In Vivo Imaging Reveals Significant Tumor Vascular Dysfunction and Increased Tumor HIF-1α Expression Induced by High Single-Dose Irradiation in a Pancreatic Tumor Model

Publication date: Available online 14 September 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Azusa Maeda, Yonghong Chen, Jiachuan Bu, Hilda Mujcic, Bradly G. Wouters, Ralph S. DaCosta
PurposeTo investigate the effect of high-dose irradiation on pancreatic tumor vasculature and microenvironment using in vivo imaging techniques.Methods and MaterialsA BxPC3 pancreatic tumor xenograft was established in a dorsal skinfold window chamber (DSWC) model and a subcutaneous hind leg model. Tumors were irradiated with a single dose of 4, 12 or 24 Gy. The DSWC model was used to assess tumor response, vascular function and permeability, platelet and leukocyte adhesion to the vascular endothelium, and tumor hypoxia for up to 14 days after 24 Gy-irradiation. The hind leg model was used to monitor tumor size, hypoxia and vascularity for up to 65 days after 24 Gy-irradiation. Tumors were assessed histologically to validate in vivo observations.ResultsIn vivo fluorescence imaging revealed temporary vascular dysfunction in tumors irradiated with a single dose of 4-24 Gy, but most significantly with a single dose of 24 Gy. Vascular functional recovery was observed by 14 days after irradiation in a dose-dependent manner. Furthermore, irradiation with 24 Gy caused platelet and leukocyte adhesion to the vascular endothelium within hours to days after irradiation. Vascular permeability was significantly higher in irradiated tumors compared with non-irradiated controls 14 days after irradiation. This observation corresponded with increased expression of Hypoxia-Inducible Factor-1α (HIF-1α) in irradiated tumors. In the hind leg model, irradiation with a single dose of 24 Gy led to tumor growth delay, followed by tumor regrowth.ConclusionsIrradiation of the BxPC3 tumors with a single dose of 24 Gy caused transient vascular dysfunction and increased expression of HIF-1α. Such biological changes may impact tumor response to high single-dose and hypofractionated irradiation, and further investigations are needed to better understand the clinical outcomes of stereotactic body radiation therapy (SBRT).

Teaser

In vivo imaging methods were used to investigate the effects of high-dose irradiation on tumor vasculature and microenvironment using a BxPC3 pancreatic tumor model. A single dose of 24 Gy caused transient vascular dysfunction associated with adhesion of platelets and leukocytes to vascular endothelium, increased vascular permeability, and HIF-1 expression. Furthermore, tumor recurrence was evident by 65 days after irradiation. These data demonstrate the extent of radiation-induced vascular damage and its potential influence on tumor response.


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Verification of dose distribution in carbon ion radiotherapy for stage I lung cancer

Publication date: Available online 14 September 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Daisuke Irie, Jun-ichi Saitoh, Katsuyuki Shirai, Takanori Abe, Yoshiki Kubota, Makoto Sakai, Shin-ei Noda, Tatsuya Ohno, Takashi Nakano
PurposeTo evaluate robustness of dose distribution of carbon-ion radiotherapy (C-ion RT) in non-small-cell lung cancer (NSCLC) and to identify factors affecting the dose distribution by simulated dose distribution (SimDD).Methods and MaterialsEighty irradiation fields for delivery of C-ion RT were analyzed in 20 patients with stage I NSCLC. Computed tomography (CT) images were obtained twice before treatment initiation. SimDD was reconstructed on CT for confirmation under the same settings as actual treatment with respiratory gating and bony structure matching. Dose–volume histogram (DVH) parameters, such as %D95 (percentage of D95 relative to the prescribed dose) were calculated. Patients with any field for which the %D95 of gross tumor volume (GTV) was below 90% were classified as unacceptable for treatment, and the optimal target margin for such cases was examined.ResultsFive patients with a total of eight fields (10% of total number of fields analyzed) were classified as unacceptable according to %D95 of GTV, although most patients showed no remarkable change in the DVH parameters. Receiver operating characteristic (ROC) curve analysis showed that tumor displacement and change in water-equivalent pathlength (WEL) were significant predictive factors of unacceptable cases (p < 0.001 and p = 0.002, respectively). The main cause of degradation of the dose distribution was tumor displacement in seven of the eight unacceptable fields. A 6-mm planning target volume margin ensured a GTV %D95 of >90% except in one extremely unacceptable field.ConclusionsAccording to this simulation analysis of C-ion RT for stage I NSCLC, a few fields were reported as unacceptable and required resetting of body position and reconfirmation. In addition, tumor displacement and change in WEL (bone shift and/or chest wall thickness) were identified as factors influencing the robustness of dose distribution. Such uncertainties should be regarded in planning.

Teaser

Dose distribution of carbon ion radiotherapy for stage I lung cancer under the bony structure-matching method was simulated, and its robustness for interfractional changes was evaluated. Eight of 80 field irradiations showed unacceptable degradation of D95 of gross tumor volume, although most field irradiations were robust. The degradation resulted from tumor displacement without correlation with respiration and change in water-equivalent pathlength on the beam pathway. Such uncertainty factors should be regarded in planning.


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Interest in Integrative Medicine Among Postmenopausal Hormone Receptor-Positive Breast Cancer Patients in the EvAluate-TM Study

Background. Breast cancer patients often use complementary and alternative medicine, but few prospectively collected data on the topic are available specifically for postmenopausal breast cancer patients. A large prospective study was therefore conducted within a noninterventional study in order to identify the characteristics of patients interested in integrative medicine. Methods. The EvAluate-TM study is a prospective, multicenter noninterventional study in which treatment with the aromatase inhibitor letrozole was evaluated in postmenopausal women with hormone receptor–positive primary breast cancer. Between 2008 and 2009, 5045 postmenopausal patients were enrolled at 339 certified breast centers in Germany. As part of the data collection process, patients were asked at the baseline about their interest in and information needs relating to integrative medicine. Results. Of the 5045 patients recruited, 3411 responded to the questionnaire on integrative medicine and took part in the analysis, 1583 patients expressed an interest in integrative medicine, and 1828 patients declared no interest. Relevant predictors of interest in integrative medicine were age, body mass index, tumor size, previous chemotherapy, and use of concomitant medications for other medical conditions. Interest in integrative medicine declined highly significantly (P < .001) with age (<50 years, 74.1%; 50-60 years, 54.1%; >65 years, 38.0%). Patients in favor of integrative medicine were significantly less satisfied with the information received about individual treatments and antihormonal therapy. Patients with interest in integrative medicine were more often interested in rehabilitation and fitness, nutritional counseling, and additional support from self-help organizations. These women were mostly interested in receiving information about their disease and integrative medicine from a physician, rather than from other sources. Conclusions. This study shows that a considerable proportion of postmenopausal breast cancer patients are interested in integrative medicine. Information about integrative medicine should therefore be provided as part of patient care for this group. It was found that receiving concomitant medication for other medical conditions is one of the main predictors for women not being interested in integrative medicine. This group of patients may need special attention and individualized information about integrative medicine. Additionally, most patients were interested in obtaining the relevant information from their doctor.

