Blood concentrations of carotenoids and retinol and lung cancer risk: an update of the WCRF–AICR systematic review of published prospective studies

Abstract

Carotenoids and retinol are considered biomarkers of fruits and vegetables intake, and are of much interest because of their anti-inflammatory and antioxidant properties; however, there is inconsistent evidence regarding their protective effects against lung cancer. We conducted a meta-analysis of prospective studies of blood concentrations of carotenoids and retinol, and lung cancer risk. We identified relevant prospective studies published up to December 2014 by searching the PubMed and several other databases. We calculated summary estimates of lung cancer risk for the highest compared with lowest carotenoid and retinol concentrations and dose–response meta-analyses using random effects models. We used fractional polynomial models to assess potential nonlinear relationships. Seventeen prospective studies (18 publications) including 3603 cases and 458,434 participants were included in the meta-analysis. Blood concentrations of α-carotene, β-carotene, total carotenoids, and retinol were significantly inversely associated with lung cancer risk or mortality. The summary relative risk were 0.66 (95% confidence interval [CI]: 0.55–0.80) per 5 μg/100 mL of α-carotene (studies [n] = 5), 0.84 (95% CI: 0.76–0.94) per 20 μg/100 mL of β-carotene (n = 9), 0.66 (95% CI: 0.54–0.81) per 100 μg/100 mL of total carotenoids (n = 4), and 0.81 (95% CI: 0.73–0.90) per 70 μg/100 mL of retinol (n = 8). In stratified analysis by sex, the significant inverse associations for β-carotene and retinol were observed only in men and not in women. Nonlinear associations were observed for β-carotene, β-cryptoxanthin, and lycopene, with stronger associations observed at lower concentrations. There were not enough data to conduct stratified analyses by smoking. In conclusion, higher blood concentrations of several carotenoids and retinol are associated with reduced lung cancer risk. Further studies in never and former smokers are needed to rule out confounding by smoking.

A systematic literature review of prospective cohort studies on blood carotenoids and lung cancer risk which support that higher blood concentration of several carotenoids and retinol are associated with reduced lung cancer risk. The findings are consistent with epidemiological studies suggesting a preventive role of fruits and vegetables intake on lung cancer risk.

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Leukocyte telomere length in relation to the risk of Barrett's esophagus and esophageal adenocarcinoma

Abstract

Chronic inflammation and oxidative damage caused by obesity, cigarette smoking, and chronic gastroesophageal reflux disease (GERD) are major risk factors associated with Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). EAC has been increasing the past few decades, and early discovery and treatment are crucial for survival. Telomere shortening due to cell division and oxidative damage may reflect the impact of chronic inflammation and could possibly be used as predictor for disease development. We examined the prevalence of shorter leukocyte telomere length (LTL) among individuals with GERD, BE, or EAC using a pooled analysis of studies from the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON). Telomere length was measured in leukocyte DNA samples by Q-PCR. Participants included 1173 patients (386 with GERD, 384 with EAC, 403 with BE) and 736 population-based controls. The association of LTL (in tertiles) along the continuum of disease progression from GERD to BE to EAC was calculated using study-specific odds ratios (ORs) and 95% confidence intervals (CIs) from logistic regression models adjusted for potential confounders. Shorter LTL were less prevalent among GERD patients (OR 0.57; 95% CI: 0.35–0.93), compared to population-based controls. No statistically significant increased prevalence of short/long LTL among individuals with BE or EAC was observed. In contrast to some earlier reports, our findings add to the evidence that leukocyte telomere length is not a biomarker of risk related to the etiology of EAC. The findings do not suggest a relationship between LTL and BE or EAC.

Chronic inflammation and oxidative damage are risk factors associated with Barrett's esophagus and esophageal adenocarcinoma (EAC). Early detection and treatment is crucial for survival. Using a pooled analysis of studies from the BEACON Consortium, this study explores whether disease severity reflects the degree of leukocyte telomere length (LTL) shortening. In contrast to earlier reports, this study could not confirm LTL as a biomarker of risk related to the etiology of EAC.

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ERCC3-MYC interactions as target in pancreatic cancer

Purpose: Even when diagnosed prior to metastasis, pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy with almost 90% lethality, emphasizing the need for new therapies optimally targeting the tumors of individual patients. Experimental Design:We first developed a panel of new physiological models for study of PDAC, expanding surgical PDAC tumor samples in culture using short-term culture and conditional reprogramming with the Rho kinase inhibitor Y-27632, and creating matched patient-derived xenografts (PDX). These were evaluated for sensitivity to a large panel of clinical agents, and promising leads further evaluated mechanistically. Results:Only a small minority of tested agents was cytotoxic in minimally passaged PDAC cultures in vitro. Drugs interfering with protein turnover and transcription were among most cytotoxic. Among transcriptional repressors, triptolide, a covalent inhibitor of ERCC3, was most consistently effective in vitro and in vivo causing prolonged complete regression in multiple PDX models resistant to standard PDAC therapies. Importantly, triptolide showed superior activity in MYC-amplified PDX models, and elicited rapid and profound depletion of the oncoprotein MYC, a transcriptional regulator. Expression of ERCC3 and MYC was interdependent in PDACs, and acquired resistance to triptolide depended on elevated ERCC3 and MYC expression. TCGA analysis indicates ERCC3 expression predicts poor prognosis, particularly in CDKN2A-null, highly proliferative tumors. Conclusions:This provides initial preclinical evidence for an essential role of MYC-ERCC3 interactions in PDAC, and suggests a new mechanistic approach for disruption of critical survival signaling in MYC-dependent cancers.

