Estrobolome Disparities May Lead To Developing Bimoarkers That Could Mitigate Cancer Risk

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The Intestinal Microbiome and Estrogen Receptor-Positive Female Breast Cancer

The huge communities of residential microbes, including bacteria, viruses, Archaea, and Eukaryotes, that colonize humans are increasingly recognized as playing important roles in health and disease. A complex populous ecosystem, the human gastrointestinal (GI) tract harbors up to 10¹¹ bacterial cells per gram of luminal content, whose collective genome, the gut metagenome, contains a vastly greater number of individual genes than the human genome. In health, the function of the microbiome might be considered to be in dynamic equilibrium with the host, exerting both local and distant effects. However, 'disequilibrium' may contribute to the emergence of disease, including malignancy. In this review, we discuss how the intestinal bacterial microbiome and in particular how an 'estrobolome,' the aggregate of enteric bacterial genes capable of metabolizing estrogens, might affect women's risk of developing postmenopausal estrogen receptor–positive breast cancer. Estrobolome composition is impacted by factors that modulate its functional activity. Exploring variations in the composition and activities of the estrobolome in healthy individuals and in women with estrogen-driven breast cancer may lead to development of microbiome-based biomarkers and future targeted interventions to attenuate cancer risk.

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Dual FASN and EGFR blockade in TNBC

Abstract Purpose: Triple Negative Breast Cancer (TNBC) lacks an approved targeted therapy. Despite initial good response to chemotherapy, 30% of the patients relapse within 5 years after treatment. EGFR overexpression is a common marker in TNBC, and its expression has been correlated with poor outcome. Inhibition of Fatty Acid Synthase (FASN) activity leads to apoptosis of human carcinoma cells overexpressing FASN. We tested the hypothesis that blocking FASN in combination with anti-EGFR signaling agents would be an effective antitumor strategy in sensitive and chemoresistant TNBC. Experimental Design: Several TNBC cell lines and 29 primary tumors were included to determine whether FASN is a potential target in TNBC. Doxorubicin-resistant TNBC cell lines (231DXR and HCCDXR) have been developed and characterized in our laboratory. Cellular and molecular interactions of anti-FASN compounds (EGCG and C75) with cetuximab were analyzed. In vivo tumor growth inhibition was evaluated after cetuximab, EGCG or the combination in TNBC orthoxenograft models. Results: TNBC cell lines showed overexpression of FASN enzyme and its inhibiton correlated to FASN levels. FASN staining was observed in all of the 29 TNBC tumor samples. In vitro, EGCG and C75 plus cetuximab showed strong synergism in sensitive and chemoresistant cells. In vivo, the combination of EGCG with cetuximab displayed strong antitumor activity against the sensitive and chemoresistant TNBC orthoxenografts, without signs of toxicity. Conclusions: Our results show that the simultaneous blockade of FASN and EGFR is effective in preclinical models of sensitive and chemoresistant TNBC.

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Targeted therapy combined with radiotherapy in non-small-cell lung cancer: a review of the Oncologic Group for the Study of Lung Cancer (Spanish Radiation Oncology Society)

Abstract

In recent years, major advances in our understanding of the molecular biology of lung cancer, together with significant improvements in radiotherapy technologies, have revolutionized the treatment of non-small cell lung cancer (NSCLC). This has led to the development of new therapies that target molecular mutations specific to each tumor type, acting on the cell surface antigens or intracellular signaling pathways, or directly affecting cell survival. At the same time, ablative dose radiotherapy can be delivered safely in the context of metastatic disease. In this article, the GOECP/SEOR (Oncological Group for Study of Lung Cancer/Spanish Society of Radiation Oncology) reviews the role of new targeted therapies used in combination with radiotherapy in patients with locally advanced (stage III) NSCLC and in patients with advanced, metastatic (stage IV) NSCLC.

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Breast cancer screening disparities among immigrant women by world region of origin: a population-based study in Ontario, Canada

Abstract

Rates of mammography screening for breast cancer are disproportionately low in certain subgroups including low-income and immigrant women. The purpose of the study was to examine differences in rates of appropriate breast cancer screening (i.e., screening mammography every 2 years) among Ontario immigrant women by world region of origin and explore the association between appropriate breast cancer screening among these women groups and individual and structural factors. A cohort of 183,332 screening-eligible immigrant women living in Ontario between 2010 and 2012 was created from linked databases and classified into eight world regions of origin. Appropriate screening rates were calculated for each region by age group and selected sociodemographic, immigration, and healthcare-related characteristics. The association between appropriate screening across the eight regions of origin and selected sociodemographic, immigration, and health-related characteristics was explored using multivariate Poisson regression. Screening varied by region of origin, with South Asian women (48.5%) having the lowest and Caribbean and Latin American women (63.7%) the highest cancer screening rates. Factors significantly associated with lower screening across the world regions of origin included living in the lowest income neighborhoods, having a refugee status, being a new immigrant, not having a regular physical examination, not being enrolled in a primary care patient enrollment model, having a male physician, and having an internationally trained physician. Multiple interventions entailing cross-sector collaboration, promotion of patient enrollment models, community engagement, comprehensive and intensive outreach to women, and knowledge translation and transfer to physicians should be considered to address screening disparities among immigrant population. Consideration should be given to design and delivery of culturally appropriate and easily accessible cancer screening programs targeted at high- risk immigrant subgroups, such as women of South Asian origin, refugees, and new immigrants.

The study found differences in rates of breast cancer screening among Ontario immigrant women by world region of origin. South Asian women had the lowest cancer screening rates. Factors associated with lower screening included living in the lowest income neighborhoods, having a refugee status, being a new immigrant, not having a regular physical examination, not being enrolled in a primary care patient enrollment model, having a male physician, and having an internationally trained physician.

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High co-expression of PD-L1 and HIF-1α correlates with tumour necrosis in pulmonary pleomorphic carcinoma

Publication date: June 2016
Source:European Journal of Cancer, Volume 60
Author(s): Yih-Leong Chang, Ching-Yao Yang, Mong-Wei Lin, Chen-Tu Wu, Pan-Chyr Yang
BackgroundPulmonary pleomorphic carcinomas (PPCs) are uncommon malignant tumours characterised by an aggressive clinical course and poor survival. These neoplasms frequently exhibit marked confluent necrosis, in which hypoxia levels are extremely high, causing low responsiveness to chemotherapy and conferring basic resistance to anti-cancer drugs. Programmed death ligand 1 (PD-L1)–mediated immune escape may be an underlying source of resistance and a suitable target for specific therapy, but its role in PPCs is unclear.Materials and methodsIn total, 122 PPCs were investigated. Paraffin-embedded tumour sections were stained with PD-L1 and hypoxia-inducible factor-1α (HIF-1α) antibodies. Overexpression was denoted by moderate-to-strong PD-L1 membrane staining in ≥5% of tumour cells and HIF-1α nuclear staining in ≥10% of tumour cells. The presence of driver mutations in the epidermal growth factor receptor (EGFR), Kirsten rat sarcoma viral oncogene homolog (KRAS), v-raf murine sarcoma viral oncogene homolog B (BRAF), telomerase reverse harscriptase gene (TERT), phosphoinositide 3-kinase catalytic alpha (PIK3CA), anaplastic lymphoma kinase (ALK), and ROS1 (ROS1 proto-oncogene receptor tyrosine kinase) genes were examined.ResultsThe overall frequencies of PD-L1 and HIF-1α overexpression and EGFR mutation were 70.5, 75.4, and 22.1%, respectively. High PD-L1 expression was significantly correlated with that of HIF-1α (p < 0.001) and tumour necrosis (p < 0.001). HIF-1α expression was associated with EGFR mutation (p = 0.015). Advanced stage and high PD-L1 expression were two independent risks for poor overall survival.ConclusionsHigh PD-L1 and HIF-1α co-expression was observed in PPCs compared with their expression in conventional non-small-cell lung carcinoma. The aggressive behaviour of PPC could be partially related to PD-L1–mediated immune escape and intratumoural hypoxia. High PD-L1 expression correlates with poor prognosis and may provide a rationale for the use of targeted immunotherapy in this subtype of high-grade PPC.



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The Current Status of SPECT or SPECT/CT in South Korea

Abstract

The first step to nuclear medicine in Korea started with introduction of the gamma camera in 1969. Although planar images with the gamma camera give important functional information, they have the limitations that result from 2-dimensional images. Single-photon emission computed tomography (SPECT) due to its 3-dimensional image acquisition is superior to earlier planar gamma imaging in image resolution and diagnostic accuracy. As demand for a hybrid functional and anatomical imaging device has increased, integrated SPECT/CT systems have been used. In Korea, SPECT/CT was for the first time installed in 2003. SPECT/CT can eliminate many possible pitfalls on SPECT-alone images, making better attenuation correction and thereby improving image quality. Therefore, SPECT/CT is clinically preferred in many hospitals in various aspects. More recently, additional SPECT/CT images taken from the region with equivocal uptake on planar images have been helpful in making precise interpretation as part of their clinical workup in postoperative thyroid cancer patients. SPECT and SPECT/CT have various advantages, but its clinical application has gradually decreased in recent few years. While some researchers investigated the myocardial blood flow with cardiac PET using F-18 FDG or N-13 ammonia, myocardial perfusion SPECT is, at present, the radionuclide imaging study of choice for the risk stratification and guiding therapy in the coronary artery disease patients in Korea. New diagnostic radiopharmaceuticals for AD have received increasing attention; nevertheless, brain SPECT will remain the most reliable modality evaluating cerebral perfusion.

