 cooperation determines the aggressiveness of pancreatic ductal adenocarcinoma

Cadherin-1 and cadherin-3 cooperation determines the aggressiveness of pancreatic ductal adenocarcinoma, Published online: 21 November 2017; doi:10.1038/bjc.2017.411

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Determination of an optimal response cut-off able to predict progression-free survival in patients with well-differentiated advanced pancreatic neuroendocrine tumours treated with sunitinib: an alternative to the current RECIST-defined response

Determination of an optimal response cut-off able to predict progression-free survival in patients with well-differentiated advanced pancreatic neuroendocrine tumours treated with sunitinib: an alternative to the current RECIST-defined response

Determination of an optimal response cut-off able to predict progression-free survival in patients with well-differentiated advanced pancreatic neuroendocrine tumours treated with sunitinib: an alternative to the current RECIST-defined response, Published online: 21 November 2017; doi:10.1038/bjc.2017.402

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miR-335 inhibited cell proliferation of lung cancer cells by target Tra2β

Abstract

Accumulating evidence has suggested that the dysregulation of miRNAs is an important factor in the pathogenesis of lung cancer. Here, we demonstrate that miR-335 expression is reduced in non-small cell lung cancer (NSCLC) tumors relative to non-cancerous adjacent tissues, whilst the expression of Tra2β is increased. In addition, clinical data revealed that the increased Tra2β and decreased miR-335 expression observed in NSCLC cells was associated with poor patient survival rates. In-vitro experimentation showed that the overexpression of miR-335 inhibited the growth, invasion and migration capabilities of A459 lung cancer cells, by targeting Tra2β. In contrast, inhibition of miR-335 or overexpression of the Tra2β target gene stimulated the growth, invasion and migratory capabilities of A459 lung cancer cells in vitro. Furthermore, overexpression of miR-335 or inhibition of Tra2β decreased the phosphorylation of Rb-S780 and Rb-AKT. Overall, these findings suggest that the downregulation of miR-335 in A459 lung cancer cells promoted cell proliferation by upregulation of Tra2β, mediated via activation of the AKT/mTOR signaling pathway, and suggest that miR-335 may have potential as a novel therapeutic target for NSCLC.

This article is protected by copyright. All rights reserved.

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miR-335 inhibited cell proliferation of lung cancer cells by target Tra2β

Abstract

Accumulating evidence has suggested that the dysregulation of miRNAs is an important factor in the pathogenesis of lung cancer. Here, we demonstrate that miR-335 expression is reduced in non-small cell lung cancer (NSCLC) tumors relative to non-cancerous adjacent tissues, whilst the expression of Tra2β is increased. In addition, clinical data revealed that the increased Tra2β and decreased miR-335 expression observed in NSCLC cells was associated with poor patient survival rates. In-vitro experimentation showed that the overexpression of miR-335 inhibited the growth, invasion and migration capabilities of A459 lung cancer cells, by targeting Tra2β. In contrast, inhibition of miR-335 or overexpression of the Tra2β target gene stimulated the growth, invasion and migratory capabilities of A459 lung cancer cells in vitro. Furthermore, overexpression of miR-335 or inhibition of Tra2β decreased the phosphorylation of Rb-S780 and Rb-AKT. Overall, these findings suggest that the downregulation of miR-335 in A459 lung cancer cells promoted cell proliferation by upregulation of Tra2β, mediated via activation of the AKT/mTOR signaling pathway, and suggest that miR-335 may have potential as a novel therapeutic target for NSCLC.

This article is protected by copyright. All rights reserved.

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Determination of an optimal response cut-off able to predict progression-free survival in patients with well-differentiated advanced pancreatic neuroendocrine tumours treated with sunitinib: an alternative to the current RECIST-defined response

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Rapid nodal staging of head and neck cancer surgical specimens with flow cytometric analysis

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Cadherin-1 and cadherin-3 cooperation determines the aggressiveness of pancreatic ductal adenocarcinoma

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The combined activation of KCa3.1 and inhibition of Kv11.1/hERG1 currents contribute to overcome Cisplatin resistance in colorectal cancer cells

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The impact of folate intake on the risk of head and neck cancer in the prostate, lung, colorectal, and ovarian cancer screening trial (PLCO) cohort

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The impact of folate intake on the risk of head and neck cancer in the prostate, lung, colorectal, and ovarian cancer screening trial (PLCO) cohort

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Determination of an optimal response cut-off able to predict progression-free survival in patients with well-differentiated advanced pancreatic neuroendocrine tumours treated with sunitinib: an alternative to the current RECIST-defined response

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Rapid nodal staging of head and neck cancer surgical specimens with flow cytometric analysis

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Cadherin-1 and cadherin-3 cooperation determines the aggressiveness of pancreatic ductal adenocarcinoma

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The combined activation of KCa3.1 and inhibition of Kv11.1/hERG1 currents contribute to overcome Cisplatin resistance in colorectal cancer cells

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Evaluating the Predictive Ability of Initial Staging F-18 FDG PET/CT for the Prognosis of Non-Hodgkin Malignant Lymphoma Patients Who Underwent Stem Cell Transplantation

Abstract

Objectives

This study aimed to determine the value of clinical prognostic factors and semiquantitative metabolic parameters from initial staging fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (F-18 FDG PET/CT) in non-Hodgkin lymphoma (NHL) patients treated with stem cell transplantation (SCT).

Methods

A total of 39 malignant lymphoma patients who underwent initial staging F-18 FDG PET/CT were enrolled in this study. SUVmax, MTV_wb, and TLG_wb were measured during the initial staging PET/CT. Receiver operating characteristic curve (ROC) analysis was adopted to dichotomize continuous variables. Log-rank test and Cox proportional hazard regression analysis were used to evaluate disease-free survival (DFS) rate.

Results

Among the 39 patients with malignant lymphoma, 17 (43.6%) had a relapse. For several clinical factors such as age, ECOG performance score, AMC/ALC score, stages, and revised International Prognostic Index score, differences between the two dichotomized groups were statistically insignificant. In univariate analysis, DFS estimates were 71.0 ± 7.8 months and 18.0 ± 5.9 months in high-SUVmax and low-SUVmax group, respectively (P < 0.01). For MTV_wb, DFS estimates were 46.6 ± 12.4 months and 69.1 ± 8.5 months in high-MTV_wb and low-MTV_wb group, respectively (P = 0.12). For TLG_wb, DFS estimates were 65.3 ± 7.5 months and 13.7 ± 8.6 months in high-TLG_wb and low-TLG_wb group, respectively (P = 0.02). In Cox proportional hazard regression analysis, only MTV_wb showed statistical significance (HR 3.01, 95% CI 1.04–8.74, P = 0.04).

