Non-invasive measurement of renal perfusion and oxygen metabolism to predict postoperative acute kidney injury in neonates and infants after cardiopulmonary bypass surgery

Background: The pathophysiology of acute kidney injury (AKI) after cardiopulmonary bypass surgery for congenital heart disease is not completely understood. The aim of this study was to carry out a prospective analysis of the diagnostic value of non-invasive monitoring of renal oxygenation and microcirculation by combining laser Doppler flowmetry and tissue spectrometry.

Methods: In 50 neonates and infants who underwent repair (n = 31) or neonatal palliation (n = 19) of congenital heart disease with cardiopulmonary bypass, renal oxygenation, and microcirculatory flow, the approximate renal metabolic rate of oxygen and Doppler-based renal resistive index were determined after surgery. Correlations between these parameters and the occurrence of AKI according to the Pediatric Risk, Injury, Failure, Loss, End Stage Renal Disease criteria were investigated.

Results: Acute kidney injury occurred in 45% of patients after repair and in 32% after palliation. Renal oxygenation was significantly lower and the approximate renal metabolic rate of oxygen significantly higher in patients with AKI (P < 0.05). The microcirculatory flow was significantly higher in patients with AKI after neonatal palliation (P < 0.05), whereas renal resistive index was significantly higher in patients with AKI after repair (P < 0.05). The sensitivity of renal oxygenation, metabolic rate of oxygen, microcirculation, and resistive index in predicting AKI was 78–80, 73–78, 64–83, and 71–74%, respectively, with a specificity of 63–65, 54–75, 64–78, and 46–74% (area under the curve: 0.73–0.75, 0.68–0.83, 0.52–0.68, and 0.60–0.75), respectively.

Conclusions: Monitoring of renal oxygen metabolism allows early prediction of AKI in infants after cardiac surgery. In contrast, renal resistive index does not allow prediction of AKI after neonatal palliation with aortopulmonary shunt establishment.

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In the November BJA ...

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MitoVitE, a mitochondria-targeted antioxidant, limits paclitaxel-induced oxidative stress and mitochondrial damage in vitro, and paclitaxel-induced mechanical hypersensitivity in a rat pain model

Background: Neuropathic pain is a common side-effect of chemotherapy. Although precise mechanisms are unclear, oxidative stress and mitochondrial damage are involved. We investigated whether the mitochondria targeted antioxidant, MitoVitE, provided better protection against paclitaxel-induced mitochondrial damage in rat dorsal root ganglion (DRG) cells, than a non-targeted form of vitamin E, Trolox. We also determined whether MitoVitE, compared with duloxetine, could limit paclitaxel-induced mechanical hypersensitivity in rats.

Methods: Mitochondrial function was measured in DRG cells exposed to paclitaxel with and without MitoVitE or Trolox. The effect of MitoVitE or Trolox on paclitaxel-induced cell killing in cancer cell lines was also determined. Rats received a cumulative dose of 8 mg kg^–1 paclitaxel plus either MitoVitE (2 mg^–1 kg day^–1), duloxetine (10 mg kg^–1 day^–1) or vehicle control daily. Mechanical hind paw withdrawal thresholds were measured every two days.

Results: Paclitaxel caused loss of membrane potential in DRG cells. At 100 µM paclitaxel median [range] change was 61[44–78]%, P < 0.0001, which was ameliorated by MitoVitE (86[62–104]%) but not Trolox (46[46–57]%). Similarly, loss of metabolic activity and glutathione induced by paclitaxel (both P < 0.0001) were reduced by MitoVitE but not Trolox. Cytotoxicity of paclitaxel was not affected by co-exposure of ovarian cancer cells to either MitoVitE or Trolox, but was slightly reduced against breast cancer cells, in the presence of Trolox. Mean (SD) areas under the curve of withdrawal thresholds at 6 h after injection in rats given paclitaxel + control, or + MitoVitE (P < 0.0001) or + duloxetine (P < 0.0001) were 110 (5), 145 (10) and 156 (13) respectively.

Conclusions: Paclitaxel affected mitochondrial function and glutathione in DRG cells, which was abrogated by MitoVitE but not Trolox, without decreasing cancer cell cytotoxicity. In rats, paclitaxel-induced mechanical hypersensitivity was ameliorated by MitoVitE treatment to an extent similar to duloxetine. These data confirm mitochondria as a mechanistic target for paclitaxel-induced damage and suggest mitochondria targeted antioxidants as future therapeutic strategies.

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New approaches to the development of expertise in anaesthesia

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Circulating and intra-thoracic vs stressed and unstressed volumes

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Psychological assessment to identify patients at risk of postsurgical pain: the need for theory and pragmatism

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The ageing brain

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Fibrinogen--is it a universal haemostatic agent?

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Reply

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Perioperative anaphylaxis grading system: 'making the grade

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Cover Page

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Simvastatin-induced apoptosis in osteosarcoma

Osteosarcoma is the most common type of primary bone tumor, novel therapeutic agents for which are urgently needed. To identify such agents, we screened a panel of approved drugs with a mouse model of osteosarcoma. The screen identified simvastatin, which inhibited the proliferation and migration of osteosarcoma cells in vitro. Simvastatin also induced apoptosis in osteosarcoma cells in a manner dependent on inhibition of the mevalonate biosynthetic pathway. It also disrupted the function of the small GTPase RhoA and induced activation of AMP-activated protein kinase (AMPK) and p38 mitogen-activated protein kinase (MAPK), with AMPK functioning upstream of p38 MAPK. Inhibitors of AMPK or p38 MAPK attenuated the induction of apoptosis by simvastatin, whereas metformin enhanced this effect of simvastatin by further activation of AMPK. Although treatment with simvastatin alone did not inhibit osteosarcoma tumor growth in vivo, its combination with a fat-free diet induced a significant antitumor effect that was enhanced further by metformin administration. Our findings suggest that simvastatin induces apoptosis in osteosarcoma cells via activation of AMPK and p38 MAPK, and that, in combination with other approaches, it holds therapeutic potential for osteosarcoma.

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Simvastatin-induced apoptosis in osteosarcoma

Osteosarcoma is the most common type of primary bone tumor, novel therapeutic agents for which are urgently needed. To identify such agents, we screened a panel of approved drugs with a mouse model of osteosarcoma. The screen identified simvastatin, which inhibited the proliferation and migration of osteosarcoma cells in vitro. Simvastatin also induced apoptosis in osteosarcoma cells in a manner dependent on inhibition of the mevalonate biosynthetic pathway. It also disrupted the function of the small GTPase RhoA and induced activation of AMP-activated protein kinase (AMPK) and p38 mitogen-activated protein kinase (MAPK), with AMPK functioning upstream of p38 MAPK. Inhibitors of AMPK or p38 MAPK attenuated the induction of apoptosis by simvastatin, whereas metformin enhanced this effect of simvastatin by further activation of AMPK. Although treatment with simvastatin alone did not inhibit osteosarcoma tumor growth in vivo, its combination with a fat-free diet induced a significant antitumor effect that was enhanced further by metformin administration. Our findings suggest that simvastatin induces apoptosis in osteosarcoma cells via activation of AMPK and p38 MAPK, and that, in combination with other approaches, it holds therapeutic potential for osteosarcoma.

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Posttraumatic stress disorder symptomatology in the course of allogeneic HSCT: a prospective study

Abstract

Purpose

Despite the life-threatening character of allogeneic hematopoietic stem cell transplantation (allogeneic HSCT), very few longitudinal research exists on posttraumatic stress disorder (PTSD) symptomatology in this patient group. We investigated prevalence, temporal course and predictors of PTSD symptomatology in this population.

Methods

Patients were assessed before conditioning (T0), 100 days (T1), and 12 months after HSCT (T2). PTSD symptomatology was measured with the PTSD Checklist—Civilian Version. We conducted multilevel modeling and multiple regression analyses.

Results

Two hundred thirty-nine patients participated at baseline, 150 at T1, and 102 at T2. Up to 15 % met the criteria for PTSD at least once during the course of assessment. Fifty-two percent showed diagnostic relevant levels of intrusion, 30 % of avoidance, and 33 % of arousal at least once. Apart from arousal, which increased between T0 and T1 (γ = 0.56, p = 0.03), no other severity score significantly differed between time points. Being impaired by pain (γ = 2.89, p < 0.01), pain level (γ = 0.63, p = 0.02), and being female (γ = 3.81, p < 0.01) emerged as significant predictors of PTSD symptomatology when taking into account all time points. Acute plus chronic graft-versus-host-disease and longer hospital stay predicted PTSD symptomatology at T2 (γ = 3.39, p = 0.04; γ = 0.1, p = 0.03).