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Pan-cancer analysis of copy number changes in programmed death-ligand 1 (PD-L1, CD274) - associations with gene expression, mutational load and survival

Abstract

Inhibition of the PD-L1 (CD274) – PD-1 axis has emerged as a powerful cancer therapy that prevents evasion of tumor cells from the immune system. While immunohistochemical detection of PD-L1 was introduced as a predictive biomarker with variable power, much less is known about copy number alterations (CNA) affecting PD-L1 and their associations with expression levels, mutational load and survival. To gain insight, we employed The Cancer Genome Atlas (TCGA) datasets to comprehensively analyze 22 major cancer types for PD-L1 CNAs. We observed a diverse landscape of PD-L1 CNAs, which affected focal regions, chromosome 9p or the entire chromosome 9. Deletions of PD-L1 were more frequent than gains (31% vs. 12%) with deletions being most prevalent in melanoma and non-small cell lung cancer. Copy number gains most frequently occurred in ovarian cancer, head and neck cancer, bladder cancer, cervical and endocervical cancer, sarcomas, and colorectal cancers. Fine-mapping of the genetic architecture revealed specific recurrently amplified and deleted regions across cancers with putative biological and clinical consequences. We noted a strong correlation between PD-L1 CNAs and mRNA expression levels for most cancers and found tumors with PD-L1 gains to harbor significantly higher mutational loads compared to non-amplified cases (median: 78 non-synonymous mutations vs. 40, p=7.1e-69). Moreover, we observed that, in general, both PD-L1 amplifications and deletions were associated with dismal prognosis.

In conclusion, PD-L1 CNAs, in particular PD-L1 copy number gains, represent frequent genetic alterations across many cancers, which influence PD-L1 expression levels, are associated with higher mutational loads, and may be exploitable as predictive biomarker for immunotherapy regimens. This article is protected by copyright. All rights reserved.

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Pre-diagnostic body size and breast cancer survival in the E3N cohort study

Abstract

Obesity has been associated with poor breast cancer prognosis, however most studies have focused on Body Mass Index (BMI) and few have considered the distribution of adipose tissue. We investigated associations between pre-diagnostic adiposity and breast cancer survival, considering BMI, waist and hip circumferences (WC and HC), and waist-to-hip ratio (WHR).

Analyses included 3,006 women from the French E3N prospective cohort study diagnosed with primary invasive breast cancer between 1995 and 2008. We investigated overall, breast cancer-specific, and disease-free survival, overall and according to stage, menopausal and hormonal status and year of diagnosis, using Cox proportional hazard models adjusted for tumor characteristics and lifestyle risk factors.

Women with a pre-diagnostic HC>100 cm were at increased risk of death from all causes (Hazard Ratio (HR)_>100vs<95cm=1.38, 95% Confidence Interval (CI)=1.02-1.86, P_trend=0.02) and from breast cancer (HR_>100vs<95cm=1.50, CI=1.03-2.17, P_trend=0.03), and of second invasive cancer event (HR_>100vs<95cm=1.36, CI=1.11-1.67, P_trend=0.002), compared to those with HC <95 cm. Associations were stronger after adjustment for BMI. BMI, WC and WHR were not associated with survival after breast cancer.

Our study underlines the importance of going beyond BMI when studying the association between adiposity and breast cancer survival. Further studies should be conducted to confirm our results on hip circumference. This article is protected by copyright. All rights reserved.

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Concurrent Lesions in Oesophagus: an Approach to Diagnosis with a Case Report

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Immunobiology and immunosurveillance in patients with intraductal papillary mucinous neoplasms (IPMNs), premalignant precursors of pancreatic adenocarcinomas

Abstract

Premalignant lesions for many cancers have been identified, and efforts are currently directed toward identification of antigens expressed on these lesions that would provide suitable targets for vaccines for cancer prevention. Intraductal papillary mucinous neoplasms (IPMNs) are premalignant pancreatic cysts of which a subset has the potential to progress to cancer. Currently, there are no validated predictive markers for progression to malignancy. We hypothesized that the presence or absence of immune surveillance of these lesions would be one such factor. Here we show that the tumor antigen MUC1, which is abnormally expressed on pancreatic cancer and is a target for cancer immunosurveillance, is also abnormally expressed on premalignant IPMN. We show that some IPMN patients make MUC1-specific IgG. Moreover, we show evidence of CD4 and CD8 T cell infiltration into IPMN areas of high dysplasia suggesting an ongoing immune response within the lesions. We also found, however, increased levels of circulating myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) in some IPMN patients as well as evidence of T cell exhaustion. Further studies correlating immunosurveillance or immunosuppression with IPMN progression to malignancy will help define the immune response as a biomarker of risk, leading potentially to a vaccine to boost spontaneous immunity and prevent progression to cancer.

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High glucose and insulin enhance uPA expression, ROS formation and invasiveness in breast cancer-derived cells

Abstract

Background

Accumulating evidence indicates that type 2 diabetes is associated with an increased risk to develop breast cancer. This risk has been attributed to hyperglycemia, hyperinsulinemia and chronic inflammation. As yet, however, the mechanisms underlying this association are poorly understood. Here, we studied the effect of high glucose and insulin on breast cancer-derived cell proliferation, migration, epithelial-mesenchymal transition (EMT) and invasiveness, as well as its relationship to reactive oxygen species (ROS) production and the plasminogen activation system.

Methods

MDA-MB-231 cell proliferation, migration and invasion were assessed using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT), scratch-wound and matrigel transwell assays, respectively. ROS production was determined using 2′ 7′-dichlorodihydrofluorescein diacetate. The expression of E-cadherin, vimentin, fibronectin, urokinase plasminogen activator (uPA), its receptor (uPAR) and its inhibitor (PAI-1) were assessed using qRT-PCR and/or Western blotting assays, respectively. uPA activity was determined using gel zymography.

Results

We found that high glucose stimulated MDA-MB-231 cell proliferation, migration and invasion, together with an increased expression of mesenchymal markers (i.e., vimentin and fibronectin). These effects were further enhanced by the simultaneous administration of insulin. In both cases, the invasion and growth responses were found to be associated with an increased expression of uPA, uPAR and PAI-1, as well as an increase in active uPA. An osmolality effect of high glucose was excluded by using mannitol at an equimolar concentration. We also found that all changes induced by high glucose and insulin were attenuated by the anti-oxidant N-acetylcysteine (NAC) and, thus, depended on ROS production.

Conclusions

From our data we conclude that hyperglycemia and hyperinsulinemia can promote breast cancer cell proliferation, migration and invasion. We found that these features were associated with increased expression of the mesenchymal markers vimentin and fibronectin, as well as increased uPA expression and activation through a mechanism mediated by ROS.

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Exosome-Transmitted lncARSR Promotes Sunitinib Resistance in Renal Cancer by Acting as a Competing Endogenous RNA

Publication date: Available online 21 April 2016
Source:Cancer Cell
Author(s): Le Qu, Jin Ding, Cheng Chen, Zhen-Jie Wu, Bing Liu, Yi Gao, Wei Chen, Feng Liu, Wen Sun, Xiao-Feng Li, Xue Wang, Yue Wang, Zhen-Yu Xu, Li Gao, Qing Yang, Bin Xu, Yao-Ming Li, Zi-Yu Fang, Zhi-Peng Xu, Yi Bao, Deng-Shuang Wu, Xiong Miao, Hai-Yang Sun, Ying-Hao Sun, Hong-Yang Wang, Lin-Hui Wang
Sunitinib resistance is a major challenge for advanced renal cell carcinoma (RCC). Understanding the underlying mechanisms and developing effective strategies against sunitinib resistance are highly desired in the clinic. Here we identified an lncRNA, named lncARSR (lncRNA Activated in RCC with Sunitinib Resistance), which correlated with clinically poor sunitinib response. lncARSR promoted sunitinib resistance via competitively binding miR-34/miR-449 to facilitate AXL and c-MET expression in RCC cells. Furthermore, bioactive lncARSR could be incorporated into exosomes and transmitted to sensitive cells, thus disseminating sunitinib resistance. Treatment of sunitinib-resistant RCC with locked nucleic acids targeting lncARSR or an AXL/c-MET inhibitor restored sunitinib response. Therefore, lncARSR may serve as a predictor and a potential therapeutic target for sunitinib resistance.

Graphical abstract

Teaser

Qu et al. identify lncARSR as a mediator of sunitinib resistance in renal cell carcinoma by acting as a competing endogenous RNA for miR-34 and miR-449, thereby increasing expression of their targets AXL and c-MET, and show that exosome-mediated transmission of lncARSR can confer resistance to sensitive cells.