Conclusion

In NHL patients treated with SCT, the MTV_wb of initial staging F-18 FDG PET/CT was an independent prognostic factor.

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Evaluating the Predictive Ability of Initial Staging F-18 FDG PET/CT for the Prognosis of Non-Hodgkin Malignant Lymphoma Patients Who Underwent Stem Cell Transplantation

Abstract

Objectives

This study aimed to determine the value of clinical prognostic factors and semiquantitative metabolic parameters from initial staging fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (F-18 FDG PET/CT) in non-Hodgkin lymphoma (NHL) patients treated with stem cell transplantation (SCT).

Methods

A total of 39 malignant lymphoma patients who underwent initial staging F-18 FDG PET/CT were enrolled in this study. SUVmax, MTV_wb, and TLG_wb were measured during the initial staging PET/CT. Receiver operating characteristic curve (ROC) analysis was adopted to dichotomize continuous variables. Log-rank test and Cox proportional hazard regression analysis were used to evaluate disease-free survival (DFS) rate.

Results

Among the 39 patients with malignant lymphoma, 17 (43.6%) had a relapse. For several clinical factors such as age, ECOG performance score, AMC/ALC score, stages, and revised International Prognostic Index score, differences between the two dichotomized groups were statistically insignificant. In univariate analysis, DFS estimates were 71.0 ± 7.8 months and 18.0 ± 5.9 months in high-SUVmax and low-SUVmax group, respectively (P < 0.01). For MTV_wb, DFS estimates were 46.6 ± 12.4 months and 69.1 ± 8.5 months in high-MTV_wb and low-MTV_wb group, respectively (P = 0.12). For TLG_wb, DFS estimates were 65.3 ± 7.5 months and 13.7 ± 8.6 months in high-TLG_wb and low-TLG_wb group, respectively (P = 0.02). In Cox proportional hazard regression analysis, only MTV_wb showed statistical significance (HR 3.01, 95% CI 1.04–8.74, P = 0.04).

Conclusion

In NHL patients treated with SCT, the MTV_wb of initial staging F-18 FDG PET/CT was an independent prognostic factor.

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Response

We thank Belkacemi and colleagues for their interest in our recent work that evaluated the impact of regional nodal irradiation (RNI) in node-positive human epidermal growth factor receptor 2 (HER2)–positive breast cancer (BC). They made several arguments questioning the validity of our findings, and below we provide our response to their comments.

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RE: Regional Nodal Irradiation After Breast-Conserving Surgery for Early HER2-Positive Breast Cancer: Results of a Subanalysis From the ALTTO Trial

We congratulate Gingras et al. for their report on regional node irradiation (RNI) in the human epidermal growth factor receptor 2 (HER2)–targeted therapy era (1). They suggest that RNI has no impact on disease-free survival (DFS) in node-positive (N+), HER2-positive breast cancer (BC) patients treated with conservative surgery, axillary node dissection (ALND), and whole breast irradiation. These results reported in the anti-HER2 era contradict RNI data from the MA20 and EORTC22922 trials (2,3).

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Social integration and survival after diagnosis of colorectal cancer

BACKGROUND

Although larger social networks have been associated with lower all-cause mortality, few studies have examined whether social integration predicts survival outcomes among patients with colorectal cancer (CRC). The authors examined the association between social ties and survival after CRC diagnosis in a prospective cohort study.

METHODS

Participants included 896 women in the Nurses' Health Study who were diagnosed with stage I, II, or III CRC between 1992 and 2012. Stage was assigned using the American Joint Committee on Cancer criteria. Social integration was assessed every 4 years since 1992 using the Berkman-Syme Social Network Index, which included marital status, social network size, contact frequency, religious participation, and other social group participation.

RESULTS

During follow-up, there were 380 total deaths, 167 of which were due to CRC. In multivariable analyses, women who were socially integrated before diagnosis had a subsequent reduced risk of all-cause mortality (hazard ratio [HR], 0.65; 95% confidence interval [95% CI], 0.46-0.92) and CRC mortality (HR, 0.63; 95% CI, 0.38-1.06) compared with women who were socially isolated. In particular, women with more intimate ties (family and friends) had lower all-cause mortality (HR, 0.61; 95% CI, 0.42-0.88) and CRC mortality (HR, 0.59; 95% CI, 0.34-1.03) compared with those with few intimate ties. Participation in religious or community activities was not found to be related to outcomes. The analysis of postdiagnosis social integration yielded similar results.

CONCLUSIONS

Socially integrated women were found to have better survival after a diagnosis of CRC, possibly due to beneficial caregiving from their family and friends. Interventions aimed at strengthening social network structures to ensure access to care may be valuable programmatic tools in the management of patients with CRC. Cancer 2017. © 2017 American Cancer Society.

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Social integration and survival after diagnosis of colorectal cancer

BACKGROUND

Although larger social networks have been associated with lower all-cause mortality, few studies have examined whether social integration predicts survival outcomes among patients with colorectal cancer (CRC). The authors examined the association between social ties and survival after CRC diagnosis in a prospective cohort study.

METHODS

Participants included 896 women in the Nurses' Health Study who were diagnosed with stage I, II, or III CRC between 1992 and 2012. Stage was assigned using the American Joint Committee on Cancer criteria. Social integration was assessed every 4 years since 1992 using the Berkman-Syme Social Network Index, which included marital status, social network size, contact frequency, religious participation, and other social group participation.

RESULTS

During follow-up, there were 380 total deaths, 167 of which were due to CRC. In multivariable analyses, women who were socially integrated before diagnosis had a subsequent reduced risk of all-cause mortality (hazard ratio [HR], 0.65; 95% confidence interval [95% CI], 0.46-0.92) and CRC mortality (HR, 0.63; 95% CI, 0.38-1.06) compared with women who were socially isolated. In particular, women with more intimate ties (family and friends) had lower all-cause mortality (HR, 0.61; 95% CI, 0.42-0.88) and CRC mortality (HR, 0.59; 95% CI, 0.34-1.03) compared with those with few intimate ties. Participation in religious or community activities was not found to be related to outcomes. The analysis of postdiagnosis social integration yielded similar results.

