bluuebunny/crossref_metadata_2025 huggingface dataset:
Modified Method of Contrast Transthoracic Echocardiography for the Diagnosis of Patent Foramen Ovale
Authors: Zhao Enfa , Du Yajuan , Xie Hang , Zhang Yushun
Published: May 2019

Purpose. To compare the sensitivity and specificity of modified and traditional methods of contrast echocardiography of the right portion of the heart in patients with a suspicion of patent foramen ovale (PFO). Methods. The study population consisted of 506 patients with high clinical suspicion of PFO. The traditional Valsalva maneuver consists of expiration against a closed glottis after a full inspiration. A modified Valsalva maneuver was performed with a handmade pressure monitoring device, which measured pressure during performance of the Valsalva maneuver. Modified and traditional methods of contrast echocardiography were performed among all patients. Contrast transesophageal echocardiography (TEE) was regarded as the gold standard. Results. A total of 279 patients with PFO were confirmed by TEE. 259 cases (sensitivity: 92.83%) were detected by a modified method of contrast echocardiography of the right portion of the heart, while 234 cases were detected using the traditional method (sensitivity: 83.87%). The sensitivity of modified contrast echocardiography of the right portion of the heart was significantly higher than that of the traditional method (92.83% vs. 83.87%, P=0.001). However, there was no significant difference in the specificity of the two methods for the diagnosis of PFO (97.35% vs. 96.03%, P=0.431). Additionally, the results of semiquantitative evaluation of PFO using modified method failed to show a more positive rate than shown by the traditional method (Z=−1.782, P=0.075). Conclusions. Modified contrast echocardiography of the right portion of the heart yielded a higher sensitivity than the traditional method, which contributed to the diagnosis of cardiac PFO. The research was a part of a register study (https://register.clinicaltrials.gov/ ClinicalTrials ID: NCT02777359).
Abstract CN04-02: Phase I trials: Limits and limitations in proof of concept
Authors: Verweij Jaap
Published: May 2019

We could and maybe should ask the question what is meant by “proof of concept” in early drug development. Do we mean that the drug hits the molecular target it is supposed to hit, which in essence may still be clinically meaningless. Or do we mean that we can proof that the drug has the expected signal of biological anti-tumor activity in a human being? And if so, what level of evidence are we looking for? Obviously the ultimate proof that a drug is beneficial can only be obtained in appropriately designed phase III studies. But these are expensive trials, and it would be worthwhile to be able to estimate earlier on in the development if the drug might be doing what it is supposed to do according to the preclinical information obtained.

Is looking for proof of concept in a phase I study stage of development like asking the impossible? Enormous amounts of effort and money have recently been invested in early clinical trials trying to better predict the outcome of later phase studies. Most of the obtained information has not been very supportive for Go/No-Go decisions. Interestingly analyzing the data for some of the recently registered agents it turns out they in retrospect predicted their activity by showing anatomical size changes as classified by RECIST, in a small or larger subset of patients in the phase I studies. For some of these agents, molecular marker changes coincided with the anatomical size changes, but in no instance was a molecular marker change without an anatomical size change predictive of relevant activity.

We should bear in mind that when starting phase I studies we frequently still have limited knowledge on the pharmacodynamics of a new agent. Thus the selection of patients is often a limiting factor in trying to assess the desired activity. The more recent focused development of Hedgehoc and ALK-fusion protein inhibitors shows that with a focused patient selection, sometimes based on early observations in the phase I studies, proof of concept prediction seems to come into reach. However for the majority of agents, we still seem to be looking into a crystal ball. Tumor size changes can be considered as biomarkers and should only be replaced by something else once we have certainty that a molecular change coincides with size change. Based on these observations models can be build that might be helpful in clinical development.

The fact that more simple assays than measuring anatomical size have not yet been able to provide us with appropriate predictions of efficacy, should not stop us from trying to develop these simple tools. And early hints that we may be on track are available.