Conclusions

A considerable number of patients undergoing allogeneic HSCT met the criteria for PTSD. PTSD symptomatology is prominent at all assessment points. Burden of pain, being female, and medical complications are risk factors for elevated levels of PTSD symptomatology.

Implications for cancer survivors

Psychological support should be offered not only after treatment but also in the long-term and even before HSCT. Professionals should be aware of the psychological consequences accompanied by pain and complications.

http://ift.tt/2dWOlSE

Posttraumatic stress disorder symptomatology in the course of allogeneic HSCT: a prospective study

Abstract

Purpose

Despite the life-threatening character of allogeneic hematopoietic stem cell transplantation (allogeneic HSCT), very few longitudinal research exists on posttraumatic stress disorder (PTSD) symptomatology in this patient group. We investigated prevalence, temporal course and predictors of PTSD symptomatology in this population.

Methods

Patients were assessed before conditioning (T0), 100 days (T1), and 12 months after HSCT (T2). PTSD symptomatology was measured with the PTSD Checklist—Civilian Version. We conducted multilevel modeling and multiple regression analyses.

Results

Two hundred thirty-nine patients participated at baseline, 150 at T1, and 102 at T2. Up to 15 % met the criteria for PTSD at least once during the course of assessment. Fifty-two percent showed diagnostic relevant levels of intrusion, 30 % of avoidance, and 33 % of arousal at least once. Apart from arousal, which increased between T0 and T1 (γ = 0.56, p = 0.03), no other severity score significantly differed between time points. Being impaired by pain (γ = 2.89, p < 0.01), pain level (γ = 0.63, p = 0.02), and being female (γ = 3.81, p < 0.01) emerged as significant predictors of PTSD symptomatology when taking into account all time points. Acute plus chronic graft-versus-host-disease and longer hospital stay predicted PTSD symptomatology at T2 (γ = 3.39, p = 0.04; γ = 0.1, p = 0.03).

Conclusions

A considerable number of patients undergoing allogeneic HSCT met the criteria for PTSD. PTSD symptomatology is prominent at all assessment points. Burden of pain, being female, and medical complications are risk factors for elevated levels of PTSD symptomatology.

Implications for cancer survivors

Psychological support should be offered not only after treatment but also in the long-term and even before HSCT. Professionals should be aware of the psychological consequences accompanied by pain and complications.

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Scientists Identify Potential Marker of Resistance to PARP Inhibitors

A team led by NCI researchers has identified a potential biomarker that could help predict whether a tumor will respond to a relatively new class of targeted cancer drugs known as PARP inhibitors.

The team's findings, published September 27 in Oncotarget, showed that cancer cell lines with high expression levels of the gene SLFN11 were more sensitive than cells with low SLFN11 expression to the PARP inhibitors olaparib (Lynparza™) and talazoparib. Cancer cell lines in which the SLFN11 gene was inactivated were resistant to both drugs.

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Scientists Identify Potential Marker of Resistance to PARP Inhibitors

A team led by NCI researchers has identified a potential biomarker that could help predict whether a tumor will respond to a relatively new class of targeted cancer drugs known as PARP inhibitors.

The team's findings, published September 27 in Oncotarget, showed that cancer cell lines with high expression levels of the gene SLFN11 were more sensitive than cells with low SLFN11 expression to the PARP inhibitors olaparib (Lynparza™) and talazoparib. Cancer cell lines in which the SLFN11 gene was inactivated were resistant to both drugs.

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Differences in global DNA methylation of testicular seminoma are not associated with changes in histone modifications, clinical prognosis, BRAF mutations or gene expression

Publication date: Available online 31 October 2016
Source:Cancer Genetics
Author(s): Louise Holm Pedersen, John E. Nielsen, Gedske Daugaard, Thomas v. O. Hansen, Ewa Rajpert-De Meyts, Kristian Almstrup
Testicular germ cell tumours of young adults are comprised of a heterogeneous group of non-seminomas and a homogeneous group of seminomas. While the majority of seminomas retain a hypo-methylated genome, a small fraction display a highly methylated genome, resembling hyper-methylated non-seminomas. It is well established from e.g. melanoma, colorectal and thyroid cancer that a methylated phenotype can be correlated to prognosis and can be related to BRAF mutations.In the present study we investigated the global methylation level in 67 seminomas and classified them as hypo-methylated, intermediate, patchy and hyper-methylated, respectively. A selected subset representing each level of DNA methylation and the TCam2 seminoma cell line, were subsequently analysed for a range of other epigenetic marks (6 histone marks and 5-hydroxymethylcytosine), the presence of the BRAF V600E de novo mutation, differences in the transcriptome and finally correlated to the clinical outcome.We did not identify any histone marks or hydroxymethylation levels that correlated with the methylation level of the genome. Some histone marks, however, showed a great variation while others were found at the same level in all the investigated seminomas. We did not identify any tumours with the BRAF V600E mutation and transcriptome analysis revealed no significant differences between hypo- and hyper-methylated seminomas. Similarly, no obvious differences in the clinical manifestation of the patients representing hypo- or hyper-methylated seminomas were identified.The level of DNA methylation in testicular seminomas consequently seems secondary to the manifestation of the tumour phenotype.



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Cover_spine

Publication date: October 2016
Source:Cancer Genetics, Volume 209, Issue 10





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Editorial Board

Publication date: October 2016
Source:Cancer Genetics, Volume 209, Issue 10





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Table of Contents

Publication date: October 2016
Source:Cancer Genetics, Volume 209, Issue 10





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[Comment] Diminished but not dead: chemotherapy for the treatment of NSCLC

With the safety and efficacy of immune checkpoint inhibitors in previously treated patients with advanced non-small-cell lung cancer (NSCLC) established,1–3 recent studies have focused on their use in the first-line setting. Data from several single-arm phase 1 cohorts have suggested increased efficacy of PD-1 inhibitors in the first-line setting.4 The recently published Keynote-024 trial randomly assigned 305 patients with treatment-naive, advanced NSCLC with PD-L1 expression in at least 50% of tumour cells to receive either the PD-1 inhibitor pembrolizumab or platinum-based chemotherapy according to investigator's choice.

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[Correspondence] Risk of cancer in patients with polycystic kidney disease

Tung-Min Yu and colleagues1 report an increased susceptibility to colon, liver, and kidney cancer in patients with autosomal dominant polycystic kidney disease (ADPKD) before receiving renal replacement therapy, when compared with patients without the disease but with a similar (or no) degree of renal impairment. Large studies have shown an excess risk of cancer in patients with chronic kidney disease, end-stage renal disease, or those on renal replacement therapy. Available data for cancer incidence in patients with ADPKD on dialysis, or after transplantation, show an increased risk of neoplasms, mostly skin and kidney, when compared with the general population, but not to other patients on renal replacement therapy without ADPKD.

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[Series] 21st century pharmacovigilance: efforts, roles, and responsibilities

In an era when the number of expedited and conditional review pathways for newly available brand-name drugs and biosimilar medicines to treat serious and life-threatening diseases is increasing, defining pharmacovigilance has never been more crucial. 21st century pharmacovigilance is not merely about uncovering, reporting, and addressing adverse events associated with already approved and marketed agents, but can be described as the systematic monitoring of the process of pre-market review and post-market surveillance, which includes the use of medicines in everyday practice.

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[Series] Safety and efficacy of biosimilars in oncology

Biosimilars are considered to be one of the solutions to combat the substantially increasing costs of cancer treatment, and its imminent introduction is expected to expand affordability worldwide. However, biosimilar monoclonal antibodies provide many challenges compared with first-generation biosimilars, growth factors, and hormones, because they have shown only a modest clinical effect, and are often used in combination with other more toxic therapies, making it difficult to design studies that allow appropriate efficacy and safety assessments compared with the original products.

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[Series] Generic oncology drugs: are they all safe?

Although the availability of generic oncology drugs allows access to contemporary care and reduces costs, there is international variability in the safety of this class of drugs. In this Series paper, we review clinical, policy, safety, and regulatory considerations for generic oncology drugs focusing on the USA, Canada, the European Union (EU), Japan, China, and India. Safety information about generic formulations is reviewed from one agent in each class, for heavy metal drugs (cisplatin), targeted agents (imatinib), and cytotoxic agents (docetaxel).

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[Correspondence] Risk of cancer in patients with polycystic kidney disease

Tung-Min Yu and colleagues1 showed, in a large cohort study, an increased incidence of kidney cancer in patients with autosomal dominant polycystic kidney disease (ADPKD) without end-stage renal disease and an increased incidence of extra-renal cancers, especially colon and liver cancer.