CONCLUSIONS

Socially integrated women were found to have better survival after a diagnosis of CRC, possibly due to beneficial caregiving from their family and friends. Interventions aimed at strengthening social network structures to ensure access to care may be valuable programmatic tools in the management of patients with CRC. Cancer 2017. © 2017 American Cancer Society.

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Correlation between lymphatic endothelial markers and lymph node status or N-staging of colorectal cancer

Abstract

Background

The purpose of this study is to examine the expression levels of lymphatic endothelial markers in colorectal cancer and to explore the correlation between the expression levels of markers and lymph node status.

Methods

Forty-seven paired fresh tumor tissues and para-cancerous tissues were collected from colorectal cancer patients who received surgical treatment between August 2015 and March 2016 in Cancer Hospital, Chinese Academy of Medical Sciences. Real-time quantitative PCR (RTQ–PCR) was used to check the expression levels of LYVE–1, VEGFR–3, Podoplanin, and Prox–1 in tumor and para-cancerous tissues.

Results

The positive expression rates of LYVE–1, VEGFR–3, Podoplanin, and Prox–1 in tumor tissues were 100, 93.6, 100, and 91.4%, but 100, 100, 100, and 87.2% in para-cancerous tissues. Comparing with para-cancerous tissues, tumor tissues had significantly lower expression levels of LYVE–1 (P < 0.001) and VEGFR–3 (P = 0.013) and higher levels of Podoplanin (P = 0.016) and Prox–1 (P = 0.078). There was no correlation between lymph node status and the expression level of LYVE–1 in tumor tissues (P = 0.354) or par-cancerous tissues (P = 0.617); similar results were found for VEGFR–3 (P = 0.631, 0.738), Podoplanin (P = 0.490, 0.625), and Prox–1 (P = 0.503, 0.174). Meanwhile, there was no correlation between N-staging and the expression level of LYVE–1 in tumor tissues (P = 0.914) or para-cancerous tissues (P = 0.784); similar results were found for VEGFR–3 (P = 0.493, 0.955), Podoplanin (P = 0.199, 0.370), and Prox–1 (P = 0.780, 0.234).

Conclusions

There was no correlation between expression levels of lymphatic endothelial markers and lymph node status; LYVE–1, VEGFR–3, Podoplanin, and Prox–1 could not be used for predicting the lymph node status or N-staging of colorectal cancer.

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Cancers, Vol. 9, Pages 159: Genomic Destabilization Triggered by Replication Stress during Senescence

Cancers, Vol. 9, Pages 159: Genomic Destabilization Triggered by Replication Stress during Senescence

Cancers doi: 10.3390/cancers9110159

Authors: Yusuke Minakawa Atsuhiro Shimizu Yusuke Matsuno Ken-ichi Yoshioka

Most cancers develop after middle age, and are often associated with multiple mutations and genomic instability, implying that genomic destabilization is critical for age-related tumor development. In this manuscript, we review current knowledge regarding (1) the senescent cellular background, which is associated with a higher risk of genomic destabilization; and (2) the contributions of genomic destabilization to cancer development.

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MicroRNA 26b promotes colorectal cancer metastasis by down-regulating PTEN and WNT5A

Summary

Invasion and metastasis are crucially important factors in the survival of malignant tumors. The epithelial-mesenchymal transition (EMT) is an early step in metastatic progression and the presence of cancer stem cells is closely related to tumor survival, proliferation, metastasis, and recurrence. Here we report that ectopic overexpression of microRNA 26b (miR-26b) in colorectal cancer (CRC) cell lines promoted EMT and stem cell-like phenotypes in vitro. Furthermore, miR-26b directly targeted and suppressed multiple tumor suppressors, including phosphatase and tensin homolog (PTEN) and wingless-type MMTV integration site family member 5A (WNT5A). Notably, miR-26b is markedly upregulated in tumor samples from patients with lymphatic metastases. These results indicate that miR-26b promotes CRC metastasis by down-regulating PTEN and WNT5A, and may represent a therapeutic target for metastatic CRC.

This article is protected by copyright. All rights reserved.

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Correlation between lymphatic endothelial markers and lymph node status or N-staging of colorectal cancer

Abstract

Background

The purpose of this study is to examine the expression levels of lymphatic endothelial markers in colorectal cancer and to explore the correlation between the expression levels of markers and lymph node status.

Methods

Forty-seven paired fresh tumor tissues and para-cancerous tissues were collected from colorectal cancer patients who received surgical treatment between August 2015 and March 2016 in Cancer Hospital, Chinese Academy of Medical Sciences. Real-time quantitative PCR (RTQ–PCR) was used to check the expression levels of LYVE–1, VEGFR–3, Podoplanin, and Prox–1 in tumor and para-cancerous tissues.

Results

The positive expression rates of LYVE–1, VEGFR–3, Podoplanin, and Prox–1 in tumor tissues were 100, 93.6, 100, and 91.4%, but 100, 100, 100, and 87.2% in para-cancerous tissues. Comparing with para-cancerous tissues, tumor tissues had significantly lower expression levels of LYVE–1 (P < 0.001) and VEGFR–3 (P = 0.013) and higher levels of Podoplanin (P = 0.016) and Prox–1 (P = 0.078). There was no correlation between lymph node status and the expression level of LYVE–1 in tumor tissues (P = 0.354) or par-cancerous tissues (P = 0.617); similar results were found for VEGFR–3 (P = 0.631, 0.738), Podoplanin (P = 0.490, 0.625), and Prox–1 (P = 0.503, 0.174). Meanwhile, there was no correlation between N-staging and the expression level of LYVE–1 in tumor tissues (P = 0.914) or para-cancerous tissues (P = 0.784); similar results were found for VEGFR–3 (P = 0.493, 0.955), Podoplanin (P = 0.199, 0.370), and Prox–1 (P = 0.780, 0.234).