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Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer

Carcinoma of the prostate is a common cancer with a wide spectrum of clinical behavior that ranges from decades of indolence to rapid metastatic progression and lethality. Prostate cancer is also among the most heritable of human cancers, with 57% (95% confidence interval [CI], 51 to 63) of the…

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A priori and a posteriori dietary patterns at the age of 1 year and body composition at the age of 6 years: the Generation R Study

Abstract

Dietary patterns have been linked to obesity in adults, however, not much is known about this association in early childhood. We examined associations of different types of dietary patterns in 1-year-old children with body composition at school age in 2026 children participating in a population-based cohort study. Dietary intake at the age of 1 year was assessed with a food-frequency questionnaire. At the children's age of 6 years we measured their body composition with dual-energy X-ray absorptiometry and we calculated body mass index, fat mass index (FMI), and fat-free mass index (FFMI). Three dietary pattern approaches were used: (1) An a priori-defined diet quality score; (2) dietary patterns based on variation in food intake, derived from principal-component-analysis (PCA); and (3) dietary patterns based on variations in FMI and FFMI, derived with reduced-rank-regression (RRR). Both the a priori-defined diet score and a 'Health-conscious' PCA-pattern were characterized by a high intake of fruit, vegetables, grains, and vegetable oils, and, after adjustment for confounders, children with higher adherence to these patterns had a higher FFMI at 6 years [0.19 SD (95 % CI 0.08;0.30) per SD increase in diet score], but had no different FMI. One of the two RRR-patterns was also positively associated with FFMI and was characterized by intake of whole grains, pasta and rice, and vegetable oils. Our results suggest that different a priori- and a posteriori-derived health-conscious dietary patterns in early childhood are associated with a higher fat-free mass, but not with fat mass, in later childhood.

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Point-of-care blood gases and critical care blood chemistry and haematology reference values in captive gyr falcons ( Falco rusticolus )

Abstract

Blood samples were obtained from a total of 94 clinically normal captive gyr falcons (Falco rusticolus) divided into two groups. The first group comprised 44 gyr falcons (35 females and 9 males). These falcons were 5 to 6 months old and were destined for the sport of falconry. The second group comprised 50 gyr falcons, (26 females and 24 males). These falcons were 2 to 9 years old and were part of the captive breeding programme at the Falcon Department, Wildlife Division, Wrsan, Abu Dhabi, United Arab Emirates (UAE). The samples were obtained in order to determine blood gases and critical care blood chemistry and haematology reference values in clinically normal captive gyr falcons. Blood samples were analysed using a new portable clinical analyser (PCA) (Enterprise Point of Care System, EPOC, Epocal Inc., Otawa, Canada). The values analysed included Per hydron (pH), partial pressure of carbon dioxide (pCO₂), partial pressure of oxygen (pO₂), sodium (Na ⁺⁺), potassium (K⁺), calcium (Ca⁺⁺), chloride (Cl⁻), glucose (Glu), lactate (Lac), haematocrit (Hct), creatinine (Crea), total carbon dioxide (cTCO₂), bicarbonate (cHCO₃), base excess at extracellular compartment (BE), oxygen saturation (cSO₂), anion gap (AGaPK) and haemoglobin (Hgb). Statistical analysis of the data obtained was carried out and included the arithmetic mean, standard deviation, standard error of mean and the inner limits of the percentiles P2.5th–P97.5th with a probability of 95 % interval. The Shapiro-Wilk's test was used to determine normality of distribution for each analyte. Inferential statistics for equality of variances using the independent sample Levene's test was used to determine statistically significant differences between the data from the hunting and breeding falcon groups. After determining the equality of variances, the pooled t test was used to analyse the parametric data while the Welch t test was used to analyse the non-parametric data. The conventional P value of 0.05 was applied, wherein a P value less than 0.05 indicated that significant differences existed between the data from the two groups. To the knowledge of the authors, this is the first set of blood gases and critical care blood chemistry and haematology reference values reported specifically for the gyr falcon using the EPOC analyser.

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Biological imaging in clinical oncology: radiation therapy based on functional imaging

Abstract

Radiation therapy is one of the most effective tools for cancer treatment. In recent years, intensity-modulated radiation therapy has become increasingly popular in that target dose-escalation can be done while sparing adjacent normal tissues. For this reason, the development of measures to pave the way for accurate target delineation is of great interest. With the integration of functional information obtained by biological imaging with radiotherapy, strategies using advanced biological imaging to visualize metabolic pathways and to improve therapeutic index and predict treatment response are discussed in this article.

