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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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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