Conclusions

There was no correlation between expression levels of lymphatic endothelial markers and lymph node status; LYVE–1, VEGFR–3, Podoplanin, and Prox–1 could not be used for predicting the lymph node status or N-staging of colorectal cancer.

http://ift.tt/2zpJ946

Cancers, Vol. 9, Pages 159: Genomic Destabilization Triggered by Replication Stress during Senescence

Cancers, Vol. 9, Pages 159: Genomic Destabilization Triggered by Replication Stress during Senescence

Cancers doi: 10.3390/cancers9110159

Authors: Yusuke Minakawa Atsuhiro Shimizu Yusuke Matsuno Ken-ichi Yoshioka

Most cancers develop after middle age, and are often associated with multiple mutations and genomic instability, implying that genomic destabilization is critical for age-related tumor development. In this manuscript, we review current knowledge regarding (1) the senescent cellular background, which is associated with a higher risk of genomic destabilization; and (2) the contributions of genomic destabilization to cancer development.

http://ift.tt/2mOBsPe

MicroRNA 26b promotes colorectal cancer metastasis by down-regulating PTEN and WNT5A

Summary

Invasion and metastasis are crucially important factors in the survival of malignant tumors. The epithelial-mesenchymal transition (EMT) is an early step in metastatic progression and the presence of cancer stem cells is closely related to tumor survival, proliferation, metastasis, and recurrence. Here we report that ectopic overexpression of microRNA 26b (miR-26b) in colorectal cancer (CRC) cell lines promoted EMT and stem cell-like phenotypes in vitro. Furthermore, miR-26b directly targeted and suppressed multiple tumor suppressors, including phosphatase and tensin homolog (PTEN) and wingless-type MMTV integration site family member 5A (WNT5A). Notably, miR-26b is markedly upregulated in tumor samples from patients with lymphatic metastases. These results indicate that miR-26b promotes CRC metastasis by down-regulating PTEN and WNT5A, and may represent a therapeutic target for metastatic CRC.

This article is protected by copyright. All rights reserved.

http://ift.tt/2B030TR

Lu-177-Based Peptide Receptor Radionuclide Therapy for Advanced Neuroendocrine Tumors

Abstract

Peptide receptor radionuclide therapy (PRRT) is a systemic cytotoxic radiation therapy using a compound of β-emitting radionuclide chelated to a peptide for the treatment of tumor with overexpressed specific cell receptor such as somatostatin receptor subtype 2 (SSTR2) of neuroendocrine tumor (NET). Surgical resection should be performed for the curative treatment for NETs when it is feasible; however, a multi-disciplinary approach is needed when locally advanced or metastasized disease. PRRT with lutetium-177 (Lu-177)-labeled somatostatin analogues, as a new treatment modality targeting metastatic or inoperable NETs expressing the SSTR2, have been developed and successfully used for the past two decades. As Lu-177 emits both β- and γ-radiation, it has the ability as a theragnostic agent for NETs compared with only β-emitting yttrium-90 labeled PRRT. Several recent studies reported that Lu-177 gave an overall positive response and improved the patients' quality of life. To fully exploit its potential, large comparative studies are needed for the assessment of distinct efficacies of Lu-177 labeled PRRT. Additionally, for extending the indications and developing new regimens of Lu-177-based PRRT, more dedicated clinical research is required.

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Lu-177-Based Peptide Receptor Radionuclide Therapy for Advanced Neuroendocrine Tumors

Abstract

Peptide receptor radionuclide therapy (PRRT) is a systemic cytotoxic radiation therapy using a compound of β-emitting radionuclide chelated to a peptide for the treatment of tumor with overexpressed specific cell receptor such as somatostatin receptor subtype 2 (SSTR2) of neuroendocrine tumor (NET). Surgical resection should be performed for the curative treatment for NETs when it is feasible; however, a multi-disciplinary approach is needed when locally advanced or metastasized disease. PRRT with lutetium-177 (Lu-177)-labeled somatostatin analogues, as a new treatment modality targeting metastatic or inoperable NETs expressing the SSTR2, have been developed and successfully used for the past two decades. As Lu-177 emits both β- and γ-radiation, it has the ability as a theragnostic agent for NETs compared with only β-emitting yttrium-90 labeled PRRT. Several recent studies reported that Lu-177 gave an overall positive response and improved the patients' quality of life. To fully exploit its potential, large comparative studies are needed for the assessment of distinct efficacies of Lu-177 labeled PRRT. Additionally, for extending the indications and developing new regimens of Lu-177-based PRRT, more dedicated clinical research is required.

http://ift.tt/2hPo4Zq

Do pregnancy characteristics contribute to rising childhood cancer incidence rates in the United States?

Abstract

Background

Since 1975, childhood cancer incidence rates have gradually increased in the United States; however, few studies have conducted analyses across time to unpack this temporal rise. The aim of this study was to test the hypothesis that increasing cancer incidence rates are due to secular trends in pregnancy characteristics that are established risk factors for childhood cancer incidence including older maternal age, higher birthweight, and lower birth order. We also considered temporal trends in sociodemographic characteristics including race/ethnicity and poverty.

Procedure

We conducted a time series county-level ecologic analysis using linked population-based data from Surveillance, Epidemiology, and End Results cancer registries (1975–2013), birth data from the National Center for Health Statistics (1970–2013), and sociodemographic data from the US Census (1970–2010). We estimated unadjusted and adjusted average annual percent changes (AAPCs) in incidence of combined (all diagnoses) and individual types of cancer among children, ages 0–4 years, from Poisson mixed models.

Results

There was a statistically significant unadjusted temporal rise in incidence of combined childhood cancers (AAPC = 0.71%; 95% CI = 0.55–0.86), acute lymphoblastic leukemia (0.78%; 0.49–1.07), acute myeloid leukemia (1.86%; 1.13–2.59), central nervous system tumors (1.31%; 0.94–1.67), and hepatoblastoma (2.70%; 1.68–3.72). Adjustment for county-level maternal age reduced estimated AAPCs between 8% (hepatoblastoma) and 55% (combined). However, adjustment for other county characteristics did not attenuate AAPCs, and AAPCs remained significantly above 0% in models fully adjusted for county-level characteristics.

Conclusion

Although rising maternal age may account for some of the increase in childhood cancer incidence over time, other factors, not considered in this analysis, may also contribute to temporal trends.