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B7-H4 expression indicates poor prognosis of oral squamous cell carcinoma

Abstract

Checkpoint blockade therapy utilizing monoclonal antibodies to reactivate T cells and recover their antitumor activity makes an epoch in cancer immunotherapy. The role of B7-H4, a novel negative immune checkpoint, in oral squamous cell carcinoma (OSCC) has still not been elucidated. In this study, tissue samples from human OSCC, which contains 165 primary OSCC, 48 oral epithelial dysplasia and 43 normal oral mucosa specimens, and Tgfbr1/Pten 2cKO mice OSCC model were stained with B7-H4 antibody to analyze the correlations between B7-H4 expression and clinicopathological characteristics. Kaplan–Meier analysis was used to compare the survival of patients with high B7-H4 expression and patients with low B7-H4 expression. We found B7-H4 is highly expressed in human OSCC tissue, and the B7-H4 expression level was associated with the clinicopathological parameters containing pathological grade and lymph node status. Moreover, we confirmed that B7-H4 was overexpressed in Tgfbr1/Pten 2cKO mice OSCC model. Our data also indicated that patients with high B7-H4 expression had poor overall survival compared with those with low B7-H4 expression. Furthermore, this study demonstrated that B7-H4 was positively associated with PD-L1, CD11b, CD33, PI3Kα p110, and p-S6 (S235/236). Taken together, these findings suggest B7-H4 is a potential target in the treatment of OSCC.

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An orthotopic mouse model of small cell lung cancer reflects the clinical course in patients

Abstract

Small cell lung cancer (SCLC) is a highly aggressive subtype of lung cancer with very poor prognosis due to early metastatic spread and development of chemoresistance. In the last 30 years the study of SCLC has been constrained by a lack of primary human tumor specimen thus highlighting the need of a suitable mouse model. In this article we present the establishment of an orthotopic xenograft mouse model which accurately reproduced the clinical course of SCLC. Orthotopic implantation enabled engraftment of primary lung tumors in all injected mice. Furthermore, immunodeficiency of mice allowed formation of spontaneous metastases in characteristic organs. Bioluminescence Imaging, Magnetic Resonance Imaging and Positron emission tomography were applied to monitor engraftment, metabolism and the exact growth of tumors over time. In order to mimic the extensive disease stage, mice were injected with aggressive human chemoresistant cells leading to development of chemoresistant tumors and early metastatic spread. As a proof of concept treatment of tumor-bearing mice with conventional chemotherapeutics reduced tumor volumes, but a complete regression of tumors was not achieved. By mimicking the extensive disease stage our mouse model can facilitate the study of mechanisms contributing to chemoresistance and metastasis formation, as well as drug screening and evaluation of new treatment strategies for SCLC patients.

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Effects of Brinzolamide, a Topical Carbonic Anhydrase Inhibitor, on Corneal Endothelial Cells

Abstract

Introduction

This clinical study aimed to investigate the effect of brinzolamide, a topical carbonic anhydrase inhibitor, on corneal endothelial cells (CECs) in patients with glaucoma using a follow-up clinical study design.

Methods

Patients with primary open-angle glaucoma or ocular hypertension were administrated an ophthalmic solution of either latanoprost alone (LT) as a control (n = 18) or latanoprost plus brinzolamide (LT + BR; n = 16). CECs were examined at baseline and at 4, 12, 24, and 48 weeks in 18 and 16 eyes of the LT and LT + BR groups, respectively, using a non-contact specular microscope. CECs were evaluated by parameters, including cell density (CD), coefficient of variation (CV) in cell size, and percentage hexagonality (Hex).

Results

Compared with the baseline intraocular pressure (IOP), the mean IOP in the LT group was significantly reduced at 12 and 24 weeks, whereas that in the LT + BR group was significantly reduced at all time points (P < 0.01). The mean CD, CV, and Hex at baseline were not significantly different between the two groups. No significant time-course changes in CD, CV, or Hex were observed in either group. At 48 weeks, there was no significant difference in the mean CD, CV, or Hex between the two groups.

Conclusion

Patients treated with LT + BR showed significant IOP reduction. However, the use of brinzolamide in addition to latanoprost had no influence on CECs during the one-year follow-up period.

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Making Insulin Accessible: Does Inhaled Insulin Fill an Unmet Need?