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[Comment] Olaparib and ovarian cancer—overall survival outcomes

Health-care providers are increasingly using targeted therapies and personalised medicine to treat patients with cancer. In ovarian cancer, tumours with BRCA gene mutations are being targeted by these treatments. BRCA1 and BRCA2 mutations are associated with 10–15% of all ovarian cancers, but with the addition of somatic mutations, about 50% of high-grade serous tumours (the commonest ovarian cancer subtype) will have some form of mutation.1 Repairing DNA defects is a common natural event and if not achievable, cellular death occurs.

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[Correspondence] HPV 16 in squamous cell carcinoma of 19th century tonsils

Human papillomavirus (HPV) is a common ancient virus of unknown origin. Most types of HPV infect the skin and cause benign warts, but 15 types are high risk and 12 are low risk for genital or oral cancer.1 Involvement of HPV 16 in head and neck squamous cell carcinoma is now well established, especially in oropharyngeal squamous cell carcinoma.1

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[Corrections] Correction to Lancet Oncol 2016; 17: 1426–34

Stintzing S, Modest DP, Rossius L,et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab for metastatic colorectal cancer (FIRE-3): a post-hoc analysis of tumour dynamics in the final RAS wild-type subgroup of this randomised open-label phase 3 trial. Lancet Oncol 2016; 17: 1426–34—In the appendix, page 9, supplementary table 3, the values for ORR 'central independent review board' should have read '113/157 (72·0%)' and for the Difference '3/157 (1·9%)' in the FOLFIRI plus cetuximab group.

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[Correspondence] Risk of cancer in patients with polycystic kidney disease – Authors’ reply

We thank Leano Violo and colleagues and Francois Cachat and Raffaele Renella for their comments. We agree that we are not able to clarify the effect of chronic kidney disease on the cancer risk without renal function data such as serum creatinine or glomerular filtration rate, and we addressed this limitation in the Article. By retrieving data from inpatient claims and analysing these data in multivariable models we attempted to attenuate the potential effect of associated confounders. Our previous study of a cohort of patients with chronic kidney disease made use of data from the Taiwan National Health Insurance Research Database (NHIRD).

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[Cancer and Society] In the shadow of disaster

In the shadow of disaster lives collateral damage. Remnants of war or environmental disaster, these humanitarian tragedies, whilst smaller than the original crises which birthed them, are just as worthy of notice.

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[Comment] Is sidedness prognostically important across all stages of colorectal cancer?

Traditionally, colorectal cancer has been topographically divided according to position of the primary tumour, either above or below the peritoneal reflection (ie, separated into colon and rectal cancer, respectively). Differences in terms of epidemiology and patterns of metastasis have been described between these two entities1 and there has been a steady evolutionary divergence in terms of their oncological management. Acceptance of this division has frequently led to either a priori exclusion of one geographical entity or the other from a specific therapeutic trial; or at least stratification to achieve balance between these two separate primary subsites across the groups of such studies.

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[Correspondence] Sarcoma and germ-line DICER1 mutations – Authors’ reply

We thank de Kock and Foulkes for their letter and compelling summary table of DICER1 mutations linked to sarcomas. For population-based studies such as ours,1 statistically robust methods are required to identify genes enriched in pathogenic variation.2,3 The principles of controls, replication sets, multiple test correction, and independent sources of experimental evidence, should be regarded as essential evidence for causality. Such an approach was the basis for reporting enrichment of pathogenic variants in ATM, ATR, BRCA2, and ERCC2 in our study.

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[Correspondence] Vemurafenib for BRAFV600E-positive metastatic papillary thyroid cancer

In their Article, Brose and colleagues1 report that vemurafenib has antitumour activity in patients with progressive BRAFV600E-positive papillary thyroid cancer refractory to radioactive iodine who have previously been treated with a multikinase inhibitor or not. This non-randomised, open-label, phase 2 trial gives a strong rationale for targeted BRAF inhibition in patients with thyroid cancer, confirming previous reports. However, we believe that crucial information is not reported that might help guide clinical practice.

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[Editorial] Cancer drug safety: time to re-focus on tackling adverse effects

Drug safety is once again under the spotlight. In a study presented at the European Society of Medical Oncology Congress (Oct 7–11, 2016; Copenhagen, Denmark), Paolo Bossi and colleagues showed that a substantial number of clinical trials testing targeted and immunotherapies have suboptimal reporting of adverse events, particularly with regards to recurrent or late toxicities. Additionally, the US Food and Drug Administration (FDA) announced on Oct 4, 2016, that 27 drugs and drug classes—several of which include cancer agents—have been put on their watch list because of worrying evidence of unacceptable adverse events.

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[Correspondence] Vemurafenib for BRAFV600E-positive metastatic papillary thyroid cancer – Authors' response

Huillard and colleagues provide a report of a patient with BRAFV600E mutated tall-cell variant papillary thyroid carcinoma who experienced a complete response after being treated with vemurafenib followed by radioactive iodine. This patient's disease converted from radioiodine non-avid to avid after the administration of vemurafenib. The authors speculate that vemurafenib might have a direct anti-tumour effect and re-sensitise tumour cells to radioactive iodine by affecting sodium iodide symporters that are dysregulated in BRAFV600E disease.

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The relationship between vegetable/fruit consumption and gallbladder/bile duct cancer: A population-based cohort study in Japan

Abstract

Vegetable and fruit consumption may have a protective effect against several types of cancers. However, the effect on biliary cancers is unclear. We investigated the association of vegetable/fruit consumption with the risks of gallbladder cancer (GBC), intrahepatic bile duct cancer (IHBDC) and extrahepatic bile duct cancer (EHBDC) in a population-based prospective cohort study in Japan. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using the Cox proportional hazard model, and the exposure level was categorized into quartiles, with the lowest group used as the reference. A total of 80,371 people aged 45–74 years were enrolled between 1995 and 1999, and followed up for 1,158,632 person-years until 2012, during which 133 GBC, 99 IHBDC, and 161 EHBDC cases were identified. Increased consumption of total vegetable and fruit was significantly associated with a decreased risk of EHBDC (HR = 0.49; 95% CI: 0.29–0.81 for the highest group; P-trend = 0.005). From the analysis of relevant nutrients, significantly decreased risk of EHBDC was associated with folate and insoluble fiber (HR = 0.48, 0.53; 95% CI: 0.28–0.85, 0.31–0.88 for the highest group; P-trend = 0.010, 0.023; respectively), and a significant trend of decreased EHBDC risk associated with vitamin C was observed (P-trend = 0.029). No decreased risk of GBC and IHBDC was found. Our findings suggest that increased vegetable/fruit consumption may decrease a risk of EHBDC, and folate, vitamin C, and insoluble fiber might be key contributors to the observed protective effect. This article is protected by copyright. All rights reserved.

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Inhibition of SRC family kinases reduces myeloid-derived suppressor cells in head and neck cancer

Abstract

SRC family kinases (SFKs), a group of nonreceptor tyrosine kinases, modulate multiple cellular functions, such as cell proliferation, differentiation and metabolism. SFKs display aberrant activity in progressive stages of human cancers. However, the precise role of SFKs in the head and neck squamous cell carcinoma (HNSCC) signaling network is far from clear. In this study, we found that the inhibition of SFKs activity by dasatinib effectively reduced the tumor size and population of MDSCs in the HNSCC mouse model. Molecular analysis indicates that phosphorylation of LYN, rather than SRC, was inhibited by dasatinib treatment. Next, we analyzed LYN expression by immunostaining and found that it was over expressed in the human HNSCC specimens. Moreover, LYN expression in stromal cells positively correlated with myeloid-derived suppressor cells (MDSCs) makers CD11b and CD33 in human HNSCC. The dual positive expression of LYN in epithelial and stromal cells (EPI⁺SRT⁺) was associated with unfavorable overall survival of HNSCC patients. These findings indicate that SFKs may be a potential target for an effective immunotherapy of HNSCC by decreasing MDSCs and moreover, LYN will have an impact on such therapeutic strategy. This article is protected by copyright. All rights reserved.