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Do pregnancy characteristics contribute to rising childhood cancer incidence rates in the United States?

Abstract

Background

Since 1975, childhood cancer incidence rates have gradually increased in the United States; however, few studies have conducted analyses across time to unpack this temporal rise. The aim of this study was to test the hypothesis that increasing cancer incidence rates are due to secular trends in pregnancy characteristics that are established risk factors for childhood cancer incidence including older maternal age, higher birthweight, and lower birth order. We also considered temporal trends in sociodemographic characteristics including race/ethnicity and poverty.

Procedure

We conducted a time series county-level ecologic analysis using linked population-based data from Surveillance, Epidemiology, and End Results cancer registries (1975–2013), birth data from the National Center for Health Statistics (1970–2013), and sociodemographic data from the US Census (1970–2010). We estimated unadjusted and adjusted average annual percent changes (AAPCs) in incidence of combined (all diagnoses) and individual types of cancer among children, ages 0–4 years, from Poisson mixed models.

Results

There was a statistically significant unadjusted temporal rise in incidence of combined childhood cancers (AAPC = 0.71%; 95% CI = 0.55–0.86), acute lymphoblastic leukemia (0.78%; 0.49–1.07), acute myeloid leukemia (1.86%; 1.13–2.59), central nervous system tumors (1.31%; 0.94–1.67), and hepatoblastoma (2.70%; 1.68–3.72). Adjustment for county-level maternal age reduced estimated AAPCs between 8% (hepatoblastoma) and 55% (combined). However, adjustment for other county characteristics did not attenuate AAPCs, and AAPCs remained significantly above 0% in models fully adjusted for county-level characteristics.

Conclusion

Although rising maternal age may account for some of the increase in childhood cancer incidence over time, other factors, not considered in this analysis, may also contribute to temporal trends.

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Isolated hepatoblastoma arising from the hepatogastric ligament: a case report

Almost all hepatoblastomas are isolated to the liver. Hepatoblastoma arising from and limited to extrahepatic tissue is an extremely rare clinical entity.

http://ift.tt/2hIl2lU

The impact of dual energy CT imaging on dose calculations for pre-clinical studies

To investigate the feasibility of using dual-energy CT (DECT) for tissue segmentation and kilovolt (kV) dose calculations in pre-clinical studies and assess potential dose calculation accuracy gain.

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Comparison of neoadjuvant chemoradiation with carboplatin/ paclitaxel or cisplatin/ 5-fluoruracil in patients with squamous cell carcinoma of the esophagus

Neoadjuvant chemoradiation (nCRT) is the treatment of choice for patients with locally advanced squamous cell carcinoma of the esophagus (SCC). Today radiation oncologists can choose between two different ther...

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The impact of dual energy CT imaging on dose calculations for pre-clinical studies

To investigate the feasibility of using dual-energy CT (DECT) for tissue segmentation and kilovolt (kV) dose calculations in pre-clinical studies and assess potential dose calculation accuracy gain.

http://ift.tt/2jLlFjb

Comparison of neoadjuvant chemoradiation with carboplatin/ paclitaxel or cisplatin/ 5-fluoruracil in patients with squamous cell carcinoma of the esophagus

Neoadjuvant chemoradiation (nCRT) is the treatment of choice for patients with locally advanced squamous cell carcinoma of the esophagus (SCC). Today radiation oncologists can choose between two different ther...

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Patients' preferences for adjuvant sorafenib after resection of renal cell carcinoma in the SORCE trial: what makes it worthwhile?

Abstract

Background

We sought to determine the survival benefits that patients judged sufficient to warrant adjuvant therapy with sorafenib for 1 year, or for 3 years after resection of renal cell carcinoma (RCC) in the SORCE trial.

Methods

SORCE participants from all sites in Australia and New Zealand, and selected sites in the UK, completed a validated preferences questionnaire at months 0, 3, 15 and 42 to elicit the minimum survival benefits they judged sufficient to warrant adjuvant sorafenib for 1 year (versus observation), or for 3 years (versus 1 year). The questionnaires used reference survival times of 5 years and 15 years; and reference survival rates at 5 years of 65% and 85%.

Results

The 233 participants had a median age of 57 years (range 29 to 78) and 71% were male. For 1 year of sorafenib versus no adjuvant therapy, the median benefits in survival times judged sufficient to warrant treatment were an extra 9 months beyond 5 years and an extra 1 year beyond 15 years; the median benefit in survival rates were an extra 4% beyond 65% and an extra 3% beyond 85% at 5 years. For 3 years of sorafenib versus 1 year of sorafenib, the median benefit in survival time judged sufficient to warrant extended treatment was an extra 1 year beyond both 5 years and 15 years. Participants randomly allocated treatment with sorafenib judged larger benefits necessary than those allocated placebo. Participants' preferences were not associated with their baseline characteristics or the interval from randomisation.

Conclusion

Most participants judged an extra year of survival necessary to warrant 1 year of adjuvant sorafenib worthwhile, and an additional year of survival to warrant extending the duration of sorafenib from 1 year to 3 years. Patients' preferences are important in shared-decision-making.SORCE trial clinical trials number = NCT00492258

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Patients' preferences for adjuvant sorafenib after resection of renal cell carcinoma in the SORCE trial: what makes it worthwhile?

Abstract

Background

We sought to determine the survival benefits that patients judged sufficient to warrant adjuvant therapy with sorafenib for 1 year, or for 3 years after resection of renal cell carcinoma (RCC) in the SORCE trial.

Methods

SORCE participants from all sites in Australia and New Zealand, and selected sites in the UK, completed a validated preferences questionnaire at months 0, 3, 15 and 42 to elicit the minimum survival benefits they judged sufficient to warrant adjuvant sorafenib for 1 year (versus observation), or for 3 years (versus 1 year). The questionnaires used reference survival times of 5 years and 15 years; and reference survival rates at 5 years of 65% and 85%.