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A Mindfulness-Based Lifestyle Intervention for Obese, Inactive Endometrial Cancer Survivors: A Feasibility Study

Background: Mindfulness-based interventions (MBIs) to address self-regulation and lifestyle behaviors (diet, physical activity) may benefit endometrial cancer survivors (ECS), who are at increased risk for morbidity and mortality associated with obesity. However, the acceptability of mindfulness training and whether it can augment behavior change in ECS is unknown. We aimed to examine; 1) the feasibility of the Mindfulness in Motion + Diet (MIM+D) intervention and 2) the preliminary efficacy of MIM+D for improving mindfulness, diet, PA and health-related quality of life (HRQL). Methods: ECS (Mage=62.4, ±5yrs from diagnosis) completed assessments at baseline, 8 and 14 weeks. Feasibility was determined by intervention completion surveys, attendance and adherence data. We used repeated measures ANOVA's (SPSS 22.0) and effect size estimates (Cohen's d) to examine changes in mindfulness, diet, PA, and HRQL over time. Results: Thirteen ECS (76%) completed the MIM+D program and attendance (≥6/8 sessions) was 90%. Women reported favorably on the overall quality (mean of 4.75/5) and benefits of the MIM+D program; however, would have preferred receiving MIM+D closer to diagnosis. Intention to treat analyses found MIM+D did not significantly improve any outcomes. However, an intervention completers analysis showed significant change in mindfulness (p=.0039) and small to moderate estimates for change in fruits and vegetable intake (d=.23), MVPA (d=.45), RAND SF-36: MCS (d=.46), and sleep quality (d=.68). Conclusions: Integrating mindfulness training into behavioral interventions is feasible and ECS that adhere to these lifestyle programs may benefit. However, to future research should examine the-long term effects of mindfulness-based behavioral lifestyle interventions.

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Examining the Long-Term Association of Personality With Cause-Specific Mortality in London: Four Decades of Mortality Surveillance in the Original Whitehall Smoking Cessation Trial

The personality domains of extraversion and neuroticism are regarded as being stable individual psychological characteristics, yet it remains unclear whether they are associated with chronic disease over an extended period of time. In a randomized controlled trial of smoking cessation nested within the original prospective Whitehall Study (1967–2012), the Eysenck Personality Questionnaire was administered to 832 male self-declared smokers who had undergone a medical examination during which their levels of extraversion and neuroticism were quantified. In the 42-year follow-up period, there were 781 deaths. In analyses in which participants from both trial arms were pooled, there was little evidence of a robust relation of either personality domain with death from all causes, coronary heart disease, stroke, respiratory disease, or cancer in any of our analyses. We therefore found no support for a role of either extraversion or neuroticism as determinants of long-term mortality risk.

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Editorial Board

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Instrumental-Variables Simultaneous Equations Model of Physical Activity and Body Mass Index: The Coronary Artery Risk Development in Young Adults (CARDIA) Study

We used full-system-estimation instrumental-variables simultaneous equations modeling (IV-SEM) to examine physical activity relative to body mass index (BMI; weight (kg)/height (m)²) using 25 years of data (1985/1986 to 2010/2011) from the Coronary Artery Risk Development in Young Adults (CARDIA) Study (n = 5,115; ages 18–30 years at enrollment). Neighborhood environment and sociodemographic instruments were used to characterize physical activity, fast-food consumption, smoking, alcohol consumption, marriage, and childbearing (women) and to predict BMI using semiparametric full-information maximum likelihood estimation to control for unobserved time-invariant and time-varying residual confounding and differential measurement error through model-derived discrete random effects. Comparing robust-variance ordinary least squares, random-effects regression, fixed-effects regression, single-equation-estimation IV-SEM, and full-system-estimation IV-SEM, estimates from random- and fixed-effects models and the full-system-estimation IV-SEM were unexpectedly similar, despite the lack of control for residual confounding with the random-effects estimator. Ordinary least squares tended to overstate the significance of health behaviors in BMI, while results from single-equation-estimation IV-SEM were notably different, revealing the impact of weak instruments in standard instrumental-variable methods. Our robust findings for fixed effects (which does not require instruments but has a high cost in lost degrees of freedom) and full-system-estimation IV-SEM (vs. standard IV-SEM) demonstrate potential for a full-system-estimation IV-SEM method even with weak instruments.

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Associations of Source-Specific Fine Particulate Matter With Emergency Department Visits in California

While many studies have investigated the health effects associated with acute exposure to fine particulate matter (particulate matter with an aerodynamic diameter less than or equal to 2.5 μm (PM_2.5)), very few have considered the risks of specific sources of PM_2.5. We used city-specific source apportionment in 8 major metropolitan areas in California from 2005–2009 to examine the associations of source-specific PM_2.5 exposures from vehicular emissions, biomass burning, soil, and secondary nitrate and sulfate sources with emergency department visits (EDVs) for cardiovascular and respiratory diseases, including 7 subclasses. Using a case-crossover analysis, we observed associations of vehicular emissions with all cardiovascular EDVs (excess risk = 1.6%, 95% confidence interval: 0.9, 2.4 for an interquartile-range increment of 2.8 µg/m³) and with several subclasses of disease. In addition, vehicular emissions, biomass burning, and soil sources were associated with all respiratory EDVs and with EDVs for asthma. The soil source, which includes resuspended road dust, generated the highest risk estimate for asthma (excess risk = 4.5%, 95% confidence interval: 1.1, 8.0). Overall, our results provide additional evidence of the public health consequences of exposure to specific sources of PM_2.5 and indicate that some sources of PM_2.5 may pose higher risks than the overall PM_2.5 mass.