Abstract

Glycemic control is fundamental to the management of diabetes. However, studies suggest that a significant proportion of people with diabetes, particularly those using insulin, are not achieving glycemic targets. The reasons for this are likely to be multifactorial. The real and perceived risk of hypoglycemia and the need for multiple daily injections are widely recognized as key barriers to effective insulin therapy. Therefore, there is a clear unmet need for a treatment option which can help mitigate these barriers. Alternative methods of insulin administration have been under investigation for several years, and pulmonary delivery has shown the most promise to date. Inhaled Technosphere^® Insulin (TI; Afrezza^®; MannKind Corporation) was approved in 2014 for use as prandial insulin in people with diabetes. TI shows a more rapid onset of action and a significantly faster decline in activity than current subcutaneous rapid-acting insulin analogs (RAAs), and TI is more synchronized to the physiologic timing of the postprandial glucose excursion. This results in lower postprandial hypoglycemia with similar glycemic control compared with RAAs, and less weight gain. Together with the ease of use of the TI inhaler and the reduction in the number of daily injections, these findings imply that TI may be useful in helping to overcome patient resistance to insulin, improve adherence and mitigate clinical inertia in health-care providers, with potential beneficial effects on glycemic control.

Funding: Writing and editorial support in the preparation of this publication was funded by Sanofi US, Inc., Bridgewater, New Jersey, USA. Funding for the article processing charges for this publication was provided by MannKind Corporation.

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Plasma cell maturity as a predictor of prognosis in multiple myeloma

Abstract

In this study, the impact of plasma cell maturity on the prognoses of multiple myeloma (MM) patients in the era of novel agents was investigated. Myeloma cell maturity was classified via immunophenotyping: myeloma cells showing mature plasma cell 1 (MPC-1)-positive and CD49e-positive cells were considered mature type; MPC-1-positive and CD49e-negative cells were considered intermediate type; and MPC-1-negative cells were considered immature type. This study included 87 newly diagnosed MM patients who were initially treated with bortezomib and/or chemotherapy. Myeloma cell maturity was a critical factor affecting overall survival (OS) in the cohort, with median OS not reached in mature-type, 50 months in intermediate-type, and 20 months in immature-type cells. Multivariate analysis showed that immature type and stage III according to the International Staging System were both independent prognostic factors affecting OS. The findings of this study demonstrate the clinical importance of myeloma cell classification according to immunophenotyping using MPC-1 and CD49e antibodies to determine patient prognosis in this era of novel therapeutic agents.

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miR-181a induces sorafenib resistance of hepatocellular carinoma cells through downregulation of RASSF1 expression

Abstract

Sorafenib, a multi-kinase inhibitor, is the only standard clinical drug against patients with advanced hepatocellular carcinoma (HCC), however, development of sorafenib resistance in HCC often prevents its long-term efficacy. Therefore, novel targets and strategies are urgently needed to improve antitumor effect of sorafenib. In the present study, we examined the novel mechanisms of sorafenib resistance of HCC cells from the difference in sorafenib resistance between two HCC cell lines. Sorafenib induced more apoptosis of HepG2 cells compared to Hep3B cells from 1 to 5 μM of its concentration. Sorafenib exposure to HepG2 cells but not Hep3B cells increased expression of proapoptotic factor PUMA, and activated PARP and caspase-3. Notably, microRNA-181a (miR-181a) expression levels were lower in HepG2 cells than in Hep3B cells. Exogenous miR-181a expression in HepG2 cells reduced apoptosis, whereas inhibition of miR-181a in Hpe3B cells increased. In addition, we demonstrated that miR-181a directly targets RASSF1, a MAPK signaling factor, and knockdown of RASSF1 increased sorafenib resistance. Taken together, these results suggest that miR-181a provokes sorafenib resistance through suppression of RASSF1. Our data provide an important insight into the novel therapeutic strategy against sorafenib resistance of HCC cells by targeting of miR-181a pathway.

This article is protected by copyright. All rights reserved.

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IL-17A-producing CD30+ Vδ1 T cells drive inflammation-induced cancer progression

Summary

Although it has been suspected that inflammation associates with increased tumor metastasis, the exact type of immune response to initiate cancer progression and metastasis remains unknown. In this study, by using an in vivo tumor progression model in which low tumorigenic cancer cells acquire malignant metastatic phenotype after exposure to inflammation, we found IL-17A is a critical cue for escalating cancer cell malignancy. We further demonstrated the length of exposure to an inflammatory microenvironment could associate with acquiring greater tumorigenicity and IL-17A was critical for amplifying such local inflammation as observed in the production of IL-1β and neutrophil infiltration following the cross-talk between cancer and host stromal cells. We further determined that γδT cells expressing Vδ1 semi-invariant TCR initiate cancer-promoting inflammation by producing IL-17A in an MyD88/IL-23 dependent manner. Finally, we identified CD30 as a key molecule in the inflammatory function of Vδ1T cells and the blockade of this pathway targeted this cancer immune-escalation process. Collectively, these results reveal the importance of IL-17A-producing CD30⁺ Vδ1T cells in triggering inflammation and orchestrating a microenvironment leading to cancer progression.

This article is protected by copyright. All rights reserved.