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Immunobiology and immunosurveillance in patients with intraductal papillary mucinous neoplasms (IPMNs), premalignant precursors of pancreatic adenocarcinomas

Abstract

Premalignant lesions for many cancers have been identified, and efforts are currently directed toward identification of antigens expressed on these lesions that would provide suitable targets for vaccines for cancer prevention. Intraductal papillary mucinous neoplasms (IPMNs) are premalignant pancreatic cysts of which a subset has the potential to progress to cancer. Currently, there are no validated predictive markers for progression to malignancy. We hypothesized that the presence or absence of immune surveillance of these lesions would be one such factor. Here we show that the tumor antigen MUC1, which is abnormally expressed on pancreatic cancer and is a target for cancer immunosurveillance, is also abnormally expressed on premalignant IPMN. We show that some IPMN patients make MUC1-specific IgG. Moreover, we show evidence of CD4 and CD8 T cell infiltration into IPMN areas of high dysplasia suggesting an ongoing immune response within the lesions. We also found, however, increased levels of circulating myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) in some IPMN patients as well as evidence of T cell exhaustion. Further studies correlating immunosurveillance or immunosuppression with IPMN progression to malignancy will help define the immune response as a biomarker of risk, leading potentially to a vaccine to boost spontaneous immunity and prevent progression to cancer.

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The Effect of Implementing Gene Expression Classifier on Outcomes of Thyroid Nodules with Indeterminate Cytology

Abstract

Thyroid nodules are classified into six cytological categories under the Bethesda classification system. Two of these categories, atypical of undetermined significance (AUS) and suspicious for a follicular neoplasm (SFN), are further labeled as "indeterminate" diagnosis. Starting in June, 2012, Kansas University-Wichita Endocrine clinic implemented Afirma® Gene Expression Classifier (AGEC) to evaluate the need for surgical resection of thyroid nodules in patients with an indeterminate diagnosis. Electronic medical records of patients who underwent thyroid nodule fine-needle aspiration from 2004–2014 were reviewed. The aim of this study was to find whether implementing AGEC was associated with decreased surgical recommendation rate, decreased cost, and increased incidence of thyroid malignancy diagnosed by surgery in patients with indeterminate diagnosis. A total of 299 consecutive patients' charts were screened. Sixty-one (20 %) patients had an indeterminate diagnosis. Out of these, 27 (44 %) patients underwent evaluation before and 34 (56 %) patients underwent evaluation after AGEC implementation, respectively. Surgical recommendation for patients with indeterminate finding decreased from 81.5 to 50 % (p = 0.01) after AGEC implementation. Surgical pathology was read as malignant in 20 and 85.7 % (p < 0.01) of patients before and after AGEC implementation, respectively. Primary cost-benefit estimate showed implementing AGEC has saved $1048/patient in medical evaluation and initial management of patients with indeterminate diagnosis. AGEC implementation has decreased the number of surgical recommendations, has lowered financial burden, and has increased incidence of thyroid malignancy diagnosed by surgical pathology in patients with indeterminate diagnosis of thyroid nodules.

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A phase 0 clinical trial of novel candidate extended-release formulations of capecitabine

Abstract

Purpose

To examine the pharmacokinetic (PK) profile of several candidate extended-release (ER) formulations of capecitabine in patients.

Methods

In a phase 0 clinical study, PK profiles of several oral candidate ER formulations of capecitabine were compared to the PK profile of capecitabine after administration of the commercially available immediate-release (IR) tablet. A single dose of 1000 mg IR formulation (two 500 mg tablets) was administered on day 1, and a single dose of a 1000 mg candidate ER formulation of capecitabine (two 500 mg tablets) was administered on day 2. Candidate ER formulations of capecitabine differed with regard to the amount of the ER excipient (Kollidon^® SR) in tablet matrix (0–5 % w/w) and coating (0–12 mg/cm²).

Results

PK profiles of nine different candidate ER formulations were examined. The tablet coating seemed the main determinant for ER of capecitabine and tablet integrity. Average (±standard deviation) AUC_0–2h, relative to AUC_0–2h after oral administration of the IR tablet, were 43.3 % (±34.9 %) and 1.2 % (±1.2 %) for candidate ER formulations coated with 3 and 6 mg/cm², respectively. Corresponding AUC_0–last were 93.6 % (±40.2 %) and 44.0 % (±5.4 %).

Conclusion

Modulation of capecitabine release in patients can be accomplished by varying tablet coating content. Proof of principle was demonstrated for candidate ER formulations with coating content of 3 mg/cm².

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The Frequency of EGFR Mutation in Lung Adenocarcinoma and the Efficacy of Tyrosine Kinase Inhibitor Therapy in a Hungarian Cohort of Patients

Abstract

In the last decades new therapeutic drugs have been developed for the treatment of non-small cell lung cancer (NSCLC) patients. Tyrosine kinase inhibitors (TKIs) significantly increase the progression free survival (PFS) of patients with NSCLC carrying epidermal growth factor receptor (EGFR) mutations. This type of lung cancer occurs mainly among non-smoking women and Asian origin. However, the new ESMO guideline recommends EGFR mutation analysis in every patient with NSCLC, because in patients with activating EGFR mutation, TKIs should be considered as first line therapy. In our recent work, we analyzed data of patients with EGFR-mutant adenocarcinoma from January 2009. The number of patients investigated was 446, among them 44 cases were positive for EGFR mutation. The ratio of positive cases was 9.86 % that is lower than the average mutation rate in Europe and much lower than that found in Asia. The exon 19 deletion was detected in 61.4 % of the patients, while L858R point mutation in exon 21 was observed in 34.1 % of them. In one subject, both exon 19 and 21 mutations were present simultaneously. A rare mutation located in exon 21 was found in another patient. TKI therapy was conducted in 38 patients. The disease control rate by TKI therapy was 85.7 %; primary resistance was documented in five subjects. Non-smoking patients with EGFR mutant adenocarcinoma had the highest benefit from TKI treatment. Our data support the recommendation that EGFR mutation status should be defined in all cases of locally advanced or metastatic lung adenocarcinoma.

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[ 18 F]tetrafluoroborate as a PET tracer for the sodium/iodide symporter: the importance of specific activity

Abstract

Background

[¹⁸F]BF₄⁻, the first ¹⁸F-labelled PET imaging agent for the sodium/iodide symporter (NIS), was produced by isotopic exchange yielding a product with limited specific activity (SA, ca. 1 GBq/μmol) posing a risk of sub-optimal target-to-background ratios (TBR) in PET images due to saturation of NIS in vivo. We sought to quantify this risk and to develop a method of production of [¹⁸F]BF₄⁻ with higher SA.

Methods

A new radiosynthesis of [¹⁸F]BF₄⁻ was developed, involving reaction of [¹⁸F]F⁻ with boron trifluoride diethyl etherate under anhydrous conditions, guided by ¹¹B and ¹⁹F NMR studies of equilibria involving BF₄⁻ and BF₃. The SA of the product was determined by ion chromatography. The IC₅₀ of [¹⁹F]BF₄⁻ as an inhibitor of [¹⁸F]BF₄⁻ uptake was determined in vitro using HCT116-C19 human colon cancer cells expressing the human form of NIS (hNIS). The influence of [¹⁹F]BF₄⁻ dose on biodistribution in vivo was evaluated in normal mice by nanoPET imaging and ex vivo tissue counting.

Results

An IC₅₀ of 4.8 μΜ was found in vitro indicating a significant risk of in vivo NIS saturation at SA achieved by the isotopic exchange labelling method. In vivo thyroid and salivary gland uptake decreased significantly with [¹⁹F]BF₄⁻ doses above ca. 10 μg/kg. The new radiosynthesis gave high radiochemical purity (>99 %) and moderate yield (15 %) and improved SA (>5 GBq/μmol) from a starting activity of only 1.5 GBq.

Conclusions

[¹⁸F]BF₄⁻ produced at previously reported levels of SA (1 GBq/μmol) can lead to reduced uptake in NIS-expressing tissues in mice. This is much less likely in humans. The synthetic approach described provides an alternative for production of [¹⁸F]BF₄⁻ at higher SA with sufficient yield and without need for unusually high starting activity of [¹⁸F]fluoride, removing the risk of NIS saturation in vivo even in mice.

Trial registration

ISRCTN75827286.

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Breast and cervical cancer screening among Asian subgroups in the USA: estimates from the National Health Interview Survey, 2008, 2010, and 2013

Abstract

Purpose

This study describes variations in mammography and Pap test use across and within subgroups of Asian women in the USA.

Methods

Using data from the National Health Interview Survey (2008, 2010, and 2013), we calculated weighted proportions for selected Asian subgroups (Asian Indian, Chinese, Filipino, Other Asian) of women reporting mammography and Pap test use.

Results

The proportion of women aged 50–74 years who reported a mammogram within the past 2 years did not differ significantly across Asian subgroups. The proportion of women aged 21–65 years who received a Pap test within the past 3 years differed significantly across Asian subgroups, with lower proportions among Asian Indian, Chinese, and Other Asian women. Recent immigrants, those without a usual source of care, and women with public or no health insurance had lower proportions of breast and cervical cancer screening test use.

Conclusions

Patterns of mammography and Pap test use vary among subgroups of Asian women, by length of residency in the USA, insurance status, usual source of care, and type of cancer screening test. These findings highlight certain Asian subgroups continue to face significant barriers to cancer screening test use.

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Predictors of biospecimen donation in the Black Women’s Health Study

Abstract

Purpose

Although African-Americans experience higher cancer morbidity and mortality rates compared to their White counterparts, their participation in biospecimen research is lower than that of their white peers. This study investigated the prevalence and predictors of biospecimen donation in a large, cohort study of Black women.

Methods

The BWHS is a follow-up study of U.S. Black women aged 21–69 years enrolled through postal health questionnaires. Between January 2004 and December 2007, participants were sent a consent form with a postage-paid return envelope, and a mouthwash collection kit. Univariate and age- and educational status-adjusted logistic regression models were used to estimate the association of socio-demographic, lifestyle and medical factors with donation of biospecimens.