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Contents Page

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Reductions in the United Kingdom's Government Housing Benefit and Symptoms of Depression in Low-Income Households

Housing security is an important determinant of mental ill health. We used a quasinatural experiment to evaluate this association, comparing the prevalence of mental ill health in the United Kingdom before and after the government's April 2011 reduction in financial support for low-income persons who rent private-sector housing (mean reduction of approximately £1,220 ($2,315) per year). Data came from the United Kingdom's Annual Population Survey, a repeated quarterly cross-sectional survey. We focused our analysis on renters in the private sector, disaggregating data between an intervention group receiving the government's Housing Benefit (n = 36,859) and a control group not receiving the Housing Benefit (n = 142,205). The main outcome was a binary measure of self-reported mental health problems. After controlling for preexisting time trends, we observed that between April 2011 and March 2013, the prevalence of depressive symptoms among private renters receiving the Housing Benefit increased by 1.8 percentage points (95% confidence interval: 1.0, 2.7) compared with those not receiving the Housing Benefit. Our models estimated that approximately 26,000 (95% confidence interval: 14,000, 38,000) people newly experienced depressive symptoms in association with the cuts to the Housing Benefit. We conclude that reducing housing support to low-income persons in the private rental sector increased the prevalence of depressive symptoms in the United Kingdom.

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Placental Nitrosative Stress and Exposure to Ambient Air Pollution During Gestation: A Population Study

The placenta plays a crucial role in fetal growth and development through adaptive responses to perturbations of the maternal environment. We investigated the association between placental 3-nitrotyrosine (3-NTp), a biomarker of oxidative stress, and exposure to air pollutants during various time windows of pregnancy. We measured the placental 3-NTp levels of 330 mother-newborn pairs enrolled in the Environmental Influence on Ageing in Early Life (ENVIRONAGE) Study, a Belgian birth cohort study (2010–2013). Daily concentrations of particulate matter with an aerodynamic diameter ≤2.5 µm (PM_2.5), black carbon (BC), and nitrogen dioxide were interpolated for each mother's residence using a spatiotemporal interpolation method. Placental 3-NTp levels, adjusted for covariates, increased by 35.0% (95% confidence interval (CI): 13.9, 60.0) for each interquartile-range increment in entire-pregnancy PM_2.5 exposure. The corresponding estimate for BC exposure was 13.9% (95% CI: –0.21, 29.9). These results were driven by the first (PM_2.5: 29.0% (95% CI: 4.9, 58.6); BC: 23.6% (95% CI: 4.4, 46.4)) and second (PM_2.5: 39.3% (95% CI: 12.3, 72.7)) gestational exposure windows. This link between placental nitrosative stress and exposure to fine particle air pollution during gestation is in line with experimental evidence on cigarette smoke and diesel exhaust exposure. Further research is needed to elucidate potential health consequences experienced later in life through particle-mediated nitrosative stress incurred during fetal life.

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Invited Commentary: Harnessing Housing Natural Experiments Is Important, but Beware Differential Misclassification of Difference in Difference

In this issue of the Journal, Reeves et al. (Am J Epidemiol. 2016;184(6):421–429) present the findings of a natural experiment analyzing the association between reduced housing affordability and mental ill health. Their difference-in-difference analysis of cross-sectional, quarterly population health surveys administered before and after implementation of a policy to reduce Housing Benefit payments in the United Kingdom in April 2011 represents an important way to assess the impact of a national housing policy shift on public health. It is a well-conducted study harnessing a natural experiment and adds to the weight of evidence supporting an association between housing costs and mental health. However, quantitative bias analysis based on the reported findings suggests that a small amount of differential (by unblinded Housing Benefit status) misclassification bias in the outcome may be enough to explain the observed association. Our analysis of possible misclassification bias in the outcome used in the study highlights the need for caution when a difference-in-difference estimate is small, the population is not blinded to its postintervention exposure status, and the outcome measure is subjective and prone to differential (by unblinded exposure or treatment status) misclassification.

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Risks of Death and Severe Disease in Patients With Middle East Respiratory Syndrome Coronavirus, 2012-2015

Middle East respiratory syndrome coronavirus (MERS-CoV) is an emerging pathogen, first recognized in 2012, with a high case fatality risk, no vaccine, and no treatment beyond supportive care. We estimated the relative risks of death and severe disease among MERS-CoV patients in the Middle East between 2012 and 2015 for several risk factors, using Poisson regression with robust variance and a bootstrap-based expectation maximization algorithm to handle extensive missing data. Increased age and underlying comorbidity were risk factors for both death and severe disease, while cases arising in Saudi Arabia were more likely to be severe. Cases occurring later in the emergence of MERS-CoV and among health-care workers were less serious. This study represents an attempt to estimate risk factors for an emerging infectious disease using open data and to address some of the uncertainty surrounding MERS-CoV epidemiology.

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Reeves et al. Respond to "Harnessing Housing Natural Experiments"

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Evaluation of a Computer-Based Recruitment System for Enrolling Men Who Have Sex With Men Into an Observational HIV Behavioral Risk Study

Enrolling large numbers of high-risk men who have sex with men (MSM) into human immunodeficiency virus (HIV) prevention studies is necessary for research with an HIV outcome, but the resources required for in-person recruitment can be prohibitive. New methods with which to efficiently recruit large samples of MSM are needed. At a sexually transmitted disease clinic in Seattle, Washington, in 2013–2014, we used an existing clinical computer-assisted self-interview that collects patients' medical and sexual history data to recruit, screen, and enroll MSM into an HIV behavioral risk study and compared enrollees with men who declined to enroll. After completing the clinical computer-assisted self-interview, men aged ≥18 years who reported having had sex with men in the prior year were presented with an electronic study description and consent statement. We enrolled men at 2,661 (54%) of 4,944 visits, including 1,748 unique individuals. Enrolled men were younger (mean age = 34 years vs. 37 years; P < 0.001) and reported more male sex partners (11 vs. 8; P < 0.001) and more methamphetamine use (15% vs. 8%; P < 0.001) than men who declined to enroll, but the HIV test positivity of the two groups was similar (1.9% vs. 2.0%; P = 0.80). Adapting an existing computerized clinic intake system, we recruited a large sample of MSM who may be an ideal population for an HIV prevention study.

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Associations between cancer and Alzheimer's disease in a U.S. Medicare population

Abstract

Several studies have reported bidirectional inverse associations between cancer and Alzheimer's disease (AD). This study evaluates these relationships in a Medicare population. Using Surveillance, Epidemiology, and End Results (SEER) linked to Medicare data, 1992–2005, we evaluated cancer risks following AD in a case–control study of 836,947 cancer cases and 142,869 controls as well as AD risk after cancer in 742,809 cancer patients and a non-cancer group of 420,518. We applied unconditional logistic regression to estimate odds ratios (ORs) and Cox proportional hazards models to estimate hazards ratios (HRs). We also evaluated cancer in relation to automobile injuries as a negative control to explore potential study biases. In the case–control analysis, cancer cases were less likely to have a prior diagnosis of AD than controls (OR = 0.86; 95% CI = 0.81–0.92). Cancer cases were also less likely than controls to have prior injuries from automobile accidents to the same degree (OR = 0.83; 95% CI = 0.78–0.88). In the prospective cohort, there was a lower risk observed in cancer survivors, HR = 0.87 (95% CI = 0.84–0.90). In contrast, there was no association between cancer diagnosis and subsequent automobile accident injuries (HR = 1.03; 95% CI = 0.98–1.07). That cancer risks were similarly reduced after both AD and automobile injuries suggest biases against detecting cancer in persons with unrelated medical conditions. The modestly lower AD risk in cancer survivors may reflect underdiagnosis of AD in those with a serious illness. This study does not support a relationship between cancer and AD.