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Associations between adherence to the World Cancer Research Fund/American Institute for Cancer Research cancer prevention recommendations and biomarkers of inflammation, hormonal and insulin response

Abstract

Adherence to the 2007 WCRF/AICR cancer prevention recommendations has been associated with lower cancer risk but the underlying biological mechanisms have not been elucidated. We utilized dietary and lifestyle data from 11,342 women in the Nurses' Health Study and 8,136 men in the Health Professionals Follow-up Study, to investigate associations between adherence scores and markers of inflammation, hormonal and insulin response. Two scores ranging from 0 to 3 were constructed to assess adherence to the energy balance-related recommendations (weight management, physical activity, energy density); and the plant, animal foods and alcohol intake recommendations; with higher scores indicating greater adherence. The following biomarkers were assessed in plasma samples donated by chronic disease-free women (1990) and men (1994): C-reactive protein (CRP), interleukin-6 (IL6), tumor necrosis factor alpha receptor 2 (TNFαR2) and adiponectin for inflammation; estrone and estradiol for hormonal response in women, C-peptide for hyperinsulinemia; and triglycerides/high density lipoprotein-cholesterol (TG/HDL) ratio for insulin resistance. In multivariable-adjusted linear regression analyses, we estimated relative concentrations of biomarkers across adherence categories. There was a significant trend of lower (higher for adiponectin) biomarker concentrations with higher adherence to the energy balance recommendations (all P-trend<0.0001). Comparing the highest (3) to the lowest recommendation category (0-1), the percent difference in relative concentrations of biomarkers was CRP, -69%; IL6, -41%; TNFαR2, -13%; adiponectin, +36; C-peptide, -43%; TG/HDL, -43%; estrone, -31%; and estradiol, -43%; in women; and CRP, -59%; IL6, -42%; TNFαR2, -10%; adiponectin, +22%; C-peptide, -44%; and TG/HDL, -40%; in men. In contrast, associations between adherence to the plant, animal foods and alcohol intake recommendations and biomarker concentrations were weaker, and mostly nonsignificant. The healthier biomarker profile associated with greater adherence to the WCRF/AICR cancer prevention recommendations is driven mainly by adherence to the energy balance-related recommendations. This article is protected by copyright. All rights reserved.

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The relationship between vegetable/fruit consumption and gallbladder/bile duct cancer: A population-based cohort study in Japan

Abstract

Vegetable and fruit consumption may have a protective effect against several types of cancers. However, the effect on biliary cancers is unclear. We investigated the association of vegetable/fruit consumption with the risks of gallbladder cancer (GBC), intrahepatic bile duct cancer (IHBDC) and extrahepatic bile duct cancer (EHBDC) in a population-based prospective cohort study in Japan. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using the Cox proportional hazard model, and the exposure level was categorized into quartiles, with the lowest group used as the reference. A total of 80,371 people aged 45–74 years were enrolled between 1995 and 1999, and followed up for 1,158,632 person-years until 2012, during which 133 GBC, 99 IHBDC, and 161 EHBDC cases were identified. Increased consumption of total vegetable and fruit was significantly associated with a decreased risk of EHBDC (HR = 0.49; 95% CI: 0.29–0.81 for the highest group; P-trend = 0.005). From the analysis of relevant nutrients, significantly decreased risk of EHBDC was associated with folate and insoluble fiber (HR = 0.48, 0.53; 95% CI: 0.28–0.85, 0.31–0.88 for the highest group; P-trend = 0.010, 0.023; respectively), and a significant trend of decreased EHBDC risk associated with vitamin C was observed (P-trend = 0.029). No decreased risk of GBC and IHBDC was found. Our findings suggest that increased vegetable/fruit consumption may decrease a risk of EHBDC, and folate, vitamin C, and insoluble fiber might be key contributors to the observed protective effect. This article is protected by copyright. All rights reserved.

http://ift.tt/2eO6262

Inhibition of SRC family kinases reduces myeloid-derived suppressor cells in head and neck cancer

Abstract

SRC family kinases (SFKs), a group of nonreceptor tyrosine kinases, modulate multiple cellular functions, such as cell proliferation, differentiation and metabolism. SFKs display aberrant activity in progressive stages of human cancers. However, the precise role of SFKs in the head and neck squamous cell carcinoma (HNSCC) signaling network is far from clear. In this study, we found that the inhibition of SFKs activity by dasatinib effectively reduced the tumor size and population of MDSCs in the HNSCC mouse model. Molecular analysis indicates that phosphorylation of LYN, rather than SRC, was inhibited by dasatinib treatment. Next, we analyzed LYN expression by immunostaining and found that it was over expressed in the human HNSCC specimens. Moreover, LYN expression in stromal cells positively correlated with myeloid-derived suppressor cells (MDSCs) makers CD11b and CD33 in human HNSCC. The dual positive expression of LYN in epithelial and stromal cells (EPI⁺SRT⁺) was associated with unfavorable overall survival of HNSCC patients. These findings indicate that SFKs may be a potential target for an effective immunotherapy of HNSCC by decreasing MDSCs and moreover, LYN will have an impact on such therapeutic strategy. This article is protected by copyright. All rights reserved.

http://ift.tt/2f6Gq2M

Associations between adherence to the World Cancer Research Fund/American Institute for Cancer Research cancer prevention recommendations and biomarkers of inflammation, hormonal and insulin response

Abstract

Adherence to the 2007 WCRF/AICR cancer prevention recommendations has been associated with lower cancer risk but the underlying biological mechanisms have not been elucidated. We utilized dietary and lifestyle data from 11,342 women in the Nurses' Health Study and 8,136 men in the Health Professionals Follow-up Study, to investigate associations between adherence scores and markers of inflammation, hormonal and insulin response. Two scores ranging from 0 to 3 were constructed to assess adherence to the energy balance-related recommendations (weight management, physical activity, energy density); and the plant, animal foods and alcohol intake recommendations; with higher scores indicating greater adherence. The following biomarkers were assessed in plasma samples donated by chronic disease-free women (1990) and men (1994): C-reactive protein (CRP), interleukin-6 (IL6), tumor necrosis factor alpha receptor 2 (TNFαR2) and adiponectin for inflammation; estrone and estradiol for hormonal response in women, C-peptide for hyperinsulinemia; and triglycerides/high density lipoprotein-cholesterol (TG/HDL) ratio for insulin resistance. In multivariable-adjusted linear regression analyses, we estimated relative concentrations of biomarkers across adherence categories. There was a significant trend of lower (higher for adiponectin) biomarker concentrations with higher adherence to the energy balance recommendations (all P-trend<0.0001). Comparing the highest (3) to the lowest recommendation category (0-1), the percent difference in relative concentrations of biomarkers was CRP, -69%; IL6, -41%; TNFαR2, -13%; adiponectin, +36; C-peptide, -43%; TG/HDL, -43%; estrone, -31%; and estradiol, -43%; in women; and CRP, -59%; IL6, -42%; TNFαR2, -10%; adiponectin, +22%; C-peptide, -44%; and TG/HDL, -40%; in men. In contrast, associations between adherence to the plant, animal foods and alcohol intake recommendations and biomarker concentrations were weaker, and mostly nonsignificant. The healthier biomarker profile associated with greater adherence to the WCRF/AICR cancer prevention recommendations is driven mainly by adherence to the energy balance-related recommendations. This article is protected by copyright. All rights reserved.

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Constitutively activated PI3K accelerates tumor initiation and modifies histopathology of breast cancer

Constitutively activated PI3K accelerates tumor initiation and modifies histopathology of breast cancer

Oncogenesis 5, e267 (October 2016). doi:10.1038/oncsis.2016.65

Authors: M R Sheen, J D Marotti, M J Allegrezza, M Rutkowski, J R Conejo-Garcia & S Fiering

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Evaluation of the reliability of preoperative descriptive airway assessment tests in prediction of the Cormack-Lehane score: A prospective randomized clinical study

In this study we investigated and compared the predictive values of different airway assessments tests including thyromental height measurement test, which has been recently suggested, in difficult laryngoscopy (Cormack and Lehane [C-L] scores 3 and 4). In addition, we compared the effectiveness of methods and C-L scores, by IDS, in terms of predicting difficult intubation.

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Recent development of targeted approaches for the treatment of breast cancer

Abstract

Breast cancer is the most prominent cause of cancer death in women worldwide. The highlights of this review are to provide an overview of the targeted therapeutic agents, challenges with metastatic breast cancer (MBCa), mechanisms of action through Hedgehog/Gli 1 signaling pathway and future prospective. Over a decade of success, several drugs have been approved and are in the advanced stages of clinical trials that target the receptors such as estrogen receptor, growth factor receptor, receptor activator of nuclear factor kappa-B, etc. Currently, several monoclonal antibodies are also used for the treatment of breast cancer. Advances in understanding tumor biology, particularly signaling pathways such as Notch signaling pathway, Hedgehog/Gli 1 signaling pathway, and inhibitors are considered to be important for bone metastasis. These studies may provide vital information for the design and development of new strategies with respect to efficacy, reduction of the side effects, and treatment strategies.