Results

Buccal cells with consent forms were obtained from 26,790 women, for a response rate of 51 %. The strongest predictors of biospecimen donation were age: response increased from 48.6 % among those aged <40 to 63.1 % among those aged 60 and older [RR 1.30 (95 % CI 1.27, 1.34)]; multivitamin use [RR (95 % CI) 1.32 (1.30, 1.34)]; physician visit in the previous 2 years [RR (95 % CI) 1.61 (1.58, 1.65)], and a history of breast [RR (95 % CI) 1.59 (1.56, 1.63)], colon [RR (95 % CI) 1.18 (1.16, 1.20)], and cervical [RR (95 % CI) 1.63 (1.60, 1.67)] cancer screening.

Conclusions

We found that 51 % of women in the geographically-dispersed Black Women's Health Study cohort were willing to provide mouthwash samples to be used for genetic analyses. The response in this study is encouraging given published findings of low overall participation rates of African-Americans in genetic studies.

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Targeted therapy combined with radiotherapy in non-small-cell lung cancer: a review of the Oncologic Group for the Study of Lung Cancer (Spanish Radiation Oncology Society)

Abstract

In recent years, major advances in our understanding of the molecular biology of lung cancer, together with significant improvements in radiotherapy technologies, have revolutionized the treatment of non-small cell lung cancer (NSCLC). This has led to the development of new therapies that target molecular mutations specific to each tumor type, acting on the cell surface antigens or intracellular signaling pathways, or directly affecting cell survival. At the same time, ablative dose radiotherapy can be delivered safely in the context of metastatic disease. In this article, the GOECP/SEOR (Oncological Group for Study of Lung Cancer/Spanish Society of Radiation Oncology) reviews the role of new targeted therapies used in combination with radiotherapy in patients with locally advanced (stage III) NSCLC and in patients with advanced, metastatic (stage IV) NSCLC.

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A superior method for cell block preparation for fine-needle aspiration biopsies

BACKGROUND

Cell block (CB) techniques for fine-needle aspiration biopsies (FNABs) vary. A direct comparison of CB techniques with statistical validation was performed to identify the best method.

METHODS

Three CB techniques were compared: 1) FNAB rinsed in saline and clotted with plasma and thrombin (SPT); 2) FNAB rinsed in formalin and clotted with HistoGel (HG); and 3) FNAB rinsed in formalin, centrifuged, and the pellet captured in a collodion bag (ColB). FNAB was performed on 35 random surgical specimens for smears and each CB technique. A randomized blinded review of hematoxylin and eosin-stained CB slides was performed and each case was scored on a scale of 1 to 3 for cellularity, preservation, and architecture and the overall best CB was identified. Significance was determined by the Mann-Whitney U test for nonparametric ordinal data.

RESULTS

The mean cellularity score was 1.71 for SPT (standard deviation [SD], 0.89), 1.68 for HG (SD, 0.67), and 3.0 for ColB (SD, 0). The mean preservation score was 1.31 for SPT (SD, 0.58), 1.54 for HG (SD, 0.70), and 2.91 for ColB (SD, 0.37). The mean architecture score was 1.45 for SPT (SD, 0.70), 1.43 for HG (SD, 0.60), and 2.71 for ColB (SD, 0.57). There was no statistical significance noted between SPT or HG when compared for each category. ColB was found to be superior to both SPT and HG when compared for each category (P<.05). The overall best CB was obtained with ColB in 33 of 35 cases (94%), with SPT proving superior in 1 of 35 cases (3%) and HG superior in 1 of 35 cases (3%).

CONCLUSIONS

ColB appears to be a superior technique for CB, yielding greater cellularity, preservation, and architecture in the majority of cases. Cancer Cytopathol 2016. © 2016 American Cancer Society.

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Pharmacokinetic drug interactions of the selective androgen receptor modulator GTx-024(Enobosarm) with itraconazole, rifampin, probenecid, celecoxib and rosuvastatin

Summary

GTx-024 (also known as enobosarm) is a first in class selective androgen receptor modulator being developed for diverse indications in oncology. Preclinical studies of GTx-024 supported the evaluation of several potential drug-drug interactions in a clinical setting. A series of open-label Phase I GTx-024 drug-drug interaction studies were designed to interrogate potential interactions with CYP3A4 inhibitor (itraconazole), a CYP3A4 inducer (rifampin), a pan-UGT inhibitor (probenecid), a CYP2C9 substrate (celecoxib) and a BCRP substrate (rosuvastatin). The plasma pharmacokinetics of GTx-024, its major metabolite (GTx-024 glucuronide), and each substrate were characterized in detail. Itraconazole administration had no effect on GTx-024 pharmacokinetics. Likewise, GTx-024 administration did not significantly change the pharmacokinetics of celecoxib or rosuvastatin. Rifampin administration had the largest impact on GTx-024 pharmacokinetics of any co-administered agent and reduced the maximal plasma concentration (C_max) by 23 % and the area under the curve (AUC_∞) by 43 %. Probenecid had a complex interaction with GTx-024 whereby both GTx-024 plasma levels and GTx-024 glucuronide plasma levels (AUC_∞) were increased by co-administration of the UGT inhibitor (50 and 112 %, respectively). Overall, GTx-024 was well tolerated and poses very little risk of generating clinically relevant drug-drug interactions.

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Pathology of emphysematous reticulitis in cattle: report of two cases and comparative overview of similar or identical conditions

Abstract

Inflammatory forestomach disorders other than those of viral, bacterial, mycotic, parasitic, chemical, or plant poisoning origin are uncommon in the bovine species. Spontaneous focal emphysematous lesions were grossly identified in the reticulum—the second part of the forestomach—of two adult Holstein-Friesian cattle (one 2-year-old steer, the other 3-year-old dairy cow). Both cattle, which appeared to be clinically normal without evidence of apparent forestomach dysfunction or other significant abnormalities on physical examination, were slaughtered conventionally for human consumption. At postmortem inspection of these two cattle, the reticulum wall showed focal spongy areas due to the occurrence of numerous minute gas bubbles (<1.0 mm in diameter). On histopathology, this emphysematous lesion was characterized by the presence of multicystic emphysematous lymphangiectasis in the submucosa. Affected lymphatics were prominently inflamed, being infiltrated to a significant degree with eosinophils and granulomas consisting of macrophages and multinucleated foreign-body giant cells in the lumen. Submucosal connective tissues surrounding the areas of lesional lymphatics exhibited varying degrees of cellular infiltrates, including eosinophils, mast cells, macrophages, plasma cells, and lymphocytes. Additionally, edema, hemorrhage, fibrin-clot formation, or collagen fiber deposition was observed throughout the lesional submucosa. There was no evidence of bacterial, mycotic, protozoal, or parasitic infection elsewhere in the lesions. Although the precise cause and pathogenesis of this emphysematous reticulitis remain unknown, there was the likelihood that a hypersensitivity reaction might have played a certain role in the development and progression of the lesions. Histopathological features of the reticulum were consistent in many respects with those documented previously in a bovine condition referred to as emphysematous eosinophilic lymphangitis in the ruminal submucosa. From the viewpoint of comparative pathology, this article provides a brief overview of similar or identical conditions involving other organs, which have previously been described in human beings and animals.

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Front-to-back & dabbing wiping behaviour post-toilet associated with anal neoplasia & HR-HPV carriage in women with previous HPV-mediated gynaecological neoplasia

Publication date: June 2016
Source:Cancer Epidemiology, Volume 42
Author(s): Steve Simpson, Penny Blomfield, Alyssa Cornall, Sepehr N. Tabrizi, Leigh Blizzard, Richard Turner
BackgroundAnal cancer is a human papillomavirus (HPV)-mediated neoplasia of the anal squamous epithelium. Anal cancer is much more common among women, particularly those with a previous high-grade gynaecological neoplasia.MethodsCross-sectional study of women with a previous HPV-mediated gynaecological neoplasia in Tasmania, Australia. Women presenting for follow-up gynaecological care had anal swab samples taken for anal cytology by Hologic Liquid ThinPrep, followed by HPV genotyping. Women with abnormal anal cytology were invited for high-resolution anoscopy. Potential risk factors, including post-toilet wiping behaviours, were queried by questionnaire while clinical covariates were extracted from medical records. Covariates of anal outcomes evaluated by log-binomial and log-multinomial regression.ResultsFrom 163 women enrolled in the study, 65 (39.9%) had abnormal cytology, with 46 (28.2%) being high-grade. Of the 50 women with abnormal anal cytology having high-resolution anoscopy, 32 (64.0%) had abnormal histology with 13 (26.0%) being high-grade. Of the 123 women tested for HR-HPV DNA, 48 (39.0%) had HR-HPV detected, the most common genotypes being 16 and 51 (14/123, 11.4% for both).In addition to some known anal cancer risk factors, we found front-to-back wiping was associated with significantly increased (Prevalence ratio (PR) range: 1.99–3.60) prevalence of cytological and histological abnormality and HR-HPV carriage/co-carriage, while dabbing post-toilet was significantly associated with decreased prevalences (PR range: 0.50–0.62).ConclusionsPost-toilet wiping behaviours were significantly associated with the prevalence of anal cytological, histological and HR-HPV carriage outcomes. This suggests a biologically plausible mechanism for HR-HPV introduction and the higher frequencies of anal neoplasia in women.