Using Surveillance, Epidemiology, and End Results (SEER) linked to Medicare data, we evaluated cancer risks following Alzheimer's disease (AD) in a large case-control study as well as AD risk after cancer in a cohort study. We also evaluated cancer in relation to automobile injuries, which are unlikely to be biologically related, to explore potential study biases. We found that cancer risks were similarly modestly reduced after both AD and automobile injuries, suggesting biases against detecting cancer in persons with unrelated medical conditions. In addition, there was a slightly lower AD risk in cancer survivors, which may reflect under-diagnosis of AD in those with a serious illness.

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Lurbinectedin Induces Degradation of RNA Pol II

We have defined the mechanism of action of lurbinectedin, a marine-derived drug exhibiting a potent antitumor activity across several cancer cell lines and tumor xenografts. This drug, currently undergoing clinical evaluation in ovarian, breast, and small cell lung cancer patients, inhibits the transcription process through (i) its binding to CG-rich sequences, mainly located around promoters of protein-coding genes; (ii) the irreversible stalling of elongating RNA polymerase II (Pol II) on the DNA template and its specific degradation by the ubiquitin/proteasome machinery; and (iii) the generation of DNA breaks and subsequent apoptosis. The finding that inhibition of Pol II phosphorylation prevents its degradation and the formation of DNA breaks after drug treatment underscores the connection between transcription elongation and DNA repair. Our results not only help to better understand the high specificity of this drug in cancer therapy but also improve our understanding of an important transcription regulation mechanism. Mol Cancer Ther; 15(10); 1–14. ©2016 AACR.

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Tracking Tumor Resistance: The Early Promise of "Liquid" Cancer Tests

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Cancer Treatment and Research Under the Affordable Care Act

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Some HER2-Negative Breast Tumors May Respond to HER2-Targeted Treatment

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Erratum

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Cover

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Editorial Board

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Relationship Between Increased Fucosylation and Metastatic Potential in Colorectal Cancer

Background: Fucose is utilized for the modification of different molecules involved in blood group determination, immunological reactions, and signal transduction pathways. We have recently reported that enhanced activity of the fucosyltransferase 3 and/or 6 promoted TGF-ß-mediated epithelial mesenchymal transition and was associated with increased metastatic potential of colorectal cancer (CRC), suggesting that fucose is required by CRC cells. With this in mind, we examined requirement of L-fucose in CRC cells and developed fucose-bound nanoparticles as vehicles for delivery of anticancer drugs specific to CRC.

Methods: In this study, we first examined the expression of fucosylated proteins in 50 cases of CRC by immunochistochemical staining with biotinylated Aleuria aurantia lectin (AAL). Then we carried out an L-fucose uptake assay using three CRC cell lines. Finally, we developed fucose-bound nanoparticles as vehicles for the delivery of an anticancer drug, SN38, and examined tumor growth inhibition in mouse xenograft model (n = 6 mice per group). All statistical tests were two-sided.

Results: We found a statistically significant relationship between vascular invasion, clinical stage, and intensity score of AAL staining (P ≤ .02). L-fucose uptake assay revealed that L-fucose incorporation, as well as fucosylated protein release, was high in cells rich in fucosylated proteins. L-fucose-bound liposomes effectively delivered Cy5.5 into CRC cells. The excess of L-fucose decreased the efficiency of Cy5.5 uptake through L-fucose-bound liposomes, suggesting an L-fucose receptor dependency. Intravenously injected, L-fucose-bound liposomes carrying SN38 were successfully delivered to CRC cells, mediating efficient tumor growth inhibition (relative tumor growth ratio: no treatment group [NT], 8.29 ± 3.09; SN38-treated group [SN38], 3.53 ± 1.47; liposome-carrying, SN38-treated group [F0], 3.1 ± 1.39; L-fucose-bound, liposome-carrying, SN38-treated group [F50], 0.94 ± 0.89; F50 vs NT, P = .003; F50 vs SN38, P = .02, F50 vs F0, P = .04), as well as prolonging survival of mouse xenograft models (log-rank test, P < .001).

Conclusions: Thus, fucose-bound liposomes carrying anticancer drugs provide a new strategy for the treatment of CRC patients.

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Uninsured Rate by State, (1963-2014)

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Erratum

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PDQ (Physician Data Query)

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Targeting Tumors Energy Needs

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Erratum

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Table of Contents

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Erratum

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The emerging role of obesity, diet and lipid metabolism in prostate cancer

Future Oncology Ahead of Print.


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Key messages from the BFR14 trial of the French Sarcoma Group

Future Oncology Ahead of Print.


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High risk of pleural plaques and parenchymal abnormalities in women living in Biancavilla (Italy)

Future Oncology Ahead of Print.


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Targeting EGFR mutation in non-small-cell lung cancer: challenges and future perspectives

Future Oncology Ahead of Print.


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Will gemcitabine monotherapy be dethroned as the adjuvant chemotherapy in pancreatic adenocarcinoma?

Future Oncology Ahead of Print.


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The multidisciplinary art and science of cancer care: integrating psycho-oncology

Future Oncology Ahead of Print.


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Integrative oncology: are we doing enough to integrate psycho-education?

Future Oncology Ahead of Print.


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CA-125 Testing, CT Scans Still Used for Ovarian Cancer Surveillance Despite Lack of Proven Benefit

Despite evidence of no benefit from a 2009 randomized clinical trial, a new study shows that doctors appear to still routinely use the CA-125 blood test to monitor women for recurrent ovarian cancer. The findings, published July 21 in JAMA Oncology, also suggest that computed tomography (CT) scans continue to be routinely used to check for recurrences even though clinical practice guidelines discourage this practice. 

Many women who are in remission after treatment for ovarian cancer will eventually have a recurrence of the disease. One approach doctors have used to monitor patients for a recurrence and make decisions about care is regular blood testing to look for a rise in levels of CA-125, a protein that may be found in high amounts in women with ovarian cancer. However, results of a randomized, phase III clinical trial reported at a national conference in 2009 and published in 2010 showed that CA-125 testing for early detection of recurrent disease increased the use of chemotherapy and decreased patients' quality of life without improving overall survival.