Citation Information: Mol Cancer Ther 2009;8(12 Suppl):CN04-02.
Abstract CN07-02: Disrupting insulin-like growth factor signaling with monoclonal antibodies
Authors: Yee Douglas , Fagan Dedra H. , Zhang Xihong , Oh Annabell S. , LaPara Kelly , Becker Marc , Sachdev Deepali , Zhang Hua
Published: May 2019

The insulin-like growth factor (IGF) system is composed of a network of ligands, receptors, and binding proteins. The type I IGF receptor (IGF1R) is a transmembrane tyrosine kinase receptor and shares a high degree of homology with the insulin receptor (InsR). Data from many sources implicate the IGF system in cancer biology. Because of the role for InsR in glucose homeostasis, specific targeting of IGF1R with monoclonal antibodies has been deemed desirable. Numerous monoclonal antibodies have been developed against this receptor and share similar properties in preclinical model systems. To date, all of the antibodies have been shown to bind IGF1R and cause its internalization and downregulation. Early clinical studies have shown that IGF1R antibodies have activity as single agents in some diseases (sarcoma) and have activity in combination with cytotoxic chemotherapy. These early promising results suggest that inhibition of this receptor will emerge as a new cancer therapy. In addition, these early clinical results raise additional questions regarding optimizing their use in cancer treatment. In a xenograft model, monoclonal antibodies to IGF1R do not suppress tumor growth of the MDA-435/LCC6 cell line yet inhibit tumor metastasis. These data suggest that a commonly measured clinical phenotype, tumor growth, may not be detected in early phase II clinical trials. Clinical trials have also shown that IGF1R monoclonal antibody therapy results in elevation of growth hormone, IGF-I, and insulin levels. Since InsR may also mediate signaling in the IGF system, it is possible that InsR is also a target for cancer therapy. To address this issue, we have used shRNA to downregulate InsR expression while leaving IGF1R levels intact. In the MDA-435/LCC6 cells, disruption of InsR decreases tumor growth and inhibits pulmonary metastases. We have also selected cells in increasing concentrations of IGF1R antibodies. Finally, long term incubation of cells with IGF1R monoclonal antibodies results in cells with low levels of receptor expression, yet the receptor remains biochemically functional and can be inhibited by IGF1R tyrosine kinase inhibitors. Thus, disruption of IGF1R signaling has promise as a new cancer therapy. Future consideration of the role of the ligands, the InsR, and combination therapies with other signaling disruptors will allow us to optimize this therapeutic strategy.

Citation Information: Mol Cancer Ther 2009;8(12 Suppl):CN07-02.
Abstract CN07-03: CD47 is an adverse prognostic factor and therapeutic antibody target on human AML stem cells
Authors: Majeti Ravindra , Chao Mark P. , Alizadeh Ash A. , Pang Wendy W. , Jaiswal Siddhartha , Gibbs Kenneth D. , Weissman Irving L.
Published: May 2019

Human acute myeloid leukemia (AML) is organized as a cellular hierarchy initiated and maintained by rare self-renewing leukemia stem cells (LSC), which must be eliminated in order to cure the patient. We identified increased expression of CD47 on human AML LSC compared to their normal counterparts. CD47 is a cell surface molecule that serves as the ligand for SIRP-alpha on the surface of phagocytes, which in turn transmits a dominant inhibitory signal for phagocytosis. In this way, CD47 essentially functions as a “don't eat me” signal. We hypothesized that increased CD47 expression contributes to pathogenesis by inhibiting phagocytosis of AML LSC. Consistent with this hypothesis, we found that increased CD47 expression predicted worse overall survival in 3 independent cohorts of adult AML patients. Furthermore, we predicted that disruption of the interaction of CD47 with SIRP-alpha would result in phagocytosis and elimination of AML LSC. We found that blocking monoclonal antibodies directed against CD47 enabled phagocytosis of AML LSC, but not normal CD34+ human bone marrow progenitor cells, by human macrophages in vitro. Additionally, coating of human AML LSC with anti-CD47 monoclonal antibodies inhibited their engraftment in vivo in a xenotransplantation assay. Finally, analogous to a clinical therapy, treatment of human AML-engrafted mice with anti-CD47 antibody eliminated AML cells in the peripheral blood and bone marrow and targeted LSC. In summary, increased CD47 expression is an independent poor prognostic factor that can be targeted on human AML stem cells with monoclonal antibodies capable of stimulating phagocytosis and elimination of LSC. Targeting of CD47 with blocking monoclonal antibodies to induce phagocytosis is a novel mechanism for antibody cancer therapy. While anti-CD47 antibodies can be effective monotherapy for human AML, such antibodies may be equally, if not more, effective as part of a combination strategy. The combination of an anti-CD47 antibody, able to block a strong inhibitory signal for phagocytosis, with a second antibody able to bind an LSC-specific molecule and engage Fc receptors on phagocytes, thereby delivering a strong positive signal for phagocytosis, may result in a synergistic stimulus for phagocytosis and specific elimination of AML LSC.