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Prostate external beam radiotherapy combined with high-dose-rate brachytherapy: dose-volume parameters from deformably-registered plans correlate with late gastrointestinal complications

Derivation of dose-volume correlated with toxicity for multi-modal treatments can be difficult due to the perceived need for voxel-by-voxel dose accumulation. With data available for a single-institution cohor...

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Prostate external beam radiotherapy combined with high-dose-rate brachytherapy: dose-volume parameters from deformably-registered plans correlate with late gastrointestinal complications

Derivation of dose-volume correlated with toxicity for multi-modal treatments can be difficult due to the perceived need for voxel-by-voxel dose accumulation. With data available for a single-institution cohor...

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Prostate external beam radiotherapy combined with high-dose-rate brachytherapy: dose-volume parameters from deformably-registered plans correlate with late gastrointestinal complications

Abstract

Background

Derivation of dose-volume correlated with toxicity for multi-modal treatments can be difficult due to the perceived need for voxel-by-voxel dose accumulation. With data available for a single-institution cohort with long follow-up, an investigation was undertaken into rectal dose-volume effects for gastrointestinal toxicities after deformably-registering each phase of a combined external beam radiotherapy (EBRT)/high-dose-rate (HDR) brachytherapy prostate treatment.

Methods

One hundred and eighteen patients received EBRT in 23 fractions of 2 Gy and HDR (TG43 algorithm) in 3 fractions of 6.5 Gy. Results for the Late Effects of Normal Tissues — Subjective, Objective, Management and Analytic toxicity assessments were available with a median follow-up of 72 months. The HDR CT was deformably-registered to the EBRT CT. Doses were corrected for dose fractionation. Rectum dose-volume histogram (DVH) parameters were calculated in two ways. (1) Distribution-adding: parameters were calculated after the EBRT dose distribution was 3D-summed with the registered HDR dose distribution. (2) Parameter-adding: the EBRT DVH parameters were added to HDR DVH parameters. Logistic regressions and Mann-Whitney U-tests were used to correlate parameters with late peak toxicity (dichotomised at grade 1 or 2).

Results

The 48–80, 40–63 and 49–55 Gy dose regions from distribution-adding were significantly correlated with rectal bleeding, urgency/tenesmus and stool frequency respectively. Additionally, urgency/tenesmus and anorectal pain were associated with the 25–26 Gy and 44–48 Gy dose regions from distribution-adding respectively. Parameter-adding also indicated the low-mid dose region was significantly correlated with stool frequency and proctitis.

Conclusions

This study confirms significant dose-histogram effects for gastrointestinal toxicities after including deformable registration to combine phases of EBRT/HDR prostate cancer treatment. The findings from distribution-adding were in most cases consistent with those from parameter-adding. The mid-high dose range and near maximum doses were important for rectal bleeding. The distribution-adding mid-high dose range was also important for stool frequency and urgency/tenesmus. We encourage additional studies in a variety of institutions using a variety of dose accumulation methods with appropriate inter-fraction motion management.

Trial registration

NCT NCT00193856. Retrospectively registered 12 September 2005.

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Prostate external beam radiotherapy combined with high-dose-rate brachytherapy: dose-volume parameters from deformably-registered plans correlate with late gastrointestinal complications

Abstract

Background

Derivation of dose-volume correlated with toxicity for multi-modal treatments can be difficult due to the perceived need for voxel-by-voxel dose accumulation. With data available for a single-institution cohort with long follow-up, an investigation was undertaken into rectal dose-volume effects for gastrointestinal toxicities after deformably-registering each phase of a combined external beam radiotherapy (EBRT)/high-dose-rate (HDR) brachytherapy prostate treatment.

Methods

One hundred and eighteen patients received EBRT in 23 fractions of 2 Gy and HDR (TG43 algorithm) in 3 fractions of 6.5 Gy. Results for the Late Effects of Normal Tissues — Subjective, Objective, Management and Analytic toxicity assessments were available with a median follow-up of 72 months. The HDR CT was deformably-registered to the EBRT CT. Doses were corrected for dose fractionation. Rectum dose-volume histogram (DVH) parameters were calculated in two ways. (1) Distribution-adding: parameters were calculated after the EBRT dose distribution was 3D-summed with the registered HDR dose distribution. (2) Parameter-adding: the EBRT DVH parameters were added to HDR DVH parameters. Logistic regressions and Mann-Whitney U-tests were used to correlate parameters with late peak toxicity (dichotomised at grade 1 or 2).

Results

The 48–80, 40–63 and 49–55 Gy dose regions from distribution-adding were significantly correlated with rectal bleeding, urgency/tenesmus and stool frequency respectively. Additionally, urgency/tenesmus and anorectal pain were associated with the 25–26 Gy and 44–48 Gy dose regions from distribution-adding respectively. Parameter-adding also indicated the low-mid dose region was significantly correlated with stool frequency and proctitis.

Conclusions

This study confirms significant dose-histogram effects for gastrointestinal toxicities after including deformable registration to combine phases of EBRT/HDR prostate cancer treatment. The findings from distribution-adding were in most cases consistent with those from parameter-adding. The mid-high dose range and near maximum doses were important for rectal bleeding. The distribution-adding mid-high dose range was also important for stool frequency and urgency/tenesmus. We encourage additional studies in a variety of institutions using a variety of dose accumulation methods with appropriate inter-fraction motion management.

Trial registration

NCT NCT00193856. Retrospectively registered 12 September 2005.

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NCCN News

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On the Effect of Triplet or Doublet Chemotherapy in Advanced Gastric Cancer: Results From a National Cancer Registry

Background: There is currently no consensus regarding first-line chemotherapy for patients with advanced gastric cancer (AGC) who are ineligible to receive trastuzumab. The objective of this study was to evaluate the efficacy and tolerance of triplets versus doublets by analyzing a national gastric cancer registry. Patients and Method: Patients with AGC treated with polychemotherapy without associating trastuzumab were included from 2008 through 2016. The effect of triplets versus doublets was compared using 3 methods: Cox proportional hazards regression, propensity score matching (PSM), and coarsened exact matching (CEM). Results: A total of 970 patients were recruited (doublets: n=569; triplets: n=401). In the multivariate Cox model, the use of triplets was associated with better overall survival (OS), with a hazard ratio (HR) of 0.84 (95% CI, 0.72–0.98; P=.035). After PSM, the sample contained 340 pairs. A significant increase in OS, 11.14 months (95% CI, 9.60–12.68) versus 9.60 months (95% CI, 8.44–10.75), was seen in favor of triplets (HR, 0.77; 95% CI, 0.65–0.92; stratified log-rank test, P=.004). The effect appeared to be comparable for anthracycline-based (HR, 0.78; 95% CI, 0.64–0.94) or docetaxel-based triplets (HR, 0.78; 95% CI, 0.60–1.009). The trend was similar after applying the CEM algorithm, with an HR of 0.78 (95% CI, 0.63–0.97; P=.03). Triplet therapy was viable and relative dose intensities exceeded 85%, except for cisplatin in DCX (docetaxel, cisplatin, capecitabine). Triplets had more severe toxicity overall, especially hematologic, hepatic, and mucosal adverse events. Conclusions: With the limitations of a retrospective study that examines a heterogeneous set of chemotherapy regimens, we found that triplets are feasible in daily practice and are associated with a discreet benefit in efficacy at the expense of a moderate increase in toxicity.

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Oncology Research Program

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Smoking Cessation, Version 1.2016, NCCN Clinical Practice Guidelines in Oncology

Cigarette smoking has been implicated in causing many cancers and cancer deaths. There is mounting evidence indicating that smoking negatively impacts cancer treatment efficacy and overall survival. The NCCN Guidelines for Smoking Cessation have been created to emphasize the importance of smoking cessation and establish an evidence-based standard of care in all patients with cancer. These guidelines provide recommendations to address smoking in patients and outlines behavioral and pharmacologic interventions for smoking cessation throughout the continuum of oncology care.

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My Knee Hurts!