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

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

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

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Mutations Linked to Immunotherapy Resistance

For many patients with melanoma whose tumors shrink after treatment with a class of immunotherapy drugs called checkpoint inhibitors, their tumors eventually grow back despite continued treatment. A new study has identified genetic mechanisms that may be responsible for this acquired treatment resistance in at least some of these patients.

The researchers found mutations in tumors from three patients with advanced melanoma that allowed the tumors to become resistant to the immune checkpoint inhibitor pembrolizumab (Keytruda®). Specifically, the mutations enabled the tumors to avoid recognition and attack by immune cells.

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Nanoparticle Delivers Cancer Drugs to Tumor Blood Vessels

In a set of studies in mice bearing human tumors, nanoparticles designed to bind to a protein called P-selectin successfully delivered both chemotherapy drugs and targeted therapies to tumor blood vessels. Targeting the blood vessels improved the delivery of drugs to tumor tissue, causing the tumors to shrink and improving how long the mice lived.

A tumor's blood vessels can serve as a barrier to engineered drug-delivery systems like nanoparticles, which may not be able to cross the blood vessel wall. However, the same blood vessels may express proteins—such as P-selectin—that researchers can potentially exploit, by engineering their nanoparticles to recognize and latch onto those proteins, which enables them to reach the tumor.

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Partner-Aided Skin Exams Increase Early Detection of New Melanomas

People who have previously been treated for melanoma—and are therefore at high risk for developing a second melanoma—can team up with a spouse, family member, or a friend and be trained to find new melanomas successfully, a new clinical trial showed.

In the trial, patients and their skin-check partners who received training in how to find and track suspicious moles over time found substantially more early-stage melanomas than pairs who only received reminders from their doctors to perform regular skin self-examinations.

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Inherited Mutations in DNA-Repair Genes Found in Advanced Prostate Cancers

Nearly 12% of men with advanced prostate cancer have inherited mutations in genes that play a role in repairing damaged DNA, according to a new study. Inherited mutations in DNA-repair genes—including BRCA2, ATM, and CHEK2—are associated with an increased risk of several other cancers, including breast, ovarian, and pancreatic cancer. 

"This finding offers a new window into understanding how metastatic prostate cancers develop," said Peter Nelson, M.D., of the Fred Hutchinson Cancer Research Center, who co-led the study.

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Olanzapine Helps Prevent Nausea and Vomiting Caused by Chemotherapy

A drug currently used to treat several psychiatric conditions can help prevent nausea and vomiting in patients receiving chemotherapy, according to results from a large NCI-funded phase III clinical trial.

Patients in the trial were being treated with chemotherapy agents that often cause substantial nausea and vomiting. Those who were randomly assigned to receive the drug olanzapine (Zyprexa®), given in combination with three standard antiemetic agents (drugs that help prevent nausea and vomiting), were far less likely to experience nausea, have vomiting episodes, or need "rescue" anti-nausea medications to treat nausea/vomiting than patients who received a placebo plus the three antiemetic drugs.

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Anthrax Toxin-Based Cancer Therapy Targets Tumor Blood Vessels

Armed with a greater understanding of the detailed structure and function of the deadly anthrax toxin, scientists have engineered components of the toxin as a potential therapy for solid cancers.

Now, NIH scientists developing the toxin-based therapy have shown that it works by selectively targeting and inhibiting proliferation of cells that line the inside wall of blood vessels that feed tumors and support their growth and spread. When given in combination with two drugs that can block the production of antibodies against the toxin, the treatment greatly suppressed tumor growth in mouse models of lung cancer and melanoma, the researchers reported June 29 in the Proceedings of the National Academy of Sciences.

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New on NCI's Websites for July 2016

NCI is constantly publishing new information on its websites, so periodically we provide updates on new content of interest to the cancer community.

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3-D View of Mutations May Identify Potential Targets for Cancer Drugs

A new computational tool may help expand the known number of mutations in cancer cells that could be targeted with new or existing drugs.

Researchers recently reported that the tool, called HotSpot3D, allowed them to model how genetic mutations change the ways proteins function and interact with each other to potentially drive cancer. It also helped them identify more than 800 novel mutations that potentially could be targeted with existing drugs. 

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Study Forecasts ‘Silver Tsunami’ of Cancer Survivors

The aging of the U.S. population will result in a substantial increase in the number of older cancer survivors over the next quarter century, particularly those 85 and older, according to a new study by NCI researchers.

Using statistical models to analyze population data, the researchers estimated that the overall number of cancer survivors in the United States will continue to grow substantially. But the proportion of survivors who are aged 65 or older will grow the most, with this group representing nearly three-quarters of cancer survivors by 2040, the researchers reported in a study published July 1 in Cancer Epidemiology, Biomarkers & Prevention.

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Mouse Study Illuminates the Spread of Breast Cancer to Bone

By tracking the spread of breast cancer cells in mice, researchers have identified two proteins that may regulate the movement of breast cancer cells into and out of bone marrow.

A protein called E-selectin may allow breast cancer cells to enter certain regions of the bone marrow, and another protein, CXCR4, may help breast cancer cells remain within the bone, according to the study results.

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Setting the Stage for the Next Decade of Tobacco Control Research

One of the biggest dangers we face in public health is prematurely declaring victory over a major health threat. Nowhere is that more true than in the case of tobacco use.

Smoking rates have dropped precipitously over the past several decades—a monumental achievement that resulted from implementing evidence based policies and programs, such as increasing tobacco taxes, implementing comprehensive smoke-free laws, and efforts to help smokers to quit.

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The Cancer Moonshot Summit: Reaching New Heights

Yesterday, I attended the Cancer Moonshot Summit, hosted by Vice President Joe Biden and Dr. Jill Biden, held at Howard University in Washington, DC. In addition to this Summit, there were more than 250 regional summits happening simultaneously, making this truly a national event.

The summits were an opportunity for the Vice President to speak directly to the American public and ask them to "convene under the national charge of doubling the rate of progress toward ending cancer as we know it."