Results

The 233 participants had a median age of 57 years (range 29 to 78) and 71% were male. For 1 year of sorafenib versus no adjuvant therapy, the median benefits in survival times judged sufficient to warrant treatment were an extra 9 months beyond 5 years and an extra 1 year beyond 15 years; the median benefit in survival rates were an extra 4% beyond 65% and an extra 3% beyond 85% at 5 years. For 3 years of sorafenib versus 1 year of sorafenib, the median benefit in survival time judged sufficient to warrant extended treatment was an extra 1 year beyond both 5 years and 15 years. Participants randomly allocated treatment with sorafenib judged larger benefits necessary than those allocated placebo. Participants' preferences were not associated with their baseline characteristics or the interval from randomisation.

Conclusion

Most participants judged an extra year of survival necessary to warrant 1 year of adjuvant sorafenib worthwhile, and an additional year of survival to warrant extending the duration of sorafenib from 1 year to 3 years. Patients' preferences are important in shared-decision-making.SORCE trial clinical trials number = NCT00492258

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Doxorubicin combined with low intensity ultrasound suppresses the growth of oral squamous cell carcinoma in culture and in xenografts

Oral squamous cell carcinoma (OSCC) invades surrounding tissues by upregulating matrix metalloproteinases (MMPs) -2 and −9, which causes over-expression of the Hedgehog signaling proteins Shh and Gli-1 and deg...

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Adenovirus vector-based prime-boost vaccination via heterologous routes induces cervicovaginal CD8+ T cell responses against HPV16 oncoproteins

Abstract

Recent advances in immunotherapy against cancer underscore the importance of T lymphocytes and tumor microenvironment, but few vaccines targeting cancer have been approved likely due in part to the dearth of common tumor antigens, insufficient immunogenicity and the evolution of immune evasion mechanisms during the progression to malignancy. Human papillomaviruses (HPV) are the primary etiologic agents of cervical cancer and progression from persistent HPV-infection to cervical intraepithelial lesions and eventually cancer requires persistent expression of the oncoproteins E6 and E7. This offers the opportunity to specifically target these virus-specific antigens for vaccine-induced clearance of infected cells before cancers develop. Here we have evaluated the immunogenicity of Adenovirus types 26 and 35 derived vectors expressing a fusion of HPV16 E6 and E7 oncoproteins after intramuscular and/or intravaginal immunization in mice. The adenovirus vectors were shown to transduce an intact cervicovaginal epithelium. Intramuscular prime followed by intravaginal boost maximized the induction and trafficking of HPV-specific CD8⁺ T cells producing IFN-γ and TNF-α to the cervicovaginal tract. Importantly, the cervicovaginal CD8⁺ T cells expressed CD69 and CD103, hallmarks of intraepithelial tissue resident memory CD8⁺ T cells. This prime/boost strategy targeting heterologous locations also induced circulating HPV-specific CD8⁺ T cell responses. Our study prompts further evaluation of intravaginal immunization with adenoviral vectors expressing modified E6 and E7 antigens for therapeutic vaccination against persistent HPV infection and cervical intraepithelial neoplasia. This article is protected by copyright. All rights reserved.

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Antibodies against human papillomaviruses as diagnostic and prognostic biomarker in patients with neck squamous cell carcinoma from unknown primary

Abstract

Treatment of patients with neck lymph node metastasis of squamous cell carcinoma (SCC) from unknown primary tumor (NSCCUP) is challenging due to the risk of missing occult tumors or inducing toxicity to unaffected sites. Human papillomavirus (HPV) is a promising biomarker given its causal link to oropharyngeal SCC and superior survival of patients with HPV-driven oropharyngeal SCC and NSCCUP. Identification of HPV-driven NSCCUP could focus diagnostic work-up and treatment on the oropharynx. For the first time, we assessed HPV antibodies and their prognostic value in NSCCUP patients.

Antibodies against E6 and E7 (HPV16/18/31/33/35), E1 and E2 (HPV16/18) were assessed in 46 NSCCUP patients in sera collected at diagnosis, and in follow-up sera from five patients. In 28 patients, HPV tumor status was determined using molecular markers (HPV DNA, mRNA and cellular p16^INK4a).

Thirteen (28%) NSCCUP patients were HPV-seropositive for HPV16, 18, 31, or 33. Of eleven patients with HPV-driven NSCCUP, ten were HPV-seropositive, while all 17 patients with non-HPV-driven NSCCUP were HPV-seronegative, resulting in 91% sensitivity (95%CI: 59-100%) and 100% specificity (95%CI: 80-100%). HPV antibody levels decreased after curative treatment. Recurrence was associated with increasing levels in an individual case. HPV-seropositive patients had a better overall and progression-free survival with hazard ratios of 0.09 (95%CI: 0.01-0.42) and 0.03 (95%CI: 0.002-0.18), respectively.

For the first time, seropositivity to HPV proteins is described in NSCCUP patients, and high sensitivity and specificity for HPV-driven NSCCUP are demonstrated. HPV seropositivity appears to be a reliable diagnostic and prognostic biomarker for patients with HPV-driven NSCCUP. This article is protected by copyright. All rights reserved.

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Ovarian Cancer Early Detection by Circulating CA125 in the context of Anti-CA125 Autoantibody Levels: Results from the EPIC cohort

Abstract

CA125 is the best ovarian cancer early detection marker to date; however, sensitivity is limited and complementary markers are required to improve discrimination between ovarian cancer cases and non-cases. Anti-CA125 autoantibodies are observed in circulation. Our objective was to evaluate whether these antibodies (1) can serve as early detection markers, providing evidence of an immune response to a developing tumor, and (2) modify the discriminatory capacity of CA125 by either masking CA125 levels (resulting in lower discrimination) or acting synergistically to improve discrimination between cases and non-cases. We investigated these objectives using a nested case-control study within the European Prospective Investigation into Cancer and Nutrition cohort (EPIC) including 250 cases diagnosed within 4 years of blood collection and up to 4 matched controls. Circulating CA125 antigen and antibody levels were quantified using an electrochemiluminescence assay. Adjusted areas under the curve (aAUCs) by 2-year lag-time intervals were calculated using conditional logistic regression calibrated towards the absolute risk estimates from a pre-existing epidemiological risk model as an offset-variable. Anti-CA125 levels alone did not discriminate cases from controls. For cases diagnosed <2 years after blood collection, discrimination by CA125 antigen was suggestively higher with higher anti-CA125 levels (aAUC, highest antibody tertile: 0.84 [0.76-0.92]; lowest tertile: 0.76 [0.67-0.86]; p_het=0.06). We provide the first evidence of potentially synergistic discrimination effects of CA125 and anti-CA125 antibodies in ovarian early detection. If these findings are replicated, evaluating CA125 in the context of its antibody may improve ovarian cancer early detection. This article is protected by copyright. All rights reserved.