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Correspondence

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Dissemination and Implementation of Guidelines for Cancer-Related Fatigue

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Validation of the Kattan Nomogram for Prostate Cancer Recurrence After Radical Prostatectomy

Background: The Kattan postoperative radical prostatectomy (RP) nomogram is used to predict biochemical recurrence-free progression (BCRFP) after RP. However, external validation among contemporary patients using modern outcome definitions is limited. Methods: A total of 1,931 patients who underwent RP at Roswell Park Cancer Institute (RPCI) between 1993 and 2014 (median follow-up, 47 months; range, 0–244 months) were assessed for NCCN-defined biochemical failure (BF) and RPCI-defined treatment failure (TF). Actual rates of biochemical failure-free survival (BFS; defined as 1 – BF) and treatment failure-free survival (TFS; defined as 1 – TF) were compared with Kattan BCRFP nomogram predictions. Results: The Kattan BCRFP nomogram predictions at 5 and 10 years were predictive of BFS (area under the receiver operating characteristic curve [AUC], 0.772) and TFS (AUC, 0.774). The Kattan BCRFP nomogram tended to underestimate BFS and TFS compared with actual outcomes. The Kattan 5-year BCRFP predictions consistently overestimated actual 5-year BFS outcomes among subgroups of high- and intermediate-risk patients with at least 5-year outcomes. Conclusions: The Kattan BCRFP nomogram is a robust predictor of NCCN-defined BF in a large sample of patients with RP with substantial follow-up and modern, standardized failure definitions

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Personalized Treatment for a Patient With a BRAF V600E Mutation Using Dabrafenib and a Tumor Treatment Fields Device in a High-Grade Glioma Arising From Ganglioglioma

Background: Gangliogliomas are slow-growing, low-grade central nervous system tumors affecting children and young adults. However, some patients will experience tumor recurrence and/or malignant progression. This article reports on the clinical history, molecular findings, and treatment response in a patient with BRAF V600–mutated high-grade glioma arising from ganglioglioma. Methods: Hematoxylin-eosin staining and comprehensive genomic profiling via Foundation One were performed on the tumor sample from a male patient undergoing treatment at the Department of Neuro-Oncology at Baylor University Medical Center. Results: The patient was eligible for participation in a clinical trial (ClinicalTrials.gov identifier: NCT00916409) of a tumor treatment fields (TTFields) device, NovoTTF-100A, with concurrent radiation and chemotherapy (CCRT). His disease relapsed 4 months after completion of his CCRT, with MRI showing areas of enhancement. Temozolomide was discontinued and he was offered dabrafenib, an oral selective inhibitor of BRAF V600E, with continued use of NovoTTF. At the time of this report, after 2 years of treatment with dabrafenib and TTFields, the patient shows a durable complete response in all areas with no active lesions or new areas of enhancement. Conclusions: This report suggests that TTFields delivered in combination with targeted therapy dabrafenib yielded a remarkable clinical and radiologic response in this recurrent high-grade glioma. Targeted therapy matched to genomic alterations combined with TTFields treatment could provide clinical benefit and should be prospectively explored in the near future.

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Psychotropic and Opioid Medication Use in Older Patients With Breast Cancer Across the Care Trajectory: A Population-Based Cohort Study

Background: Older patients with breast cancer represent a vulnerable population at higher risk of experiencing distress and pain, as well as medication-related adverse events from pharmacological treatment of these symptoms. The purpose of this study is to estimate the prevalence of psychotropic (anxiolytic, antidepressant, and antipsychotic) and opioid medication use by older women diagnosed with breast cancer. Methods: This population-based cohort study followed 19,353 women older than 65 years diagnosed with incident, nonmetastatic breast cancer in Quebec, Canada. Data were obtained from provincial, universal health and drug insurance plans covering all medical and pharmaceutical care. Descriptive statistics were calculated for demographic information, breast cancer characteristics, and treatments. Psychotropic and opioid medication use was assessed across the care trajectory: precancer baseline, active care, and first-year survivorship. Results: There was a marked increase in the prevalence of medication use from precancer baseline to active care, followed by a decrease into first-year survivorship. Anxiolytics were used most often across the care trajectory (36.3%, 50.6%, and 44.4% at baseline, active care, and survivorship, respectively). In contrast, antipsychotic and opioid medications were sought primarily during active care (4.5- and 7-fold increases from baseline, respectively), with opioid use during active care increasing dramatically over the study period (9.0% to 40.9% from 1998 to 2010). Unlike other drugs, antidepressant use peaked in active care but persisted into survivorship (14.7%, 22.4%, and 22.3% at baseline, active care, and survivorship, respectively). Conclusions: A substantial proportion of older patients with breast cancer use psychotropic and opioid medications. The different patterns of medication use represent distress and pain experienced by patients across the care trajectory. Given that medication use in this vulnerable population is associated with an increased risk of adverse events, a multidimensional approach integrating psychological interventions in cancer care may better address psychosocial needs of older patients with breast cancer.

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NCCN Guidelines Insights: Older Adult Oncology, Version 2.2016

Cancer is the leading cause of death in older adults aged 60 to 79 years. Older patients with good performance status are able to tolerate commonly used treatment modalities as well as younger patients, particularly when adequate supportive care is provided. For older patients who are able to tolerate curative treatment, options include surgery, radiation therapy (RT), chemotherapy, and targeted therapies. RT can be highly effective and well tolerated in carefully selected patients, and advanced age alone should not preclude the use of RT in older patients with cancer. Judicious application of advanced RT techniques that facilitate normal tissue sparing and reduce RT doses to organs at risk are important for all patients, and may help to assuage concerns about the risks of RT in older adults. These NCCN Guidelines Insights focus on the recent updates to the 2016 NCCN Guidelines for Older Adult Oncology specific to the use of RT in the management of older adults with cancer.

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Tobacco Cessation Treatment Pathways for Patients With Cancer: 10 Years in the Making

Tobacco use is the most common cause of preventable morbidity and mortality in the United States; it accounts for one-third of all cancer deaths and is thought to account for half of preventable cancer deaths. This article describes the Tobacco Treatment Program at a major academic cancer center. Patients and employees may access these services in a number of ways. All current smokers and recent quitters are proactively contacted and invited to participate. Services provided are tailored to the motivational level of individual patients and their immediate medical needs. The treatment pathways we present are based on our experience from the last 10 years in treating more than 5,000 unique patients with around 60,000 patient visits. These pathways include behavioral counseling and pharmacotherapy, including first-line, second-line, and off-label medication use. This article describes the program with the goal of providing guidance and ideas to others who are developing treatment programs and providing treatment to tobacco users.

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Refining the Patient Navigation Role in a Colorectal Cancer Screening Program: Results From an Intervention Study

Background: Oncology patient navigators help individuals overcome barriers to increase access to cancer screening, diagnosis, and timely treatment. This study, part of a randomized intervention trial investigating the efficacy of patient navigation in increasing colonoscopy completion, examined navigators' activities to ameliorate barriers to colonoscopy screening in a medically disadvantaged population. Methods: This study was conducted from 2012 through 2014 at Boston Medical Center. We analyzed navigator service delivery and survey data collected on 420 participants who were navigated for colonoscopy screening after randomization to this intervention. Key variables under investigation included barriers to colonoscopy, activities navigators undertook to reduce barriers, time navigators spent on each activity and per contact, and patient satisfaction with navigation services. Descriptive analysis assessed how navigators spent their time and examined what aspects of patient navigation were most valued by patients. Results: Navigators spent the most time assessing patient barriers/needs; facilitating appointment scheduling; reminding patients of appointments; educating patients about colorectal cancer, the importance of screening, and the colonoscopy preparation and procedures; and arranging transportation. Navigators spent an average of 44 minutes per patient. Patients valued the navigators, especially for providing emotional/peer support and explaining screening procedures and bowel preparation clearly. Conclusions: Our findings help clarify the role of the navigator in colonoscopy screening within a medically disadvantaged community. These findings may help further refine the navigator role in cancer screening and treatment programs as facilities strive to effectively and efficiently integrate navigation into their services.

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Arguing (About) the Value of Cancer Care

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Risk algorithms that include pathology adjustment for HER2 amplification need to make further downward adjustments in likelihood scores

Abstract

To assess the need for adjustment in the likelihood of germline BRCA1/2 mutations in women with HER2+ breast cancers. We analysed primary mutation screens on women with breast cancer with unequivocal HER2 overexpression and assessed the likelihood of BRCA1/BRCA2 mutations by age, oestrogen receptor status and Manchester score. Of 1111 primary BRCA screens with confirmed HER2 status only 4/161 (2.5%) of women with HER2 amplification had a BRCA1 mutation identified and 5/161 (3.1%) a BRCA2 mutation. The pathology adjusted Manchester score between 10 and 19% and 20%+ thresholds resulted in a detection rate of only 6.5 and 15% respectively. BOADICEA examples appeared to make even less downward adjustment. There is a very low detection rate of BRCA1 and BRCA2 mutations in women with HER2 amplified breast cancers. The Manchester score and BOADICEA do not make sufficient downward adjustment for HER2 amplification. For unaffected women, assessment of breast cancer risk and BRCA1/2 probability should take into account the pathology of the most relevant close relative. Unaffected women undergoing mutation testing for BRCA1/2 should be advised that there is limited reassurance from a negative test result if their close relative had a HER2+ breast cancer.