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Phase I study of nintedanib in Japanese patients with advanced hepatocellular carcinoma and liver impairment

Summary

This phase I, dose-escalation study evaluated the safety, preliminary efficacy and pharmacokinetics of nintedanib, a triple angiokinase inhibitor, in Japanese patients with advanced hepatocellular carcinoma and mild/moderate liver impairment. Thirty patients with unresectable hepatocellular carcinoma were enrolled to groups, depending on whether liver impairment was mild (Group I: AST and ALT ≤2x ULN and Child–Pugh score 5 [n=14] or 6 [n=2]) or moderate (Group II: Child–Pugh score 5–6 and AST or ALT >2x to ≤5x ULN [n=7] or Child–Pugh score 7 [n=7]); 22 patients had prior sorafenib treatment. Nintedanib was administered twice daily in 28-day cycles until disease progression or unacceptable adverse events, starting at 150 mg (Group I) or 100 mg (Group II) and escalating to 200 mg. The primary objective was to define the maximum tolerated dose based on occurrence of dose-limiting toxicities during Cycle 1 (Grade ≥3 non-hematological and Grade 4 hematological adverse events). No dose-limiting toxicities were reported during Cycle 1 and the maximum tolerated dose for both groups was 200 mg twice daily. The most frequent adverse events were gastrointestinal (diarrhea, nausea, vomiting, decreased appetite). No patients discontinued nintedanib due to adverse events; 31% of Group I and 21% of Group II had dose reductions. Median time to progression was 2.8 months (95% CI 1.05–5.52) for Group I and 3.2 months (95% CI 0.95–6.70) for Group II. Nintedanib showed a manageable safety profile and efficacy signals, including in patients previously treated with sorafenib.

ClinicalTrials. gov NCT01594125; 1199.120

This article is protected by copyright. All rights reserved.

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YAP and TAZ modulate cell phenotype in a subset of small cell lung cancer

Summary

Small cell lung cancer (SCLC) is a highly aggressive and metastatic malignancy that shows rapid development of chemoresistance and a high rate of recurrence. Recent genome and transcriptome studies have provided the whole landscape of genomic alterations and gene expression changes in SCLC. In light of the inter-individual heterogeneity of SCLC, subtyping of SCLC might be helpful for prediction of therapeutic response and prognosis. Based on the transcriptome data of SCLC cell lines, we performed transcriptional network-defined SCLC classification and identified a unique SCLC subgroup characterized by relatively high expression of Hippo pathway regulators YAP and TAZ (YAP/TAZ subgroup). YAP/TAZ subgroup displayed adherent cell morphology, lower expression of ASCL1 and neuroendocrine markers, and higher expression of laminin and integrin. YAP knockdown caused cell morphological alteration reminiscent of floating growth pattern in many SCLC cell lines, and microarray analyses revealed a subset of genes regulated by YAP, including Ajuba LIM protein (AJUBA). AJUBA also contributed to cell morphology regulation. Of clinical importance, SCLC cell lines of YAP/TAZ subgroup showed unique patterns of drug sensitivity. Our findings shed light on a subtype of SCLC with YAP and TAZ expression, and delineate molecular networks underlying the heterogeneity of SCLC.

This article is protected by copyright. All rights reserved.

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First-line EGFR-TKI alone or with whole-brain radiotherapy for brain metastases in EGFR-mutated lung adenocarcinoma patients

Abstract

We proposed to compare the outcome of first-line epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) alone with EGFR-TKI plus whole-brain radiotherapy (WBRT) in treatment of brain metastases (BM) from EGFR-mutated lung adenocarcinoma patients. 1665 patients were screened from 2008 to 2014, and 132 were enrolled in our study. Among the 132 patients, 72 (54.5%) harbored a deletion in exon 19, 97 (73.5%) showed multiple intracranial lesions, and 67 (50.8%) had asymptomatic BM. 79 patients (59.8%) were treated with EGFR-TKI alone, 53 with concomitant WBRT. The intracranial objective response rate was significantly higher in EGFR-TKI plus WBRT (67.9%) compared with EGFR-TKI alone group (39.2%), P = 0.001. After a median follow-up of 36.2 months, 62.1% of patients were still alive. The median intracranial time to progression (TTP) was 24.7 months (95% CI, 19.5 to 29.9) in patients who received WBRT, which was significantly longer than that in those who received EGFR-TKI alone with the median intracranial TTP of 18.2 months (95% CI, 12.5 to 23.9), P = 0.004. There was no significant difference in overall survival (OS) between WBRT and EGFR-TKI alone groups, (median, 48.0 vs. 41.1 months; P = 0.740). The OS is significantly prolonged in patients who had an intracranial TTP exceeding 22 months compared to those who developed intracranial progression less than 22 months after treatment, (median, 58.0 vs. 28.0 months; P = 0.001). For EGFR-mutated lung adenocarcinoma patients with BM, administration of concomitant WBRT achieved higher response rate of BM and significant improvement in intracranial progression-free survival compared with EGFR-TKI alone.

This article is protected by copyright. All rights reserved.

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Percutaneous Minimally Invasive Techniques in the Treatment of Spinal Metastases

Opinion Statement

Spinal metastases are a common and morbid condition in America. Of the 1.6 million new cases of cancer estimated to be diagnosed in the USA in 2015, approximately 5–10 % will develop spinal metastases. This number is expected to increase as the life expectancy of cancer patients increases. Patients with osteolytic spinal metastases experience severe and often debilitating pain, which significantly reduces quality of life. Due to the morbidity of open surgery, particularly in oncologic patients, the treatment paradigm has shifted towards minimally invasive therapy. The advent and evolution of percutaneous treatments of spinal metastases has shown progressive success in reducing pain, improving function, and providing mechanical stability. There are various currently available interventions including vertebroplasty, vertebral augmentation, and coblation and radiofrequency ablation systems. For more complex spinal metastases, combined treatments including vertebral augmentation in conjunction with radiofrequency ablation, external beam radiation, and the novel treatment of intraoperative radiotherapy are also available. Ultimately, the goal of treatment in this patient population is palliative with the intention of improving the remaining quality of life. There is no established algorithm or specific technique that has proved best for the many variations of vertebral compression fractures (VCFs), so treatment tends to be dependent on the operator and/or based on institution preference or bias. Each technique provides its own unique value in the various types of metastatic VCFs encountered, and understanding the uses, advantages, and safety profile of each specific treatment is imperative in providing the best patient care. Percutaneous treatment of metastatic spinal disease is an excellent alternative to medical and surgical management in carefully selected patients. We believe that a multidisciplinary approach and combination therapy allows for optimal pain reduction and improvement of function.