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Recurrences in stage II rectal carcinoma after curative resection alone: from the viewpoint of angiogenesis

Abstract

Background

Angiogenesis plays a pivotal role in malignant tumor progression. The count of blood microvessels of the tumor has been recognized as an indicator of malignant potential of the tumors and provides the ability to predict tumors recurrence. The role endoglin in the Dukes B rectal cancer is still unexplored. The aims of this study were to examine immunohistochemical expression of endoglin in resected rectal cancer and investigate the relationship of tumor recurrence and other clinicopathological variables to the endoglin-assessed microvessel density of the tumor tissue and distal resection margins.

Methods

The study included 95 primary rectal adenocarcinomas, corresponding to 95 distal and 95 proximal resection margin specimens from surgical resection samples. Tumor specimens were paraffin embedded, and immunohistochemical staining for the CD105 endothelial antigen was performed to count CD105-MVD. For exact measurement of the CD105-MVD used, a computer-integrated system Alphelys Spot Browser 2 was used.

Results

The MVD was significantly higher in the tumor samples compared with the distal resection margins (p < 0.0001) and the proximal resection margins (p < 0.0001). There was no significant difference in the MVD between distal and proximal resection margins (p = 0.147). The type of surgical resection was a significant factor for determining the recurrence of tumors (p = 0.0104). There was no significant effect of patients' age, gender, tumor location, grade of differentiation, histological tumor type, and the size and depth of tumor invasion on the recurrence of the tumor. The recurrence rate was significantly higher in the low CD105-MVD group of patients than in the high CD105-MVD group of patients (log rank test, p = 0.0406). Result of the multivariate analysis showed that the type of surgery (p = 0.0086), MVD tumors (p = 0.0385), and MVD of proximal resection margin (p = 0.0218) were the independent prognostic factors for the recurrent tumors.

Conclusions

CD105-assessed MVD could help to identify patients with more aggressive disease and increased risk of developing tumor recurrence after surgical treatment in stage II rectal cancer (RC).

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Immunobiology and immunosurveillance in patients with intraductal papillary mucinous neoplasms (IPMNs) premalignant precursors of pancreatic adenocarcinomas

Abstract

Premalignant lesions for many cancers have been identified, and efforts are currently directed toward identification of antigens expressed on these lesions that would provide suitable targets for vaccines for cancer prevention. Intraductal papillary mucinous neoplasms (IPMNs) are premalignant pancreatic cysts of which a subset has the potential to progress to cancer. Currently, there are no validated predictive markers for progression to malignancy. We hypothesized that the presence or absence of immune surveillance of these lesions would be one such factor. Here we show that the tumor antigen MUC1, which is abnormally expressed on pancreatic cancer and is a target for cancer immunosurveillance, is also abnormally expressed on premalignant IPMN. We show that some IPMN patients make MUC1-specific IgG. Moreover, we show evidence of CD4 and CD8 T cell infiltration into IPMN areas of high dysplasia suggesting an ongoing immune response within the lesions. We also found, however, increased levels of circulating myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) in some IPMN patients as well as evidence of T cell exhaustion. Further studies correlating immunosurveillance or immunosuppression with IPMN progression to malignancy will help define the immune response as a biomarker of risk, leading potentially to a vaccine to boost spontaneous immunity and prevent progression to cancer.

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Immunobiology and immunosurveillance in patients with intraductal papillary mucinous neoplasms (IPMNs) premalignant precursors of pancreatic adenocarcinomas

Abstract

Premalignant lesions for many cancers have been identified, and efforts are currently directed toward identification of antigens expressed on these lesions that would provide suitable targets for vaccines for cancer prevention. Intraductal papillary mucinous neoplasms (IPMNs) are premalignant pancreatic cysts of which a subset has the potential to progress to cancer. Currently, there are no validated predictive markers for progression to malignancy. We hypothesized that the presence or absence of immune surveillance of these lesions would be one such factor. Here we show that the tumor antigen MUC1, which is abnormally expressed on pancreatic cancer and is a target for cancer immunosurveillance, is also abnormally expressed on premalignant IPMN. We show that some IPMN patients make MUC1-specific IgG. Moreover, we show evidence of CD4 and CD8 T cell infiltration into IPMN areas of high dysplasia suggesting an ongoing immune response within the lesions. We also found, however, increased levels of circulating myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) in some IPMN patients as well as evidence of T cell exhaustion. Further studies correlating immunosurveillance or immunosuppression with IPMN progression to malignancy will help define the immune response as a biomarker of risk, leading potentially to a vaccine to boost spontaneous immunity and prevent progression to cancer.

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Enhancement of anti-tumor effects of 5-fluorouracil on hepatocellular carcinoma by low-intensity ultrasound

Abstract

Background

Hepatocellular carcinoma (HCC) accounts for 75 % of liver cancers and is the second most lethal cancer, associated with its multiple etiologies, poor prognosis and resistance to chemotherapy drugs. Chemotherapy treatment on HCC suffers low efficacy of drug uptake and can produce a range of side effects. Here we report an investigation on the effect of a combined treatment on human hepatocellular carcinoma BEL-7402 cells using low-intensity ultrasound (US) and 5-fluorouracil (5-FU).

Methods

The uptake of 5-FU was measured by the high-performance liquid chromatography (HPLC). DNA damage was detected by the comet assay. MTT assay was used to examine cell viability. Intracellular reactive oxygen species (ROS) and mitochondrial membrane potential (Δψm) were respectively detected by the fluorescent probes DCFH-DA or JC-1. Endogenous apoptosis-associated proteins were analyzed by the western blot and immunohistochemistry. Histopathological changes were evaluated by the hematoxylin and eosin (H&E) staining. Cell apoptosis was evaluated by the TUNEL and flow cytometry assays. Cell proliferation was measured using the immunohistochemical staining of PCNA.

Results

Our results showed that low-intensity US (1.1 MHz, 1.0 W/cm², 10 % duty cycle) significantly enhanced the uptake of 5-FU, 5-FU-mediated DNA damage and reactive oxygen species (ROS) generation. The increased ROS production up-regulated the p53 protein level, which led to the up-regulation of Bax and down-regulation of Bcl-2. The enhancement of ROS generation and the activation of the apoptosis-associated proteins further triggered the collapse of mitochondrial membrane potential, released cytochrome c from mitochondria into cytosol and activated the mitochondria-caspase pathway, and cell apoptosis. Such enhanced effects could be partially blocked by the ROS scavenger N-acetylcysteine (NAC). Overall, low-intensity US combined with 5-FU led to an effective inhibition of tumor growth and prolonged overall survival of BEL-7402 HCC-bearing nude mice by more than 15 % compared with 5-FU treatment alone.

Conclusions

Our results showed that low-intensity ultrasound combined with 5-FU produced much enhanced synergistic anti-tumor effects via enhanced ROS production in treating HCC.

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Biological evaluation of antibody-maytansinoid conjugates as a strategy of RON targeted drug delivery for treatment of non-small cell lung cancer

Abstract

Background

Aberrant expression of the RON receptor tyrosine kinase, a member of the MET proto-oncogene family, in breast cancer and non-small cell lung cancer (NSCLC) has therapeutic implication. Here we evaluated the efficacy of a novel anti-RON antibody-drug maytansinoid conjugate Zt/g4-DM1 for treatment of breast and NSCLC xenograft tumors in mouse models and explored a treatment strategy by combination of Zt/g4-DM1 with chemotherapeutics to achieve the maximal therapeutic activity.

Methods

Mouse monoclonal antibody Zt/g4 (IgG1a/κ) specific to human RON was conjugated to DM1 via thioether linkage to form Zt/g4-DM1 with a drug-antibody ratio of 4:1. Several breast cancer and NSCLC cell lines, expressing different levels of RON, were used as the model. Immunofluorescence was used to determine Zt/g4-induced RON internalization. Flow cytometric analysis and cell viability assay were used to determine the effect of Zt-g4-DM1 on cell cycle and death. Mouse xenograft NSCLC models were used in vivo to determine the therapeutic efficacy of Zt/g4-DM1 alone or in combination with chemotherapeutics.

Results

In vitro, Zt/g4 treatment of breast cancer and NSCLC cells rapidly induced cell surface RON internalization, which results in intracellular delivery of DM1 sufficient to arrest cell cycle at G2/M phase, reduce cell viability, and cause massive cell death. In mouse tumor xenograft models, Zt/g4-DM1 at 20 mg/kg in a Q12 × 2 regimen effectively blocked breast cancer and NSCLC cell- mediated tumor growth. More than 95 % inhibition of tumor growth among three tumor xenograft models tested was achieved according to the measured tumor volume. The minimal dose to balance the tumor growth and inhibition (tumoristatic concentration) was established at 2.02 mg/kg for H2228, 1.94 mg/kg for H358 cell, and 6.25 mg/kg for T-47D cell-mediated xenograft tumors.

Conclusion

Zt/g4 is highly effective in RON-directed drug delivery for targeted inhibition of NSCLC cell-derived tumor growth in mouse xenograft models. This work provides the basis for clinical development of humanized Zt/g4-DM1 for potential cancer therapy in the future.