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Atrial fibrillation after lung cancer surgery: incidence, severity, and risk factors

Abstract

Purpose

Atrial fibrillation (Af) is a common post-operative cardiac complication after lung cancer surgery; however, the type of lung cancer surgery being performed has evolved, remarkably, into minimally invasive surgical procedures. The purpose of this study was to quantify the incidence and severity of post-operative Af and to identify the risk factors for Af, using a recent cohort of lung cancer surgery patients.

Methods

We reviewed, retrospectively, the medical records of 593 patients, who underwent lung cancer surgery between 2011 and 2013, for the development of post-operative Af.

Results

The overall incidence of post-operative Af in our study was 6.4 % (38/593). Three (8 %) of these 38 patients, subsequently, suffered brain infarction. Multivariate analysis revealed that mediastinal lymph node dissection (OR ND-2/ND-0–1 = 3.06; 95 % CI 1.06–10.9) was associated with the development of post-operative Af.

Conclusion

Omission of mediastinal lymph dissection for patients with early stage lung cancer and a high risk of Af should be considered to prevent post-operative Af.

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Neoplasia in flat head grey mullet, Mugil cephalus Linnaeus, 1758 (Perciforms: Mugilidae): two case reports of myxoinflammatory fibroblastic sarcoma and leiomyoma

Abstract

The presence of cutaneous neoplasms is reported in two cases of wild female grey mullet (Mugil cephalus) from Pazhayar and Parangipettai fish landing centre, southeast coast of India. A gross morphological examination case 1 revealed obvious reddish white, solitary and fleshy appearance of tumour located on behind the right-side of the anal fin, and the overlying epidermis was ulcerated, hyperemic and hyperchromatic. The tumour had a gelatinous consistency and released jelly-like matters. The tumour-affected case 2 revealed well-circumscribed, solitary and reddish fleshy appearance of tumour located on the left-side of the deep margin of the flank, the lesion covered with whitish-grey thin epidermal layer. Histolopathologically, the (case 1) tumour growth had distinct simulate bizarre tumour cells embedded in myxoid matrix with inflammatory infiltrates. The (case 2) tumour lesion showed interlacing bundles of spindled to elongated tumour cells with cigar-shaped nuclei. On the basis of the clinical and histolopathological findings, these tumours are diagnosed as myxoinflammatory fibroblastic sarcoma and leiomyoma.

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Laparoscopic radical prostatectomy outcome data: how should surgeon’s performance be reported? A retrospective learning curve analysis of two surgeons

Sarah Mason, Mieke Van Hemelrijck, Ashish Chandra, Christian Brown and Declan Cahill

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Feasibility evaluation of hypofractionated radiotherapy with concurrent temozolomide in elderly patients with glioblastoma

Abstract

Background

Although hypofractionated radiotherapy (HFRT) is preferred to conventionally fractionated radiotherapy when treating elderly patients with glioblastoma, the benefits and tolerability of HFRT with concurrent temozolomide (TMZ) remain unknown for such patients. We assessed the feasibility and outcomes of elderly patients with glioblastoma treated with HFRT and concurrent TMZ.

Methods

We retrospectively reviewed the medical records of 11 patients aged ≥70 years who were treated with HFRT and concurrent TMZ. All patients had newly diagnosed and histologically confirmed glioblastoma and were treated at our institution between October 2011 and April 2015. The median age was 74 years (range, 70–85 years). Total resection/subtotal resection/biopsy were performed in 2/5/4 patients, respectively. The planning target volume included the T1-enhancing tumor and the resection cavity plus 2-cm margins, and all surrounding edema. The median prescription dose was 35 Gy (range, 35–42.5 Gy), delivered in 10 fractions. Seven patients received TMZ at 150 mg/m² for 5 days and 4 received TMZ at 75 mg/m² during HFRT. Overall survival (OS) was defined as the time from surgery to death or the last follow-up.

Results

The median follow-up period was 13.2 months. The median OS and progression-free survival (PFS) times were 13.2 and 7.0 months, respectively. One patient experienced grade 4 neutropenia, lymphocytopenia, and thrombocytopenia. No grade 3 or higher nonhematological adverse event was noted.

Conclusion

Our analysis demonstrated the feasibility of HFRT with concurrent TMZ used to treat elderly patients with glioblastoma. Further prospective clinical trials are needed to define therapies that balance efficacy with tolerability.