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Hint1 suppresses migration and invasion of hepatocellular carcinoma cells in vitro by modulating girdin activity

Abstract

Histidine triad nucleotide-binding protein 1 (Hint1) is a haploinsufficient tumor suppressor gene. Its role in cancer cell migration has not been previously speculated. In the current study, we examined the expression of Hint1 in metastatic and non-metastatic lymph nodes of hepatocellular carcinoma (HCC) patients and further elucidated the effect of Hint1 expression on girdin expression and phosphorylation of AKT and ERK1/2 and on the migration of HCC cells in vitro. Expression of Hint1 and girdin in primary HCC tissues and metastatic and non-metastatic lymph nodes was determined by RT-PCR assays. HepG2 cells were transfected with plasmid vectors overexpressing Hint1 or small interfering RNA (siRNA) targeting Hint1, girdin, Hint1 plus girdin, or the scrambled RNA. Migration and invasion of HCC cells were examined by wound and Transwell assays. Protein expression was detected by immunofluorescence and immunoblotting assays. RT-PCR assays revealed that the messenger RNA (mRNA) transcript levels of Hint1 were markedly lower than those of primary HCC tissues and non-metastatic lymph nodes (P < 0.01). By contrast, the mRNA transcript levels of girdin were significantly higher than non-metastatic lymph nodes (P < 0.05). Furthermore, siRNA knockdown of HINT1 resulted in a significant increase in the mRNA transcript levels of girdin in HepG2 cells (P < 0.05). Wound assays and Transwell assays showed that Hint1 knockdown by siRNA significantly enhanced the migration and invasion of HepG2 cells compared to HepG2 cells transfected with scrambled siRNA. Hint1 knockdown also led to significantly increased phosphorylation of girdin and AKT in HepG2 cells (P < 0.05), which, however, was effectively aborted by girdin knockdown by siRNA (P < 0.05). Hint1 is downregulated in metastatic lymph nodes and is implicated in migration and invasion of HCC cells in vitro by modulating girdin and AKT expression and phosphorylation. The Hint1-girdin-AKT signaling axis should be further dissected for its role in HCC migration and invasion and may be therapeutically targeted to suppress tumor growth and metastasis.

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TRPM7 channel inhibition mediates midazolam-induced proliferation loss in human malignant glioma

Abstract

The melastatin-like transient receptor potential 7 (TRPM7) has been implicated in proliferation or apoptosis of some cancers, indicating the potential of TRPM7 as an anti-anaplastic target. Here, we identified the characteristic TRPM7 channel currents in human malignant glioma MGR2 cells, which could be blocked by a pharmacologic inhibitor Gd³⁺. We mined the clinical sample data from Oncomine Database and found that human malignant glioma tissues expressed higher TRPM7 mRNA than normal brain ones. Importantly, we identified a widely used clinical anesthetic midazolam as a TRPM7 inhibitor. Midazolam treatment for seconds suppressed the TRPM7 currents and calcium influx, and treatment for 48 h inhibited the TRPM7 expression. The inhibitory effect on TRPM7 accounts for the proliferation loss and G₀/G₁ phase cell cycle arrest induced by midazolam. Our data demonstrates that midazolam represses proliferation of human malignant glioma cells through inhibiting TRPM7 currents, which may be further potentiated by suppressing the expression of TRPM7. Our result indicates midazolam as a pharmacologic lead compound with brain-blood barrier permeability for targeting TRPM7 in the glioma.

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Emerging tale of UPR and cancer: an essentiality for malignancy

Abstract

A set of cellular response to counter any alteration in homeostasis of a cell originating at endoplasmic reticulum is collectively termed as unfolded protein response (UPR). It initially is adaptive in nature as to restore cellular normalcy failing in course often activates pro-apoptotic signaling pathway resulting in cell death. UPR has emerged as an essential adaptation mechanism that cross talk with various cellular processes for cancer pathogenesis. Interestingly, it plays diverse role in plethora of signaling pathways instrumental in transformation, cell invasion, cell migration, metastasis, neovascularization, proliferation, and maintenance of energy metabolism of cancerous cells. In cancerous cells, it is triggered by change in microenvironment of a cell usually driven by hypoxia, acidosis, and nutrient deprivation, which often leads to positive selection pressure involving the reprogramming of energy metabolism which promotes channelization of limited metabolites into the hexosamine biosynthetic pathway (HBP). Substantial evidences suggest the role of UPR in oncogene (Myc, mTOR, RAS, HER2) driven cancer transformation and progression. In this review, we have comprehensively underlined the role played by UPR in adaptation, transformation, proliferation, invasion, and metastasis of cancerous cells.

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IL-13 receptor α2 stimulates human glioma cell growth and metastasis through the Src/PI3K/Akt/mTOR signaling pathway

Abstract

Glioma is a malignant tumor that affects all kinds of people all over the world. It demonstrates remarkable infiltrative and invasive features. The high expression of interleukin-13 receptor subunit alpha-2 (IL-13Rα2) reportedly plays a pivotal role in some cancers. However, whether IL-13Rα2 contributes to glioma remains unknown. This study demonstrates that IL-13Rα2 is significantly up-regulated in human glioma tissue samples. It is also associated with late stages of disease progression and diminished survival in glioma patients. Gain- and loss-of-function studies demonstrate that IL-13Rα2 promotes the growth, migration, and invasion of glioma cells. In addition, mechanistic investigations show that IL-13Rα2 activates Scr, phosphatidylinositol 3 kinase (PI3K), Akt, and mTOR. Also, restraining Scr in glioma cells attenuates the activation of Scr/PI3K/Akt/mTOR pathway by IL-13Rα2, whereas the silencing of Scr markedly rescues the pro-invasive effect of IL-13Rα2. In conclusion, our results suggest that the high expression of IL-13Rα2 is significantly associated with the growth and metastasis of human glioma cells via the Scr/PI3K/Akt/mTOR pathway, while IL-13Rα2 may be a potential therapeutic target for glioma treatment.

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Reoperations after primary breast conserving surgery in women with invasive breast cancer in Catalonia, Spain: a retrospective study

Abstract

Background

Although complete tumor resection is accepted as the best means to reduce recurrence, reoperations after lumpectomy are a common problem in breast cancer. The aim of this study was to assess the reoperation rates after primary breast conserving surgery in invasive breast cancer cases diagnosed in Catalonia, Spain, between 2005 and 2011 and to identify variations based on patient and tumour characteristics.

Methods

Women with invasive incident breast cancer identified from the Patient's Hospital Discharge Database [174.0–174.9 codes of the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) as the primary diagnosis] and receiving primary breast conserving surgery were included in the study and were followed up to 3 and 12 months by collecting information about repeat breast cancer surgery.

Results

Reoperation rates after primary breast conserving surgery decreased from 13.0 % in 2005 to 11.7 % in 2011 at 3 months and from 14.2 % in 2005 to 12.9 % in 2011 at 12 months' follow-up. While breast conservation reoperations saw a slight, non-significant increase in the same period (from 5.7 to 7.3 % at 3 months, and from 6.0 to 7.5 % at 12 months), there was a significant decrease in radical reoperation (from 7.3 to 4.4 % at 3 months and from 8.2 to 5.4 % at 12 months). Overall, additional breast surgeries decreased among younger women.