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Phase I study of safety and tolerability of sunitinib in combination with sirolimus in patients with refractory solid malignancies and determination of VEGF (VEGF-A) and soluble VEGF-R2 (sVEGFR2) in plasma

Abstract

Purpose

Sirolimus, an oral mTOR inhibitor, may complement the anti-angiogenic and anti-tumor activity of sunitinib, an oral small molecule inhibitor of multiple receptor tyrosine kinases, by vertical disruption of vascular epithelial growth factor receptor (VEGFR) signaling, by reducing the compensatory production of VEGF in sunitinib-treated patients and also by directly inhibiting tumor cell proliferation. We conducted this phase 1 study to investigate the maximum tolerated dose (MTD) for this combination of sunitinib and sirolimus in humans.

Patients and methods

Sunitinib was given at 50 mg daily × 28 every 6 weeks. The first cohort received sunitinib alone for cycle 1 (50 mg daily for 2 weeks followed by 2 weeks off) and received sunitinib at standard dose 50 mg daily for 4 weeks followed by 2 weeks off in combination with sirolimus 4 mg weekly; this dose and schedule were further investigated in second cohort. The third cohort received decreased dose of sunitinib at 37.5 mg daily for 4 weeks followed by 2 weeks off in combination with sirolimus at 4 mg weekly. Sirolimus dose was escalated to 8 mg weekly in fourth cohort.

Results

Eighteen patients with ECOG PS of 0 or 1 were enrolled, median age 57 years (range 24–76), M:F ratio: 11:7. Median number of prior treatments is 2 (range 0–5); six patients had no prior systemic therapy. Half of patients from the first two cohorts required dose reduction or early discontinuation of treatment; therefore, sunitinib dose was decreased to 37.5 mg daily in third and fourth cohort. In third and fourth cohort, one-third of patients required dose modification during cycle 1 or cycle 2. Multiple patients had significant toxicities including fatigue and hand–foot syndrome. One patient developed interstitial pneumonitis, and one patient died suddenly on day 8 due to progressive disease. There were six patients who tolerated four or more cycles. Among these six patients, two patients with renal cell carcinoma (RCC) achieved partial response; one subsequently underwent surgical resection of residual renal mass and lymph node dissection and achieved complete response afterward. One with metastatic melanoma also achieved complete response after metastatectomy. There was no apparent pharmacokinetic interaction between sunitinib and sirolimus. 4 mg weekly sirolimus did not reduce the sunitinib-induced circulating VEGF production but stimulated more VEGF production through some unknown compensatory mechanism.

Conclusion

Toxicity precluded dose escalation of weekly sirolimus in combination with a standard sunitinib dose/schedule. These results suggest caution when combining targeted agents lacking specificity for tumor signaling or vasculature.

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A phase 0 clinical trial of novel candidate extended-release formulations of capecitabine

Abstract

Purpose

To examine the pharmacokinetic (PK) profile of several candidate extended-release (ER) formulations of capecitabine in patients.

Methods

In a phase 0 clinical study, PK profiles of several oral candidate ER formulations of capecitabine were compared to the PK profile of capecitabine after administration of the commercially available immediate-release (IR) tablet. A single dose of 1000 mg IR formulation (two 500 mg tablets) was administered on day 1, and a single dose of a 1000 mg candidate ER formulation of capecitabine (two 500 mg tablets) was administered on day 2. Candidate ER formulations of capecitabine differed with regard to the amount of the ER excipient (Kollidon^® SR) in tablet matrix (0–5 % w/w) and coating (0–12 mg/cm²).

Results

PK profiles of nine different candidate ER formulations were examined. The tablet coating seemed the main determinant for ER of capecitabine and tablet integrity. Average (±standard deviation) AUC_0–2h, relative to AUC_0–2h after oral administration of the IR tablet, were 43.3 % (±34.9 %) and 1.2 % (±1.2 %) for candidate ER formulations coated with 3 and 6 mg/cm², respectively. Corresponding AUC_0–last were 93.6 % (±40.2 %) and 44.0 % (±5.4 %).

Conclusion

Modulation of capecitabine release in patients can be accomplished by varying tablet coating content. Proof of principle was demonstrated for candidate ER formulations with coating content of 3 mg/cm².

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The combination of HLA - B15:01 and DRB115:01 is associated with gemcitabine plus erlotinib-induced interstitial lung disease in patients with advanced pancreatic cancer

Abstract

Purpose

In a phase III study of gemcitabine plus erlotinib for advanced pancreatic cancer conducted in Canada, the incidence of interstitial lung disease (ILD) was 3.5 %. However, the incidence of ILD was reported as high as 8.5 % in a Japanese phase II study. These results suggest the influence of ethnic factors in the association of the use of gemcitabine plus erlotinib with the incidence of ILD. Here, we conducted a prospective study to analyze the relationship between human leukocyte antigen (HLA) alleles and ILD in Japanese patients with advanced pancreatic cancer receiving gemcitabine plus erlotinib.

Methods

Patients were treated with gemcitabine (1000 mg/m²; administered by intravenous infusion on days 1, 8, and 15 every 4 weeks) and erlotinib (given orally at 100 mg/day). We compared the frequencies of HLA alleles in patients who did and did not develop ILD.

Results

A total of 57 patients were treated, and 4 patients (7.0 %) developed ILD. The combination of HLA-B*15:01 and DRB1*15:01 was observed in 2 of 4 patients (50 %) with ILD and in only 1 of 53 patients without ILD (2 %) resulting in odds ratio of 52.0 (95 % CI 3.2–842.5; p = 0.011).

Conclusion

These results suggest that the combination of HLA-B*15:01 and DRB1*15:01 is associated with ILD in Japanese patients with advanced pancreatic cancer receiving gemcitabine plus erlotinib.

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A meta-analysis identifies ERCC1 gene polymorphism as a predictor of better patient response to treatment with radiochemotherapy

Abstract

Purpose

This meta-analysis aimed to evaluate whether an association exists between the ERCC1 rs11615 (C>T) polymorphism and patient response to platinum-based chemotherapy and radiation-based chemotherapy.

Methods

Publications were selected from PubMed and MEDLINE. A meta-analysis was conducted to determine the association between genetic polymorphisms and response to platinum-based chemotherapy and radiation-based chemotherapy by checking the odds ratios (ORs) and 95 % confidence intervals (CIs).

Results

In our overall analysis, the ERCC1 rs11615 (C>T) polymorphism was not associated with response to platinum-based chemotherapy in five comparison models. In the subgroup analyses by ethnicity, the ERCC1 rs11615 (C>T) polymorphism was shown to be significantly associated with objective response in Caucasian patients treated with platinum-based chemotherapy in the recessive model (TT vs. CT/CC: OR 0.696, 95 % CI 0.508–0.954, heterogeneity = 0.330), but the association was not observed in the Asian population. The C allele was significantly associated with better response to radiochemotherapy in the recessive model comparison (TT vs. CC/CT: OR 0.724, 95 % CI 0.585–0.869, heterogeneity = 0.008). Subgroup analysis by cancer type revealed that the C allele of ERCC1 rs11615 predicted a better response in esophageal cancers in two comparison models (T vs. C: OR 0.756, 95 % CI 0.648–0.880, heterogeneity = 0.653; TT vs. TC/CC: OR 0.457, 95 % CI 0.306–0.684, heterogeneity = 0.723). Stratified analysis by ethnicity showed a better response in Caucasians in allelic comparison model (T vs. C: OR 0.895, 95 % CI 0.819–0.977, heterogeneity = 0.095).

Conclusion

Together, our results suggest that the ERCC1 rs11615 (C>T) polymorphism was associated with therapeutic response in Caucasian patients and C allele of ERCC1 rs11615 could represent a genetic molecular marker to predict better patient response to radiochemotherapy in recessive model. However, larger prospective randomized trials will be required.

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Tanshinone I induces apoptosis and pro-survival autophagy in gastric cancers

Abstract

Purpose

To investigate the occurrence of apoptosis and autophagy on human gastric cancer cells after treatment by Tanshinone I, as well as the relationship between them.

Methods

BGC823 and SGC7901 cells were treated with Tanshinone I; the cell proliferation was measured using CCK-8 and clone formation assay; and the expression of apoptosis- and autophagy-associated proteins was detected by Western blot. Autophagic vacuoles in cells were observed with LC3 dyeing using confocal fluorescent microscopy, and apoptotic cells were detected via flow cytometry. Bcl-2 was overexpressed in gastric cells treated with Tanshinone I or not, and autophagy relative protein was investigated; the interaction between Beclin-1 and Bcl-2 was detected by immunoprecipitation. Cell apoptosis was detected when autophagy was inhibited by ATG7-siRNA. Tumor growth was assessed by subcutaneous inoculation of cells into BALB/c nude mice.

Results

Tanshinone I inhibited the proliferation of BGC823 and SGC7901 cells, and induced cell apoptosis by inhibiting anti-apoptosis protein Bcl-2. Tanshinone I also increased the conversion of LC3I to LC3II and triggered autophagosome formation, without changing the expression of Beclin-1. However, the Beclin-1 VPS34 complexes were increased after Tanshinone I treatment via inhibiting Bcl-2 expression. Moreover, disturbing autophagy by knockdown of ATG7 expression contributed to Tanshinone I-induced apoptosis. In vivo assay showed that combination with autophagy inhibitor chloroquine in nude mice bearing BGC823 xenograft significantly augmented the antitumor effect of Tanshinone I.

Conclusions

Tanshinone I induced apoptosis and pro-survival autophagy via inhibiting Bcl-2 expression on gastric cancer, and the combination of chloroquine and Tanshinone I could inhibit tumor growth more efficiently than monotherapy, which might be considered as an effective strategy for the treatment for gastric cancer.