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Cancer stem cell mediated acquired chemoresistance in head and neck cancer can be abrogated by Aldehyde dehydrogenase 1 A1 inhibition

Abstract

Chemoresistance leading to disease relapse is one of the major challenges to improve outcome in head and neck cancers. Cancer Stem Cells (CSCs) are increasingly being implicated in chemotherapy resistance, this study investigates the correlation between CSC behavior and acquired drug resistance in in vitro cell line models. Cell lines resistant to Cisplatin (Cal-27 CisR, Hep-2 CisR) and 5FU (Cal-27 5FUR) with high Resistance Indices (RI) were generated (RI ≥3) by short-term treatment of Head and Neck Squamous Cell Carcinoma (HNSCC) cell lines with chemotherapeutic drugs (Cisplatin, Docetaxel, 5FU), using a dose-incremental strategy. The cell lines (Cal-27 DoxR, Hep-2 DoxR, Hep-2 5FUR) showed low RI, nevertheless had a high cross resistance to Cisplatin/5FU (p < 0.05). Cal-27 CisR and DoxR showed 12-14% enrichment of CD44+ cells, while CisR/5FUR showed 4-6% increase in ALDH1A1+ cells as compared to parental cells (p < 0.05). Increased expression of stem cell markers (CD44, CD133, NOTCH1, ALDH1A1, OCT4, SOX2) in these cell lines, correlated with enhanced spheroid/colony formation, migratory potential and increased in vivo tumor burden (p < 0.05). Inhibition of ALDH1A1 in Cal-27 CisR led to down regulation of the CSC markers, reduction in migratory, self-renewal and tumorigenic potential (p < 0.05) accompanied by an induction of sensitivity to Cisplatin (p < 0.05). Further, ex vivo treatment of explants (n = 4) from HNSCC patients with the inhibitor (NCT-501) in combination with Cisplatin showed a significant decrease in proliferating cells as compared to individual treatment (p = 0.001). This study hence suggests an ALDH1A1-driven, CSC-mediated mechanism in acquired drug resistance of HNSCC, which may have therapeutic implications. This article is protected by copyright. All rights reserved

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Noninvasive detection of gastric cancer

Abstract

Gastric cancer (GC) is the fifth most common cancer and the third common cause of cancer death worldwide. Endoscopy is the most effective method for GC screening, but its application is limited by the invasion. Therefore, continuous efforts have been made to develop noninvasive methods for GC detection and promising results have been reported. Here, we review the advances in GC detection by protein and nucleic acid tumor markers, circulating tumor cells, and tumor-associated autoantibodies in peripheral blood. Some potential new noninvasive methods for GC detection are also reviewed, including exhaled breath analysis, blood spectroscopy analysis and molecular imaging.

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GPC-HCC model: a combination of glybican-3 with other routine parameters improves the diagnostic efficacy in hepatocellular carcinoma

Abstract

Conflicting results for circulating glypican-3 (GPC3) were reported in hepatocellular carcinoma (HCC) diagnosis. We aimed to improve the diagnostic power of GPC3 by developing a GPC-HCC model for diagnosing HCC. GPC3 was tested for HCC (138), liver cirrhosis (56), and fibrosis (62) patients by ELISA. Data from patient groups were retrospectively analyzed. A novel score, GPC-HCC, based on combination of GPC3 and routine laboratory tests, was developed for HCC diagnosis. The GPC-HCC model values produced a significant 1.7-fold increase in liver cirrhosis and 3.2-fold increase in HCC, in comparison with liver fibrosis. In contrast to GPC3 and alpha fetoprotein (AFP), the GPC-HCC model showed high HCC diagnostic power with area under the curve (AUC) of 0.939, sensitivity 93 %, specificity 93 %, positive predictive value 89 %, negative predictive value 95 %, and efficiency 93 %. GPC-HCC AUC in HCC with single tumor, absent vascular invasion, and tumor size ≤3 cm were 0.93, 0.92, and 0.92, respectively, compared with 0.63, 0.63, and 0.64, respectively, for GPC3 and 0.69, 0.70, 0.55, respectively, for AFP. In conclusion, owing to these promising findings, the combination of GPC3 with other laboratory simple routine tests (GPC-HCC model) could improve the diagnostic power of GPC3 in HCC screening and follow up of cirrhotic patients.

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Remarkable response in 2 cases of Advanced Poorly Differentiated Thyroid Carcinoma with liposomal doxorubicin plus cisplatin

Volume 17, Issue 6, June 2016, pages 693-697<br/>10.1080/15384047.2016.1167295<br/>Haiyan Yang

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Combination therapy targeting both cancer stem-like cells and bulk tumor cells for improved efficacy of breast cancer treatment

Volume 17, Issue 6, June 2016, pages 698-707<br/>10.1080/15384047.2016.1190488<br/>Tao Wang

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Molecular correlates and prognostic value of tmTNF-α expression in colorectal cancer of 5-Fluorouracil-Based Adjuvant Therapy

Volume 17, Issue 6, June 2016, pages 684-692<br/>10.1080/15384047.2016.1187551<br/>Xiaogai Li

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Prognostic evaluation of VEGFA genotypes and haplotypes in a cohort of Brazilian women with non metastatic breast cancer

Volume 17, Issue 6, June 2016, pages 674-683<br/>10.1080/15384047.2016.1190486<br/>Hayra de Andrade Vieira-Monteiro

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A place for precision medicine in bladder cancer: targeting the FGFRs

Future Oncology Ahead of Print.