Conclusions

Despite the rise of breast conserving surgery, reoperation rates following initial lumpectomy in Catalonia decreased by 10 % at 3 and 12 months' follow-up, remaining low and almost unchanged. Ultimately, there was also a significant decrease in mastectomies.

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Early postoperative complications after middle lobe-preserving surgery for secondary lung cancer

Abstract

Purpose

Preservation of the middle lobe during lung surgery is traditionally avoided, because its presence in the hemithoracic cavity is considered a cause of complications. We report a series of lung cancer patients who underwent a secondary pulmonary resection with the preservation of the middle lobe to explore the complications and feasibility of these procedures.

Methods

We reviewed the clinical courses of six patients who underwent surgery for metachronous lung cancers. Five patients underwent right upper lobectomy, including one sleeve lobectomy, after having undergone prior right lower lobectomy. The remaining patient underwent a right lower lobectomy after having undergone a prior right upper lobectomy.

Results

There were no treatment-related deaths. One patient was readmitted for surgery to treat delayed air leakage progressing to pyothorax. One patient was treated for persistent air leakage. Two patients required intermittent drainage of pulmonary effusion, because of middle lobe atelectasis. The postoperative forced vital capacity and forced expiratory volume in 1 s were greater than the values predicted post-pneumonectomy in four evaluable patients.

Conclusions

While postoperative complications after middle lobe-preserving surgery are manageable, their high incidence should be considered when performing this surgery.

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Practice Patterns in Distinguishing Between Background Pain and Breakthrough Pain During Patient Education: a Korean Physician Survey

Abstract

This study sought to explore the association between physician practice patterns and patient education, with a focus on breakthrough cancer pain (BTcP). A nationwide online survey was conducted by 92 Korean physicians. Thirteen questions on Korean physician's assessment, prescription, patient education practices, and knowledge regarding BTcP were administered. Based on their responses, physicians were divided using two methods: (1) by their patient education practices, where the "education group" always explained the distinction between background pain and BTcP and the "less education group" which explained it less frequently; and (2) by their definition of BTcP, as occurring "after control of background pain" or "regardless of background pain." We compared practice patterns using Fisher's exact test or Student's t test and performed multiple logistic regression analysis. The "education group" (65 physicians, 70.7 %) was more likely than the "less education group" to assess BTcP meticulously (odds ratio [OR] 17.13, 95 % confidence interval [CI] 4.98–58.94), prepare rescue medications in advance (OR 3.67, 95 % CI 1.36–9.90), and give explicit instructions regarding medications (OR 36.68, 95 % CI 5.63–239.15). Physicians who defined BTcP as occurring "after control of background pain" were more likely to explain how to take rescue medication (P < 0.05) than physicians who defined BTcP as occurring "regardless of background pain." Korean physicians' BTcP practice patterns may be affected by whether they consistently educate patients on the distinction between background pain and BTcP, regardless of their knowledge of the definition of BTcP.

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Current status and unanswered questions on the use of Denosumab in giant cell tumor of bone

Abstract

Denosumab is a monoclonal antibody to RANK ligand approved for use in giant cell tumour (GCT) of bone. Due to its efficacy, Denosumab is recommended as the first option in inoperable or metastatic GCT. Denosumab has also been used pre-operatively to downstage tumours with large soft tissue extension to allow for less morbid surgery. The role of Denosumab for conventional limb GCT of bone is yet to be defined. Further studies are required to determine whether local recurrence rates will be decreased with the adjuvant use of Denosumab along with surgery. The long term use and toxicity of this agent is unknown as is the proportion of patients with primary or secondary resistance. It is advised that complicated cases of GCT requiring Denosumab treatment should be referred and followed up at expert centres. Collaborative studies involving further clinical trials and rigorous data collection are strongly recommended to identify the optimum use of this drug.

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Tumour biology of obesity-related cancers: understanding the molecular concept for better diagnosis and treatment

Abstract

Obesity continues to be a major global problem. Various cancers are related to obesity and proper understanding of their aetiology, especially their molecular tumour biology is important for early diagnosis and better treatment. Genes play an important role in the development of obesity. Few genes such as leptin, leptin receptor encoded by the db (diabetes), pro-opiomelanocortin, AgRP and NPY and melanocortin-4 receptors and insulin-induced gene 2 were linked to obesity. MicroRNAs control gene expression via mRNA degradation and protein translation inhibition and influence cell differentiation, cell growth and cell death. Overexpression of miR-143 inhibits tumour growth by suppressing B cell lymphoma 2, extracellular signal-regulated kinase-5 activities and KRAS oncogene. Cancers of the breast, uterus, renal, thyroid and liver are also related to obesity. Any disturbance in the production of sex hormones and insulin, leads to distortion in the balance between cell proliferation, differentiation and apoptosis. The possible mechanism linking obesity to cancer involves alteration in the level of adipokines and sex hormones. These mediators act as biomarkers for cancer progression and act as targets for cancer therapy and prevention. Interestingly, many anti-cancerous drugs are also beneficial in treating obesity and vice versa. We also reviewed the possible link in the mechanism of few drugs which act both on cancer and obesity. The present review may be important for molecular biologists, oncologists and clinicians treating cancers and also pave the way for better therapeutic options.

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Global methylation profiling to identify epigenetic signature of gallbladder cancer and gallstone disease

Abstract

Promoter methylation in various tumor suppressor genes is reported to influence gallbladder carcinogenesis. Here, we aimed to identify methylation status in gallbladder cancer (GBC) by performing a comprehensive genome-wide DNA methylation profiling. The methylation status of 485,577 CpG sites were investigated using Illumina's Infinium Human Methylation 450 BeadChip array in 24 tissues (eight each of tumor, adjacent non-tumor, and gallstone). About 33,443 differentially methylated sites (DMRs) were obtained in the whole human genome, of which 24,188 (72 %) were hypermethylated and 9255 (28 %) were hypomethylated. The data also revealed that majority of the DMRs are localized on the proximal promoter region [Transcription start sites (TSS200, TSS1500) and 5′ untranslated region (5′UTR)] and first exon. Exclusion of first exon detected a total of 10,123 (79 %) hypermethylated and 2703 (21 %) hypomethylated sites. Comparative analysis of the later with our differential proteomics data resulted in identification of 7 hypermethylated or down-regulated (e.g., FBN1, LPP, and SOD3) and 61 hypomethylated or up-regulated markers (e.g., HBE1, SNRPF, TPD52) for GBC. These genes could be further validated on the basis of their methylation/expression status in order to identify their utility to be used as biomarker/s for early diagnosis and management of GBC.

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