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The dark side of glucose transporters in prostate cancer: Are they a new feature to characterize carcinomas?

Abstract

One of the hallmarks of cancer cells is the increased ability to acquire nutrients, particularly glucose and glutamine. Proliferating cells need precursors for cell growth and NADPH reducing equivalents for survival. The principal responsible for glucose uptake is facilitative glucose transporters (GLUTs), which usually are overexpressed in cancer cells. Besides their role in glucose uptake, GLUT transporters are able to transport other compounds such as dehydroascorbic acid or uric acid. They play a major role in tumor progression and cellular processes such as regulated cell death. The prostate gland has the particular characteristic of being more glycolytic than other non-pathological tissues given an accumulation of citrate in the seminal fluid and the inhibition of m-aconitase that affects to Tricarboxylic Acid Cycle. In prostate cancer (PCa), androgens increase glucose uptake, upregulate GLUT transporters such as GLUT1 and GLUT3 and stimulate AMPK pathway, suggesting a possible connection between glycolytic and androgenic signaling. Interestingly, diabetes is not a risk factor of PCa, as it is in other cancers, while insulin stimulates progression and IGF1 pathway plays an important role in PCa progression. It was recently found that PCa cells overexpress GLUT4 and, more importantly, that it seems to be related to the castration-resistant phenotype, though little is known about its participation in tumor progression. This review will focus on the role of GLUT transporters along with PCa progression, and the involvement of GLUT4 on castration-resistant phenotype transition would be considered. This article is protected by copyright. All rights reserved.

from Cancer via ola Kala on Inoreader http://ift.tt/2iCLw9p
via IFTTT

Administration of Adjuvant Chemotherapy for Stage II-III Colon Cancer Patients: A European Population-based Study

Abstract

The advantage of adjuvant chemotherapy (ACT) for treating stage III colon cancer patients is well established and widely accepted. However, many patients with stage III colon cancer do not receive ACT. Moreover, there are controversies around the effectiveness of ACT for stage II patients.

We investigated the administration of ACT and its association with overall survival in resected stage II (overall and stratified by low-/high-risk) and stage III colon cancer patients in three European countries including The Netherlands (2009-2014), Belgium (2009-2013), and Sweden (2009-2014). Hazard ratios (HR) for death were obtained by Cox regression models adjusted for potential confounders.

A total of 60244 resected colon cancer patients with pathological stage II&III were analyzed. A small proportion (range 9% -24%) of stage II and over half (range 55%-68%) of stage III patients received ACT. Administration of ACT in stage II&III tumors decreased with higher age of patients. Administration of ACT was significantly associated with higher overall survival in high-risk stage II patients (in The Netherlands (HR; 95%CI= 0.82 (0.67 - 0.99), Belgium (0.73; 0.59- 0.90), and Sweden (0.58; 0.44- 0.75)), and in stage III patients (in The Netherlands (0.47; 0.43- 0.50), Belgium (0.46; 0.41- 0.50), and Sweden (0.48; 0.43- 0.54)). In stage III, results were consistent across subgroups including elderly patients.

Our results show an association of ACT with higher survival among stage III and high-risk stage II colon cancer patients. Further investigations are needed on the selection criteria of stage II&III colon cancer patients for ACT. This article is protected by copyright. All rights reserved.

from Cancer via ola Kala on Inoreader http://ift.tt/2AYv7my
via IFTTT

Adenovirus vector-based prime-boost vaccination via heterologous routes induces cervicovaginal CD8+ T cell responses against HPV16 oncoproteins

Abstract

Recent advances in immunotherapy against cancer underscore the importance of T lymphocytes and tumor microenvironment, but few vaccines targeting cancer have been approved likely due in part to the dearth of common tumor antigens, insufficient immunogenicity and the evolution of immune evasion mechanisms during the progression to malignancy. Human papillomaviruses (HPV) are the primary etiologic agents of cervical cancer and progression from persistent HPV-infection to cervical intraepithelial lesions and eventually cancer requires persistent expression of the oncoproteins E6 and E7. This offers the opportunity to specifically target these virus-specific antigens for vaccine-induced clearance of infected cells before cancers develop. Here we have evaluated the immunogenicity of Adenovirus types 26 and 35 derived vectors expressing a fusion of HPV16 E6 and E7 oncoproteins after intramuscular and/or intravaginal immunization in mice. The adenovirus vectors were shown to transduce an intact cervicovaginal epithelium. Intramuscular prime followed by intravaginal boost maximized the induction and trafficking of HPV-specific CD8⁺ T cells producing IFN-γ and TNF-α to the cervicovaginal tract. Importantly, the cervicovaginal CD8⁺ T cells expressed CD69 and CD103, hallmarks of intraepithelial tissue resident memory CD8⁺ T cells. This prime/boost strategy targeting heterologous locations also induced circulating HPV-specific CD8⁺ T cell responses. Our study prompts further evaluation of intravaginal immunization with adenoviral vectors expressing modified E6 and E7 antigens for therapeutic vaccination against persistent HPV infection and cervical intraepithelial neoplasia. This article is protected by copyright. All rights reserved.

http://ift.tt/2iBAHob

Antibodies against human papillomaviruses as diagnostic and prognostic biomarker in patients with neck squamous cell carcinoma from unknown primary

Abstract

Treatment of patients with neck lymph node metastasis of squamous cell carcinoma (SCC) from unknown primary tumor (NSCCUP) is challenging due to the risk of missing occult tumors or inducing toxicity to unaffected sites. Human papillomavirus (HPV) is a promising biomarker given its causal link to oropharyngeal SCC and superior survival of patients with HPV-driven oropharyngeal SCC and NSCCUP. Identification of HPV-driven NSCCUP could focus diagnostic work-up and treatment on the oropharynx. For the first time, we assessed HPV antibodies and their prognostic value in NSCCUP patients.