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Long-term exposure to fine particulate matter air pollution and the risk of lung cancer among participants of the Canadian National Breast Screening Study

Abstract

Recently, air pollution has been classified as a carcinogen largely on the evidence of epidemiological studies of lung cancer. However, there have been few prospective studies that have evaluated associations between fine particulate matter (PM_2.5) and cancer at lower concentrations. We conducted a prospective analysis of 89,234 women enrolled in the Canadian National Breast Screening Study between 1980 and 1985, and for whom residential measures of PM_2.5 could be assigned. The cohort was linked to the Canadian Cancer Registry to identify incident lung cancers through 2004. Surface PM_2.5 concentrations were estimated using satellite data. Cox proportional hazards models were used to characterize associations between PM_2.5 and lung cancer. Hazard ratios (HRs) and 95% confidence intervals (CIs) computed from these models were adjusted for several individual-level characteristics, including smoking. The cohort was composed predominantly of Canadian-born (82%), married (80%) women with a median PM_2.5 exposure of 9.1 µg/m³. In total, 932 participants developed lung cancer. In fully adjusted models, a 10 µg/m³ increase in PM_2.5 was associated with an elevated risk of lung cancer (HR: 1.34; 95% CI = 1.10, 1.65). The strongest associations were observed with small cell carcinoma (HR: 1.53; 95% CI = 0.93, 2.53) and adenocarcinoma (HR: 1.44; 95% CI = 1.06, 1.97). Stratified analyses suggested increased PM_2.5 risks were limited to those who smoked cigarettes. Our findings are consistent with previous epidemiological investigations of long-term exposure to PM_2.5 and lung cancer. Importantly, they suggest associations persist at lower concentrations such as those currently found in Canadian cities. This article is protected by copyright. All rights reserved.

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Benefit of low dose tamoxifen in a large observational cohort of high risk ER positive breast DCIS

Abstract

Low-dose tamoxifen has comparable antiproliferative effect to the standard dose of 20 mg/day in biomarker trials, but its clinical efficacy remains unclear. We assessed the effect of low-dose tamoxifen on ipsilateral recurrence in ductal carcinoma in situ (DCIS) patients treated in a referral Institution between 1996 and 2008. Following conserving surgery, women received radiotherapy and/or low-dose tamoxifen upon clinical judgment and patient preferences. Cox regression analyses were used with and without confounding factors. Among 1,091 women with DCIS and median age 53 years (IQR 46-62), 544 (49.9%) received radiotherapy. Of the 833 women with oestrogen receptor (ER) positive DCIS, 467 (56.1%) received low-dose tamoxifen. After a median of 7.7 years, 235 ipsilateral recurrences and 62 contralateral breast tumors were observed. Low-dose tamoxifen significantly decreased any breast event (HR=0.70, 95% CI, 0.54-0.91) and ipsilateral DCIS recurrence (HR=0.66, 95% CI, 0.49-0.88), but not ipsilateral invasive recurrence or contralateral tumors. Radiotherapy showed a large significant reduction for any breast event (HR=0.55, 95% CI, 0.42-0.72). Tamoxifen was more effective on all breast events in women aged >50 years than in women aged ≤50 (HR=0.51, 95% CI, 0.33-0.77 versus HR=0.84, 95% CI, 0.60-1.18, p-interaction=0.03). Age ≤50 years, positive margins, high Ki67, high grade and low BMI were independent predictors of ipsilateral recurrence. No increase of endometrial cancers and fewer deaths (P=0.015) were observed on tamoxifen.

Low-dose tamoxifen seems to be safe and effective in reducing ipsilateral recurrence in ER positive DCIS in women aged >50 years. A randomized trial is underway to confirm these findings. This article is protected by copyright. All rights reserved.

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KSP inhibitor SB743921 inhibits growth and induces apoptosis of breast cancer cells by regulating p53, Bcl-2, and DTL.

Kinesin spindle protein (KSP) is a microtubule-associated motor protein that is specifically expressed by mitosis cells. It is highly expressed in various types of tumors including hematomalignances and solid tumors. Chemical KSP inhibition has become a novel strategy in the development of anticancer drugs. SB743921 is a selective inhibitor for KSP, which is a mitotic protein essential for cell-cycle progression. Although SB743921 has shown antitumor activities for several types of cancers and entered into clinical trials, its therapeutic effects on breast cancer and mechanisms have not been explored. In this study, we tested the antitumor activity of SB743921 in breast cancer cell lines and partly elucidated its mechanisms. KSP and denticleless E3 ubiquitin-protein ligase homolog (DTL) are overexpressed in breast cancer cells compared with no-cancer tissues. Chemical inhibition of KSP by SB743921 not only reduces proliferation but also induces cell-cycle arrest and leads to apoptosis in breast cancer cells. Treatment of MCF-7 and MDA-MB-231 breast cancer cell lines with SB743921 results in decreased ability of colony formation in culture. SB743921 treatment also causes a KSP accumulation in protein level that is associated with cell arrest. Furthermore, we showed that SB743921 treatment significantly reduces the expression of bcl-2 and cell cycle-related protein DTL, and upregulates p53 and caspase-3 in breast cancer cells. Taken together, these data indicated that SB743921 can be expected to be a novel treatment agent for breast cancers. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. http://ift.tt/1hexVwJ Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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Chromatin Regulators for Chemotherapy Response