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Synchronous perforations of the oesophagus and stomach by air insufflation: an uncommon complication of endoscopic dilation

A 72-year-old woman had a history of carcinoma of the hypopharynx treated by total laryngectomy, circumferential pharyngectomy and free jejunal graft. Endoscopic dilation of the pharyngojejunal anastomotic stricture resulted in synchronous perforations of the oesophagus and stomach. We postulate that the perforations were caused by high intraoesophageal and intragastric pressure resulted from air insufflation during the procedure; in a situation simulating closed-loop obstruction, because of proximal obstruction by the endoscope at the stricture site and distal obstruction by pylorospasm. The sites of perforations were inherent points of weakness at the left side of the distal oesophagus and at the high lesser curve of stomach. Satisfactory outcome of our patient was attributed to prompt diagnosis and surgical repair. Endoscopists should be aware of this possibility during oesophagogastroduodenoscopy and dilation. Rapid and over insufflation of air should be avoided.

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Prolonged unassisted survival in an infant with anencephaly

Anencephaly is one of the most lethal congenital defects. This case report is of an anencephalic infant who lived to 28 months of life and defies current literature. She is the longest surviving anencephalic infant who did not require life-sustaining interventions. This case presents the obstacles that arose from this infant's prolonged life and recommendations based on these findings.

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Metastatic prostate adenocarcinoma presenting as a large right supraclavicular and anterior chest wall mass

Left-sided cervical lymphadenopathy as first presentation of metastatic prostate carcinoma is not a novel observation. Here, we discuss a case of metastatic prostate primary carcinoma with an initial presentation of a right supraclavicular mass with extension into the anterior chest wall, which on radiological investigation was suggestive of a sarcomatous tumour; however, was confirmed to be pervasive metastatic prostatic adenocarcinoma. This is the second case in literature, which reports a prostatic primary cancer presenting as a right-sided supraclavicular and anterior chest wall mass.

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Disseminated Mycobacterium haemophilum infection in a renal transplant recipient

Opportunistic infections are a major concern in renal and transplant medicine. We present the case of a renal transplant recipient with a generalised Mycobacterium haemophilum infection after an increase in immunosuppressive therapy and treatment with a tumour necrosis factor-α (TNF-α) inhibitor. Infection involved skin and soft tissue, joints and bones, as well as the renal transplant with an interstitial nephritis. Rapid diagnosis using PCR and DNA sequencing allowed early appropriate treatment. Triple antibiotic therapy and reduction in immunosuppression resulted in a slow but sustained recovery. Immunosuppression causes severe opportunistic infections. TNF-α inhibitors are very effective and well tolerated but have an increased susceptibility to infections with mycobacteria. Mycobacterial infections represent a significant clinical risk to transplant recipients because of their aggressive clinical course and the need for complex toxic antibiotic treatments. In these patients, M. haemophilum is a cause of skin infections.

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Severe metallosis following oxidised zirconium wear in total hip arthroplasty

Description

We present a case of a man aged 81 years who underwent a primary cementless total hip arthroplasty. Eight years after the index surgery, failure of the arthroplasty was revealed by the presence of the radiographic 'cloud sign' (figure 1). The original components used were the R3 acetabular cup with a Synergy femoral stem, highly crossed linked polyethylene liner and an oxidised zirconium (Oxinium) femoral head (Smith & Nephew Synergy, Memphis, Tennessee, USA). The initial investigation included a CT scan, full blood tests and a tissue biopsy which revealed no malignancy. Subsequently, during revision surgery, there was extensive osteolysis with metallosis. There was black staining of the periprosthetic soft tissues and the hip pseudocapsule was filled with thick black fluid (figure 2). There was severe wear of the femoral head and the polyethylene liner. Following debridement and removal of the components, a revision...

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Multimodality Cardiac Imaging in a Patient with Kawasaki Disease and Giant Aneurysms

Kawasaki disease is a well-known cause of acquired cardiac disease in the pediatric and adult population, most prevalent in Japan but also seen commonly in the United States. In the era of intravenous immunoglobulin (IVIG) treatment, the morbidity associated with this disease has decreased, but it remains a serious illness. Here we present the case of an adolescent, initially diagnosed with Kawasaki disease as an infant, that progressed to giant aneurysm formation and calcification of the coronary arteries. We review his case and the literature, focusing on the integral role of multimodality imaging in managing Kawasaki disease.

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Mercury Vapour Long-Lasting Exposure: Lymphocyte Muscarinic Receptors as Neurochemical Markers of Accidental Intoxication

Introduction. Chronic poisoning may result in home setting after mercury (Hg) vapours inhalation from damaged devices. We report a chronic, nonoccupational Hg poisoning due to 10-year indoor exposure to mercury spillage. Case Report. A 72-year-old man with polyneuropathy of suspected toxic origin. At hospitalization, toxicological clinical evaluations confirmed the altered neurological picture documented across the last decade. Periodic blood and urine Hg levels (BHg, UHg) monitoring were performed from admission (), until 1 year later (), paralleled by blood neurochemical markers assessment, that is, lymphocytes muscarinic receptors (l-MRs). At : BHg and UHg were 27 and 1.4 microg/L, respectively (normal values: BHg 1–4.5; UHg 0.1–4.5), associated with l-MRs increase, 185.82 femtomoL/million lymphocytes (normal range: 8.0–16.0). At (two days after DMSA-mobilization test), BHg weak reduction, paralleled by UHg 3.7-fold increase, was measured together with further l-MRs enhancement (205.43 femtomoL/million lymphocytes). At (eight months after two cycles of DMSA chelating therapy ending), gradual improving of clinical manifestations was accompanied by progressive decrease of BHg and UHg (4.0 and 2.8 microg/L, resp.) and peripheral l-MRs neurochemical marker (24.89 femtomoL/million lymphocytes). Conclusion. l-MRs modulatory effect supports their use as peripheral neurochemical marker in Hg poisoning diagnosis and chelation therapy monitoring.

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Constitutively activated PI3K accelerates tumor initiation and modifies histopathology of breast cancer

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Constitutively activated PI3K accelerates tumor initiation and modifies histopathology of breast cancer

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Self-Administration of Medicines and Dietary Supplements Among Female Amateur Runners: A Cross-Sectional Analysis

Abstract

Introduction

Self-administration of medicines or dietary supplements without any physician's advice is a widespread behavior and appears to be more frequently practiced by women. Moreover, reasons to self-administer products are often pains and injuries especially among athletes who might also use remedies to improve physical performance. The objective of this study was thus to assess the prevalence of self-administration of medicines and dietary supplements as well as its determinants among female amateur runners.

Methods

Our sample was comprised of women who took part in amateur running events. Data regarding self-administration of substances, exclusively aiming at being physically prepared for the running event (i.e., intake the week before), were collected through an anonymous self-administered questionnaire including four specific themes (i.e., general information, self-administered medicines and dietary supplements, context of self-administration of substances and knowledge of the anti-doping regulations).

Results

A total of 136 women, with a median age of 39 years (interquartile range: 27–47), volunteered. Among them, 34.6% reported self-administration of medicines during the period immediately preceding the running event, with the aim to be physically prepared. More than one third (33.8%) also declared self-administration of dietary supplements. Furthermore, we observed that about 8.1% of the sample had consumed a potentially doping substance. After adjustments for confounding variables, the probability of self-administration of products (medicines or supplements) increased significantly with the intensity of the activity and the membership in a sports club.

Conclusions

Our study showed that self-administration of products among female runners seems to be a widespread behavior, where the intensity of the sports practice and the network of runners seem to influence the decision to resort to this behavior.

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Self-Administration of Medicines and Dietary Supplements Among Female Amateur Runners: A Cross-Sectional Analysis

Abstract

Introduction

Self-administration of medicines or dietary supplements without any physician's advice is a widespread behavior and appears to be more frequently practiced by women. Moreover, reasons to self-administer products are often pains and injuries especially among athletes who might also use remedies to improve physical performance. The objective of this study was thus to assess the prevalence of self-administration of medicines and dietary supplements as well as its determinants among female amateur runners.

Methods

Our sample was comprised of women who took part in amateur running events. Data regarding self-administration of substances, exclusively aiming at being physically prepared for the running event (i.e., intake the week before), were collected through an anonymous self-administered questionnaire including four specific themes (i.e., general information, self-administered medicines and dietary supplements, context of self-administration of substances and knowledge of the anti-doping regulations).