Antibodies against E6 and E7 (HPV16/18/31/33/35), E1 and E2 (HPV16/18) were assessed in 46 NSCCUP patients in sera collected at diagnosis, and in follow-up sera from five patients. In 28 patients, HPV tumor status was determined using molecular markers (HPV DNA, mRNA and cellular p16^INK4a).

Thirteen (28%) NSCCUP patients were HPV-seropositive for HPV16, 18, 31, or 33. Of eleven patients with HPV-driven NSCCUP, ten were HPV-seropositive, while all 17 patients with non-HPV-driven NSCCUP were HPV-seronegative, resulting in 91% sensitivity (95%CI: 59-100%) and 100% specificity (95%CI: 80-100%). HPV antibody levels decreased after curative treatment. Recurrence was associated with increasing levels in an individual case. HPV-seropositive patients had a better overall and progression-free survival with hazard ratios of 0.09 (95%CI: 0.01-0.42) and 0.03 (95%CI: 0.002-0.18), respectively.

For the first time, seropositivity to HPV proteins is described in NSCCUP patients, and high sensitivity and specificity for HPV-driven NSCCUP are demonstrated. HPV seropositivity appears to be a reliable diagnostic and prognostic biomarker for patients with HPV-driven NSCCUP. This article is protected by copyright. All rights reserved.

http://ift.tt/2jK93J2

Ovarian Cancer Early Detection by Circulating CA125 in the context of Anti-CA125 Autoantibody Levels: Results from the EPIC cohort

Abstract

CA125 is the best ovarian cancer early detection marker to date; however, sensitivity is limited and complementary markers are required to improve discrimination between ovarian cancer cases and non-cases. Anti-CA125 autoantibodies are observed in circulation. Our objective was to evaluate whether these antibodies (1) can serve as early detection markers, providing evidence of an immune response to a developing tumor, and (2) modify the discriminatory capacity of CA125 by either masking CA125 levels (resulting in lower discrimination) or acting synergistically to improve discrimination between cases and non-cases. We investigated these objectives using a nested case-control study within the European Prospective Investigation into Cancer and Nutrition cohort (EPIC) including 250 cases diagnosed within 4 years of blood collection and up to 4 matched controls. Circulating CA125 antigen and antibody levels were quantified using an electrochemiluminescence assay. Adjusted areas under the curve (aAUCs) by 2-year lag-time intervals were calculated using conditional logistic regression calibrated towards the absolute risk estimates from a pre-existing epidemiological risk model as an offset-variable. Anti-CA125 levels alone did not discriminate cases from controls. For cases diagnosed <2 years after blood collection, discrimination by CA125 antigen was suggestively higher with higher anti-CA125 levels (aAUC, highest antibody tertile: 0.84 [0.76-0.92]; lowest tertile: 0.76 [0.67-0.86]; p_het=0.06). We provide the first evidence of potentially synergistic discrimination effects of CA125 and anti-CA125 antibodies in ovarian early detection. If these findings are replicated, evaluating CA125 in the context of its antibody may improve ovarian cancer early detection. This article is protected by copyright. All rights reserved.

http://ift.tt/2AXWVay

The dark side of glucose transporters in prostate cancer: Are they a new feature to characterize carcinomas?

Abstract

One of the hallmarks of cancer cells is the increased ability to acquire nutrients, particularly glucose and glutamine. Proliferating cells need precursors for cell growth and NADPH reducing equivalents for survival. The principal responsible for glucose uptake is facilitative glucose transporters (GLUTs), which usually are overexpressed in cancer cells. Besides their role in glucose uptake, GLUT transporters are able to transport other compounds such as dehydroascorbic acid or uric acid. They play a major role in tumor progression and cellular processes such as regulated cell death. The prostate gland has the particular characteristic of being more glycolytic than other non-pathological tissues given an accumulation of citrate in the seminal fluid and the inhibition of m-aconitase that affects to Tricarboxylic Acid Cycle. In prostate cancer (PCa), androgens increase glucose uptake, upregulate GLUT transporters such as GLUT1 and GLUT3 and stimulate AMPK pathway, suggesting a possible connection between glycolytic and androgenic signaling. Interestingly, diabetes is not a risk factor of PCa, as it is in other cancers, while insulin stimulates progression and IGF1 pathway plays an important role in PCa progression. It was recently found that PCa cells overexpress GLUT4 and, more importantly, that it seems to be related to the castration-resistant phenotype, though little is known about its participation in tumor progression. This review will focus on the role of GLUT transporters along with PCa progression, and the involvement of GLUT4 on castration-resistant phenotype transition would be considered. This article is protected by copyright. All rights reserved.

http://ift.tt/2iCLw9p

Administration of Adjuvant Chemotherapy for Stage II-III Colon Cancer Patients: A European Population-based Study

Abstract

The advantage of adjuvant chemotherapy (ACT) for treating stage III colon cancer patients is well established and widely accepted. However, many patients with stage III colon cancer do not receive ACT. Moreover, there are controversies around the effectiveness of ACT for stage II patients.

We investigated the administration of ACT and its association with overall survival in resected stage II (overall and stratified by low-/high-risk) and stage III colon cancer patients in three European countries including The Netherlands (2009-2014), Belgium (2009-2013), and Sweden (2009-2014). Hazard ratios (HR) for death were obtained by Cox regression models adjusted for potential confounders.

A total of 60244 resected colon cancer patients with pathological stage II&III were analyzed. A small proportion (range 9% -24%) of stage II and over half (range 55%-68%) of stage III patients received ACT. Administration of ACT in stage II&III tumors decreased with higher age of patients. Administration of ACT was significantly associated with higher overall survival in high-risk stage II patients (in The Netherlands (HR; 95%CI= 0.82 (0.67 - 0.99), Belgium (0.73; 0.59- 0.90), and Sweden (0.58; 0.44- 0.75)), and in stage III patients (in The Netherlands (0.47; 0.43- 0.50), Belgium (0.46; 0.41- 0.50), and Sweden (0.48; 0.43- 0.54)). In stage III, results were consistent across subgroups including elderly patients.

Our results show an association of ACT with higher survival among stage III and high-risk stage II colon cancer patients. Further investigations are needed on the selection criteria of stage II&III colon cancer patients for ACT. This article is protected by copyright. All rights reserved.

http://ift.tt/2AYv7my