The limited capacity to predict a patient's response to distinct chemotherapeutic agents is a major hurdle in cancer management. The efficiency of a large fraction of current cancer therapeutics (radio- and chemotherapies) is influenced by chromatin structure. Reciprocally, alterations in chromatin organization may affect resistance mechanisms. Here, we explore how the misexpression of chromatin regulators—factors involved in the establishment and maintenance of functional chromatin domains—can inform about the extent of docetaxel response. We exploit Affymetrix and NanoString gene expression data for a set of chromatin regulators generated from breast cancer patient-derived xenograft models and patient samples treated with docetaxel. Random Forest classification reveals specific panels of chromatin regulators, including key components of the SWI/SNF chromatin remodeler, which readily distinguish docetaxel high-responders and poor-responders. Further exploration of SWI/SNF components in the comprehensive NCI-60 dataset reveals that the expression inversely correlates with docetaxel sensitivity. Finally, we show that loss of the SWI/SNF subunit BRG1 (SMARCA4) in a model cell line leads to enhanced docetaxel sensitivity. Altogether, our findings point toward chromatin regulators as biomarkers for drug response as well as therapeutic targets to sensitize patients toward docetaxel and combat drug resistance. Mol Cancer Ther; 15(7); 1768–77. ©2016 AACR.

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NQO1-Dependent Radiosensitization of Head and Neck Cancer

Ionizing radiation (IR) is a key therapeutic regimen for many head and neck cancers (HNC). However, the 5-year overall survival rate for locally advanced HNCs is approximately 50% and better therapeutic efficacy is needed. NAD(P)H:quinone oxidoreductase 1 (NQO1) is overexpressed in many cancers, and β-lapachone (β-lap), a unique NQO1 bioactivatable drug, exploits this enzyme to release massive reactive oxygen species (ROS) that synergize with IR to kill by programmed necrosis. β-Lap represents a novel therapeutic opportunity in HNC leading to tumor-selective lethality that will enhance the efficacy of IR. Immunohistochemical staining and Western blot assays were used to assess the expression levels of NQO1 in HNC cells and tumors. Forty-five percent of endogenous HNCs expressed elevated NQO1 levels. In addition, multiple HNC cell lines and tumors demonstrated elevated levels of NQO1 expression and activity and were tested for anticancer lethality and radiosensitization by β-lap using long-term survival assays. The combination of nontoxic β-lap doses and IR significantly enhanced NQO1-dependent tumor cell lethality, increased ROS, TUNEL-positive cells, DNA damage, NAD⁺, and ATP consumption, and resulted in significant antitumor efficacy and prolonged survival in two xenograft murine HNC models, demonstrating β-lap radiosensitization of HNCs through a NQO1-dependent mechanism. This translational study offers a potential biomarker-driven strategy using NQO1 expression to select tumors susceptible to β-lap–induced radiosensitization. Mol Cancer Ther; 15(7); 1757–67. ©2016 AACR.

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Genome and Immune Profiling of Inflammatory Breast Cancer

Inflammatory breast cancer (IBC) is a rare and aggressive form of breast cancer that remains poorly understood at the molecular level. Comprehensive tumor profiling was performed to understand clinically actionable alterations in IBC. Targeted next-generation sequencing (NGS) and IHC were performed to identify activated pathways in IBC tumor tissues. siRNA studies examined the impact of IBC genomic variants in cellular models. IBC tumor tissues were further characterized for immune infiltration and immune checkpoint expression by IHC. Genomic analysis identified recurrent alterations in core biologic pathways, including activating and targetable variants in HER/PI3K/mTOR signaling. High rates of activating HER3 point mutations were discovered in IBC tumors. Cell line studies confirmed a role for mutant HER3 in IBC cell proliferation. Immunologic analysis revealed a subset of IBC tumors associated with high CD8⁺/PD-L1⁺ lymphocyte infiltration. Immune infiltration positively correlated with an NGS-based estimate of neoantigen exposure derived from the somatic mutation rate and mutant allele frequency, iScore. Additionally, DNA mismatch repair alterations, which may contribute to higher iScores, occurred at greater frequency in tumors with higher immune infiltration. Our study identifies genomic alterations that mechanistically contribute to oncogenic signaling in IBC and provides a genetic basis for the selection of clinically relevant targeted and combination therapeutic strategies. Furthermore, an NGS-based estimate of neoantigen exposure developed in this study (iScore) may be a useful biomarker to predict immune infiltration in IBC and other cancers. The iScore may be associated with greater levels of response to immunotherapies, such as PD-L1/PD-1–targeted therapies. Mol Cancer Ther; 15(7); 1746–56. ©2016 AACR.

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