Results

A total of 136 women, with a median age of 39 years (interquartile range: 27–47), volunteered. Among them, 34.6% reported self-administration of medicines during the period immediately preceding the running event, with the aim to be physically prepared. More than one third (33.8%) also declared self-administration of dietary supplements. Furthermore, we observed that about 8.1% of the sample had consumed a potentially doping substance. After adjustments for confounding variables, the probability of self-administration of products (medicines or supplements) increased significantly with the intensity of the activity and the membership in a sports club.

Conclusions

Our study showed that self-administration of products among female runners seems to be a widespread behavior, where the intensity of the sports practice and the network of runners seem to influence the decision to resort to this behavior.

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Whole-body diffusion-weighted magnetic resonance imaging (WB-DW-MRI) vs choline-positron emission tomography-computed tomography (choline-PET/CT) for selecting treatments in recurrent prostate cancer

Abstract

Objective

To determine the effectiveness of whole-body diffusion-weighted magnetic resonance imaging (WB-DW-MRI) in detecting metastases by comparing the results with those from choline-positron emission tomography-computed tomography (choline-PET/CT) in patients with biochemical relapse after primary treatment, and no metastases in bone scintigraphy, CT and/or pelvic MRI, or metastatic/oligometastatic prostate cancer (PCa). Patients with this disease profile who could benefit from treatment with stereotactic body radiation therapy (SBRT) were selected and their responses to these techniques were rated.

Materials and methods

This was a prospective, controlled, unicentric study, involving 46 consecutive patients from our centre who presented biochemical relapse after adjuvant, salvage or radical treatment with external beam radiotherapy, or brachytherapy. After initial tests (bone scintigraphy, CT, pelvic MRI), 35 patients with oligometastases or without them were selected. 11 patients with multiple metastases were excluded from the study. WB-DW-MRI and choline-PET/CT was then performed on each patient within 1 week. The results were interpreted by specialists in nuclear medicine and MRI. If they were candidates for treatment with ablative SBRT (SABR), they were then evaluated every three months with both tests.

Results

Choline-PET/CT detected lesions in 16 patients that were not observable using WB-DW-MRI. The results were consistent in seven patients and in three cases, a lesion was observed using WB-DW-MRI that was not detected with choline-PET/CT. The Kappa value obtained was 0.133 (p = 0.089); the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of WB-DW-MRI were estimated at 44.93, 64.29, 86.11, and 19.15%, respectively. For choline-PET/CT patients, the sensitivity, specificity, PPV, and NPV were 97.10, 58.33, 93.06, and 77.78%, respectively.

Conclusions

Choline-PET/CT has a high global sensitivity while WB-DW-MRI has a high specificity, and so they are complementary techniques. Future studies with more enrolled patients and a longer follow-up period will be required to confirm these data. The initial data show that the best technique for evaluating response after SBRT is choline-PET/CT.

Trial registration number NCT02858128.

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Whole-body diffusion-weighted magnetic resonance imaging (WB-DW-MRI) vs choline-positron emission tomography-computed tomography (choline-PET/CT) for selecting treatments in recurrent prostate cancer

Abstract

Objective

To determine the effectiveness of whole-body diffusion-weighted magnetic resonance imaging (WB-DW-MRI) in detecting metastases by comparing the results with those from choline-positron emission tomography-computed tomography (choline-PET/CT) in patients with biochemical relapse after primary treatment, and no metastases in bone scintigraphy, CT and/or pelvic MRI, or metastatic/oligometastatic prostate cancer (PCa). Patients with this disease profile who could benefit from treatment with stereotactic body radiation therapy (SBRT) were selected and their responses to these techniques were rated.

Materials and methods

This was a prospective, controlled, unicentric study, involving 46 consecutive patients from our centre who presented biochemical relapse after adjuvant, salvage or radical treatment with external beam radiotherapy, or brachytherapy. After initial tests (bone scintigraphy, CT, pelvic MRI), 35 patients with oligometastases or without them were selected. 11 patients with multiple metastases were excluded from the study. WB-DW-MRI and choline-PET/CT was then performed on each patient within 1 week. The results were interpreted by specialists in nuclear medicine and MRI. If they were candidates for treatment with ablative SBRT (SABR), they were then evaluated every three months with both tests.

Results

Choline-PET/CT detected lesions in 16 patients that were not observable using WB-DW-MRI. The results were consistent in seven patients and in three cases, a lesion was observed using WB-DW-MRI that was not detected with choline-PET/CT. The Kappa value obtained was 0.133 (p = 0.089); the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of WB-DW-MRI were estimated at 44.93, 64.29, 86.11, and 19.15%, respectively. For choline-PET/CT patients, the sensitivity, specificity, PPV, and NPV were 97.10, 58.33, 93.06, and 77.78%, respectively.

Conclusions

Choline-PET/CT has a high global sensitivity while WB-DW-MRI has a high specificity, and so they are complementary techniques. Future studies with more enrolled patients and a longer follow-up period will be required to confirm these data. The initial data show that the best technique for evaluating response after SBRT is choline-PET/CT.

Trial registration number NCT02858128.

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BRAF V600D mutation in a paediatric high-grade glioma

The authors report a case of high-grade glioma with unusual pathology that has not previously been reported in glioma pathology. The 5-year-old patient presented to the emergency department with a 1-day history of a right temporal swelling on a background history of increasing nausea and vomiting for the preceding 5 months. A computed tomography brain was performed, which showed a large right-sided temporoparietal lesion. The patient underwent surgery to remove the mass and pathology confirmed anaplastic astrocytoma (WHO Grade 3). This report focuses on prognostic factors in high-grade glioma, particularly on pathological indicators, namely epidermal growth factor receptor, O6-methylguanine-DNA-methyltransferase expression and BRAF V600D mutation.

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Spontaneous resolution of symptomatic lumbar synovial cyst

Lumbar synovial cyst arises from the facet joint and can lead to back pain, radiculopathy, neurogenic claudication or even cauda equina syndrome. Although most surgeons would consider surgery to be the treatment of choice, the natural history of the disease process remains unknown and uncertainty still exists regarding optimal management of this controversial entity. We illustrate a case of large L5/S1 synovial cyst for which surgery was initially planned. However, it resolved spontaneously without any treatment. We also provide a brief literature review regarding conservative, surgical and minimally invasive management of symptomatic lumbar synovial cyst with special reference to patient outcome.

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Extensive upper extremity deep venous thrombosis following brief application of an operative arm tourniquet

Extensive upper extremity deep venous thrombosis and compartment syndrome secondary to operative tourniquet application are rare outcomes of established practice. We present the case of a 54-year-old female who underwent elective removal of a right olecranon plate under general anaesthetic with brief application of a tourniquet. In recovery, she developed a swollen and erythematous forearm, without significant pain and paraesthesia. An urgent dual-phase computed tomography angiogram identified no venous outflow proximal to the axillary vein. Concern for early compartment syndrome necessitated emergency fasciotomies of the right forearm and hand, precluding thrombolysis. Thrombosis was found in the superficial and deep veins throughout the forearm, but the muscles were healthy. The patient commenced anticoagulation therapy early and made good recovery. Further haematology review concluded that she had a 'provoked thrombosis' and no need for long-term anticoagulation.

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Rosai-Dorfman Disease Involving Multiple Organs: An Unusual Case with Poor Prognosis

Rosai-Dorfman disease is a rare, benign histiocytic proliferative disorder that usually affects the lymph nodes. Although extranodal involvement has been reported in diverse sites, manifestation in the cardiovascular system is extremely rare. Specifically, cardiac involvement in Rosai-Dorfman disease is an extraordinarily infrequent event. We describe a case of a 36-year-old female who presented Rosai-Dorfman disease of multiple organs including the heart, with poor prognosis.

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Letter to the Editor, Re: van der Heijden AG, Mengual L, Lozano JJ, Ingelmo-Torres M, Ribal MJ, Fernández PL, Oosterwijk E, Schalken JA, Alcaraz A, Witjes JA. A five-gene expression signature to predict progression in T1G3 bladder cancer. Eur J Cancer. 2016; 64:127–136

Publication date: Available online 30 October 2016
Source:European Journal of Cancer
Author(s): Anna Orsola, Stephanie A. Mullane, Joaquim Bellmunt




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Reply to letter commenting on: A five-gene expression signature to predict progression in T1G3 bladder cancer

Publication date: Available online 30 October 2016
Source:European Journal of Cancer
Author(s): Antoine G. van der Heijden, Lourdes Mengual




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Inhibitory effects of silibinin on proliferation and lung metastasis of human high metastasis cell line of salivary gland adenoid cystic carcinoma via autophagy induction

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BCL3 exerts an oncogenic function by regulating STAT3 in human cervical cancer

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Effective treatment with icotinib in lung adenocarcinoma with EGFR and ALK co-alterations and brain metastasis

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