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MicroRNA: a connecting road between apoptosis and cholesterol metabolism

Abstract

Resistance to apoptosis leads to tumorigenesis and failure of anti-cancer therapy. Recent studies also highlight abrogated lipid/cholesterol metabolism as one of the root causes of cancer that can lead to metastatic transformations. Cancer cells are dependent on tremendous supply of cellular cholesterol for the formation of new membranes and continuation of cell signaling. Cholesterol homeostasis network tightly regulates this metabolic need of cancer cells on cholesterol and other lipids. Genetic landscape is also shared between apoptosis and cholesterol metabolism. MicroRNAs (miRNAs) are the new fine tuners of signaling pathways and cellular processes and are known for their ability to post-transcriptionally repress gene expression in a targeted manner. This review summarizes the current knowledge about the cross talk between apoptosis and cholesterol metabolism via miRNAs. In addition, we also emphasize herein recent therapeutic modulations of specific miRNAs and their promising potential for the treatment of deadly diseases including cancer and cholesterol related pathologies. Understanding of the impact of miRNA-based regulation of apoptosis and metabolic processes is still at its dawn and needs further research for the development of future miRNA-based therapies. As both these physiological processes affect cellular homeostasis, we believe that this comprehensive summary of miRNAs modulating both apoptosis and cholesterol metabolism will open uncharted territory for scientific exploration and will provide the foundation for discovering novel drug targets for cancer and metabolic diseases.

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Establishing a national paediatric radiology global outreach group recent developments in the British Society of Paediatric Radiology

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Cancers Vol. 8 Pages 46: A Phase I Study of Unimolecular Pentavalent (Globo-H-GM2-sTn-TF-Tn) Immunization of Patients with Epithelial Ovarian Fallopian Tube or Peritoneal Cancer in First Remission

We conducted a phase I study in ovarian cancer patients to evaluate the safety and immunogenicity of a synthetic unimolecular pentavalent carbohydrate vaccine (Globo-H, GM2, sTn, TF, and Tn) supported on a peptide backbone, conjugated to keyhole limpet haemocyanin (KLH), and mixed with immunological adjuvant QS-21. Twenty-four advanced-stage, poor-risk, first-remission ovarian cancer patients were enrolled from January 2011–Septermber 2013. Three dose levels were planned (25, 50, 100 mcg) with three cohorts of six patients each, with an additional 6-patient expansion cohort at the MTD. ELISA serologic IgM and IgG responses for each antigen was defined as positive response if antibody titers were ≥1:80 over the respective patient's pre-vaccination serum. The study would be considered positive if at least four of 12 patients treated at the MTD showed immune responses for at least three of the five antigens. Twenty-four patients (median age, 54 years [range, 36–68]) were included in the safety analysis. Histology was high-grade serous in 22 patients (92%); 18 had stage III and six stage IV disease. The vaccine was well-tolerated at all doses, with no DLTs. At the highest treated dose, IgG and/or IgM responses were recorded against ≥3 antigens in 9/12 patients (75%), ≥4 in 7/12 (58%), and 5 in 3/12 (25%). With a median follow-up of 19 months (range, 2–39), 20 patients (83%) recurred and six (25%) died. The unimolecular pentavalent vaccine construct was shown to be safe and immunogenic. Such a construct greatly simplifies regulatory requirements and manufacturing, facilitates scalability, and provides adaptability.

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Nevus count associations with pigmentary phenotype histopathological melanoma characteristics and survival from melanoma

Abstract

Although nevus count is an established risk factor for melanoma, relationships between nevus number and patient and tumor characteristics have not been well studied and the influence of nevus count on melanoma-specific survival is equivocal. Using data from the Genes, Environment, and Melanoma (GEM) study, a large population-based study of primary cutaneous melanoma, we evaluated associations between number of nevi and patient features, including sun-sensitivity summarized in a phenotypic index, and tumor characteristics, and we assessed the association of nevus count with melanoma-specific survival. Higher nevus counts were independently and positively associated with male gender and younger age at diagnosis and inversely associated with lentigo maligna histology. We observed a borderline significant trend of poorer melanoma-specific survival with increasing quartile of nevus count, but little or no association between number of nevi and pigmentary phenotypic characteristics or prognostic tumor features. This article is protected by copyright. All rights reserved.

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Stillbirth and neonatal death among female cancer survivors: A national cohort study

Abstract

The number of cancer survivors continues to increase worldwide. Many of these survivors have had children of their own. It is less well-known whether radiation therapy or chemotherapy could affect the risk of stillbirth and neonatal death for these children. To explore this research questions, we identified all women diagnosed with cancer between 1958 and 2012 from the Swedish Cancer Register and they were further linked to the Swedish Medical Birth Register to identify their subsequent child birth between 1973 and 2012. Multivariate logistic regression was used to estimate odds ratios and 95% confidence intervals for the association between stillbirth and neonatal death and maternal cancer diagnosis. As compared to the children without maternal cancer, the risk of stillbirth was significantly higher among children of female cancer survivors born within three years after cancer diagnosis with an OR of 1.92 (95%CI 1.03-3.57). The incidence of neonatal death did not show a significant change. For women with more than one pregnancy after cancer diagnosis, the risk of stillbirth and neonatal death was lower for the second child birth compared to the first child birth. Our study suggested that the risk of stillbirth was negatively associated with the time after cancer diagnosis, providing evidence that the adverse effect associated with cancer treatment may diminish with time. This article is protected by copyright. All rights reserved.

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Antitumoural activity of a cytotoxic peptide of Lactobacillus casei peptidoglycan and its interaction with mitochondrial-bound hexokinase.

In a previous study, we reported the cytotoxic activity against various tumour cells of the peptidoglycan of Lactobacillus casei. To isolate the most active components, we performed column-chromatography separation of the peptidoglycan complex and tested the related fractions for their cytotoxic activity. The most active fractions were then lyophilized and the residue was analysed by gas chromatography for its amino acid content and composition. On the basis of the known chemical formula of the basic peptidic component of the peptidoglycan complex of L. casei, a peptide was then synthesized [Europ. (CH-DE-FR-GB) Patent number 1217005; IT number 01320177] and its cytotoxicity was tested against tumoural and normal cells. The synthetic peptide was found to impair the entire metabolism of cultured tumour cells and to restore the apoptotic process. By contrast, normal cells appeared to be stimulated rather than inhibited by the peptide, whereas primary mouse embryo fibroblasts behaved similarly to tumour cells. On the basis of these results, L. casei peptidoglycan fragments and their constituent basic peptide might be applicable as potent antitumour agents. 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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Analysis of the Relationship Between Response to Chemotherapy and Response to Radiation Therapy in Patients With Non-Small Cell Lung Cancer Receiving Sequential Treatment.

Objectives: We examine whether induction chemotherapy response predicts thoracic radiotherapy response in locally advanced or oligometastatic non-small cell lung cancer. Materials and Methods: Between January 2001 to August 2010, 25 consecutive patients were identified who received systemic dose chemotherapy followed by definitive thoracic radiotherapy alone. All patients had measurable disease after chemotherapy that was evaluable for response to radiotherapy. Response to each modality was scored by RECIST as stable disease (SD), progressive disease (PD), partial response (PR), or complete response (CR). Results: Patients had adenocarcinoma (n=13), squamous cell carcinoma (n=8), or other histologies (n=4). They had stage IIIA (n=6), IIIB (n=14), and IV (n=5) disease. Patients received 2 to 6 cycles (median 4) of platinum-based chemotherapy followed by radiotherapy (median 66.6/1.8 Gy [range 50 to 84 Gy]). Median time between chemotherapy end and radiotherapy start was 6.7 weeks (range, 1.6 to 53.4 wk). Twelve patients responded to chemotherapy (all were PRs) and 13 did not (SD+PD). Fifteen patients responded to radiotherapy (7 CR, 8 PR) and 10 did not (SD+PD). Of the 12 patients who responded to chemotherapy, 8 also responded to radiotherapy (4 CR, 4 PR). Of the 13 chemotherapy nonresponders, 7 responded to radiotherapy (3 CR, 4 PR). [chi]2 analysis did not find any association between chemotherapy and radiotherapy response (P=0.513). Regression analysis also failed to identify any correlation between chemotherapy and radiotherapy response (r2=0.008). Conclusions: This study suggests that response to chemotherapy does not predict response to radiotherapy in locally advanced or oligometastatic non-small cell lung cancer. Lack of response to chemotherapy, therefore, should not preclude treatment with definitive radiotherapy. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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High-dose chemotherapy and autologous stem cell transplant compared with conventional chemotherapy for consolidation in newly diagnosed primary CNS lymphomaa randomized phase III trial (MATRix)

Abstract

Background

Primary central nervous system lymphoma (PCNSL) is a highly aggressive Non-Hodgkin lymphoma (NHL) with rising incidence over the past 30 years in immunocompetent patients. Although outcomes have improved, PCNSL is still associated with inferior prognosis compared to systemic NHL. Many questions regarding the optimal therapeutic approach remain unanswered.

Methods/Design

This is a randomized, open-label, international phase III trial with two parallel arms. We will recruit 250 patients with newly diagnosed PCNSL from approximately 35 centers within the networks of the German Cooperative PCNSL study group and the International Extranodal Lymphoma Study Group. All enrolled patients will undergo induction chemotherapy consisting of 4 cycles of rituximab 375 mg/m²/d (days 0 & 5), methotrexate 3.5 g/m² (d1), cytarabine 2 × 2 g/m²/d (d2-3), and thiotepa 30 mg/m² (d4) every 21 days. All patients will undergo stem-cell harvest after the second cycle. After 4 cycles of induction chemotherapy, patients achieving partial or complete response will be centrally randomized to 2 different consolidation treatments: (A) conventional-dose immuno chemotherapy with rituximab 375 mg/m² (d0), dexamethasone 40 mg/d (d1-3), etoposide 100 mg/m²/d (d1-3), ifosfamide 1500 mg/m²/d (d1-3) and carboplatin 300 mg/m² (d1) (R-DeVIC) or (B) high-dose chemotherapy with BCNU (or busulfan) and thiotepa followed by autologous stem cell transplantation (HCT-ASCT). The objective is to demonstrate superiority of HCT-ASCT compared to R-DeVIC with respect to progression-free survival (PFS, primary endpoint). Secondary endpoints include overall survival (OS), treatment response and treatment-related morbidities. Minimal follow-up after treatment completion is 24 months.

Discussion

The rationale for consolidation treatment in PCNSL is to eliminate residual lymphoma cells and to decrease the risk for relapse. This can be achieved by agents crossing the blood brain barrier either applied at conventional doses or at high doses requiring autologous stem cell support. HCT-ASCT has been shown to be feasible and highly effective in patients with newly-diagnosed PCNSL. However, it is unclear whether HCT-ASCT is really superior compared to conventional-dose chemotherapy after an intensified antimetabolites-based immunochemotherapy in patients with newly-diagnosed PCNSL. To answer this question, we designed this investigator initiated randomized phase III trial.

Trial registration

German clinical trials registry DRKS00005503 registered 22 April 2014 and ClinicalTrials.gov NCT02531841 registered 24 August 2015.

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Relevance of internal time and circadian robustness for cancer patients

Abstract

Background

Adequate circadian timing of cancer treatment schedules (chronotherapy) can enhance tolerance and efficacy several-fold in experimental and clinical situations. However, the optimal timing varies according to sex, genetic background and lifestyle. Here, we compute the individual phase of the Circadian Timing System to decipher the internal timing of each patient and find the optimal treatment timing.

Methods

Twenty-four patients (11 male; 13 female), aged 36 to 77 years, with advanced or metastatic gastro-intestinal cancer were recruited. Inner wrist surface Temperature, arm Activity and Position (TAP) were recorded every 10 min for 12 days, divided into three 4-day spans before, during and after a course of a set chronotherapy schedule. Pertinent indexes, I < O and a new biomarker, DI (degree of temporal internal order maintenance), were computed for each patient and period.

Results

Three circadian rhythms and the TAP rhythm grew less stable and more fragmented in response to treatment. Furthermore, large inter- and intra-individual changes were found for T, A, P and TAP patterns, with phase differences of up to 12 hours among patients. A moderate perturbation of temporal internal order was observed, but the administration of fixed chronomodulated chemotherapy partially resynchronized temperature and activity rhythms by the end of the study.

Conclusions

The integrated variable TAP, together with the asynchrony among rhythms revealed by the new biomarker DI, would help in the personalization of cancer chronotherapy, taking into account individual circadian phase markers.

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Alcohol-related breast cancer in postmenopausal women effect of CYP19A1 PPARG and PPARGC1A polymorphisms on female sex-hormone levels and interaction with alcohol consumption and NSAID usage in a nested case-control study and a randomised controlled trial

Abstract

Background

Alcohol consumption is associated with increased risk of breast cancer (BC), and the underlying mechanism is thought to be sex-hormone driven. In vitro and observational studies suggest a mechanism involving peroxisome proliferator-activated receptor gamma (PPARγ) in a complex with peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α) and interaction with aromatase (encoded by CYP19A1). Use of non-steroidal anti-inflammatory drugs (NSAID) may also affect circulating sex-hormone levels by modifying PPARγ activity.

Methods

In the present study we assessed whether genetic variation in CYP19A1 is associated with risk of BC in a case-control study group nested within the Danish "Diet, Cancer and Health" cohort (n_cases = 687 and n_controls = 687) and searched for gene-gene interaction between CYP19A1 and PPARGC1A, and CYP19A1 and PPARG, and gene-alcohol and gene-NSAID interactions. Association between the CYP19A1 polymorphisms and hormone levels was also examined among 339 non-HRT users. Incidence rate ratios were calculated based on Cox' proportional hazards model. Furthermore, we performed a pilot randomised controlled trial to determine the effect of the PPARG Pro¹²Ala polymorphism and the PPARγ stimulator Ibuprofen on sex-hormone levels following alcohol intake in postmenopausal women (n = 25) using linear regression.

Results

Genetic variations in CYP19A1 were associated with hormone levels (estrone: P _rs11070844 = 0.009, estrone sulphate: P _rs11070844 = 0.01, P _rs749292 = 0.004, P _rs1062033 = 0.007 and P _rs10519297 = 0.03, and sex hormone-binding globulin (SHBG): P _rs3751591 = 0.03) and interacted with alcohol intake in relation to hormone levels (estrone sulphate: P _{interaction/rs2008691} = 0.02 and P _{interaction/rs1062033=} 0.03, and SHBG: P _{interaction/rs11070844} = 0.03). CYP19A1/rs3751591 was both associated with SHBG levels (P = 0.03) and with risk of BC (Incidence Rate Ratio = 2.12; 95 % Confidence Interval: 1.02–4.43) such that homozygous variant allele carriers had increased levels of serum SHBG and were at increased risk of BC. Acute intake of alcohol decreased blood estrone (P = <0.0001), estrone sulphate (P = <0.0001), and SHBG (P = 0.009) levels, whereas Ibuprofen intake and PPARG Pro¹²Ala genotype had no effect on hormone levels.

Conclusions

Our results suggest that genetically determined variation in CYP19A1 is associated with differences in sex hormone levels. However, the genetically determined differences in sex hormone levels were not convincingly associated with BC risk. The results therefore indicate that the genetically determined variation in CYP19A1 contributes little to BC risk and to alcohol-mediated BC risk.

Trial registration

NCT02463383, June 3, 2015.

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Cancer incidence in urban Shanghai 1973-2010: an updated trend and age-period-cohort effects

Abstract

Background

To provide a comprehensive overview of temporal trends in cancer incidence during 1973–2010 in urban Shanghai.

Methods

The estimated annual percent changes (EAPCs) for the whole period and for the time segments in age-standardized incidence rates (ASR) were evaluated with Joinpoint analysis. Age-period-cohort (APC) models were modeled to examine the effects of age, period and birth cohort on cancer incidence.

Results

The overall ASR decreased slightly and significantly in males (EAPC of −0.41) but increased significantly in females (EAPC of 0.57) during 1973–2010 in urban Shanghai. The incidence trend was not linear and varied by time segments. During the most recent 10 years (2001–2010), the ASR in males decreased by 1.65 % per year and stabilized in females. Incidence rates continued to decline during 1973–2010 for esophagus, stomach, and liver cancer in both sexes, as well as male lung cancer and cervix cancer. It should be noted that it was the first time to document a significant decline in lung cancer incidence among males during 1973–2010 with EAPC of −0.58 %, and a notable upward for cervix cancer since 1996 with EAPC of 8.94 %. Unfavorable trends in incidence were observed for the most common cancer sites in the 38 years period: colorectum, gallbladder & biliary tract, pancreas, kidney, bladder, brain & central nervous system (CNS), thyroid, non-Hodgkin's lymphoma (NHL), prostate, female breast, corpus uteri, and ovary. APC analysis showed age, period and birth cohort yielded different effects by cancer sites.

Conclusions

The observed trends primarily reflect dramatic changes in socioeconomic development and lifestyles in urban Shanghai over the past four decades.

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90Y radiation lobectomy: Outcomes following surgical resection in patients with hepatic tumors and small future liver remnant volumes

Background

The purpose of this study is to assess operative, post-operative, and long-term outcomes in patients who underwent radiation lobectomy (RL) for tumor control and/or hypertrophy of small future liver remnant (FLR) prior to resection.

Methods

Right lobar +/− segment 4 radioembolization was performed prior to lobectomy/tri-segmentectomy in patients with hepatic tumor but inadequate FLR. Parenchymal/tumor volumes were calculated from pre/post-RL imaging; FLR/%FLR hypertrophy were determined. Complications were graded by the Clavien-Dindo classification.

Results

Thirteen patients (HCC n = 10, cholangiocarcinoma n = 2, mCRC n = 1) underwent RL prior to resection. The median time between RL and post-RL imaging was 40 days (23–190 days); the median time to resection was 86 days (30–210 days). Median FLR increased significantly [pre: 33% (22–43%); post: 43% (29–69%), P < 0.01] to yield a median %FLR hypertrophy of 30% (4–105%). The median hospital stay after resection was 4 days (3–11 days). Transient hepatobiliary toxicities normalized post-operatively. Ninety-two percent of resected tumors had >50% pathologic necrosis. Median follow up time after surgery was 604 days (144–1,416 days); one death occurred.

Conclusions

In this preliminary study, radiation lobectomy was a safe and effective method to achieve remnant liver hypertrophy while providing tumor control. This approach may facilitate safe resection and favorable post-operative outcomes.J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.

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