Citation Information: Mol Cancer Ther 2009;8(12 Suppl):CN07-03.
Abstract PL07-03: Targeting the hedgehog pathway in cancer
Authors: de Sauvage Frederic J.
Published: May 2019

The Hedgehog (Hh) pathway is an ancient signaling cascade that directs patterning in most animals and is crucial for proper development. While Hh signaling is very active during most stages in embryogenesis, it remains relatively quiet in adult life. However, aberrant reactivation of the pathway in adult tissue can lead to the development of cancer (1). Hh pathway activation in tumors such as basal cell carcinoma (BCC) and medulloblastoma is the result of inactivating mutations in PATCHED (PTCH) or activating SMOOTHENED (SMO) mutations. Targeting the Hh pathway with small molecule antagonists therefore provides a new therapeutic opportunity for the treatment of these tumor types. GDC-0449, a systemic Hedgehog (Hh) pathway inhibitor, was tested in a first-in-human, first-in-class, phase I study BCC patients. Strong anti-tumor activity was observed in patients with locally advanced, multifocal or metastatic thereby confirming the importance of inhibiting aberrant Hh signaling in BCC (2). In addition to its role in BCC and medulloblastoma, Hh pathway activation in other solid tumor types, such as pancreatic, ovarian or colon cancer is the result of upregulation of Hh ligand expression in epithelial tumor cells, which acts in a paracrine manner to activate the pathway in stromal fibroblasts (3, 4). These may in turn provide growth factor(s) and/or a microenvironement that promotes tumor growth directly or by affecting other compartments such as the vasculature. Inhibition of the Hh pathway may therefore also provide benefit in these tumors and is currently being explored in the clinic with GDC-0449.

Citation Information: Mol Cancer Ther 2009;8(12 Suppl):PL07-03.
Abstract A10: Analysis of gene expression and DNA methylation profiles of Notch signaling pathway genes in human glioblastoma
Authors: Aithal Madhuri G S , Narayanappa Rajeswari
Published: May 2019

In cancer, DNA methylation affects important signal transduction pathways leading to altered receptor function, disruption of normal cell-cell interaction, etc. Since methylation occurs at a very early stage, hypermethylated promoters hold great promise as biomarkers for early detection and an effective drug target for gene reactivation. The Notch signaling pathway is one such developmental pathway governing cell fate decisions. Dysregulated Notch signaling is found to have a prominent role in the development of various cancers. Glioblastoma is the most common primary brain tumor with a very poor prognosis. Therefore it is important to study genetic and epigenetic events leading to gliomagenesis and to guide new treatment strategies. The aim of this study was to detect Notch pathway genes potentially regulated by promoter methylation in human glioblastoma. We used real-time PCR and methylation-specific PCR to study gene expression and methylation status of seven Notch pathway genes (Notch1, Notch2, Notch3, Notch4, JAG1, JAG2 and DLL3) from human glioblastoma formalin fixed paraffin embedded sections. We identified Notch3 and JAG2 promoters as methylated and Notch4 with both methylated and unmethylated promoter. Despite methylation, Notch3 gene showed robust gene expression suggesting its partial dependency on promoter methylation and the presence of alternative regulatory mechanisms. However, low gene expression of JAG2 and the absence of Notch4 gene expression suggest a possibility of epigenetic silencing. This study for the first time provides gene expression and DNA methylation profiles of Notch pathway genes from glioblastoma patient samples. We have identified genes whose expression may be regulated by epigenetic mechanisms and thus can be used as markers that may guide treatment decisions.

Note: This abstract was not presented at the conference.

Citation Format: Madhuri G S Aithal, Rajeswari Narayanappa. Analysis of gene expression and DNA methylation profiles of Notch signaling pathway genes in human glioblastoma. [abstract]. In: Proceedings of the AACR Special Conference: Improving Cancer Risk Prediction for Prevention and Early Detection; Nov 16-19, 2016; Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(5 Suppl):Abstract nr A10.
Abstract A12: Urinary levels of PGE-M and estrogens are independently associated with postmenopausal breast cancer risk
Authors: Kim Sangmi , Campbell Jeff , Yoo Wonsuk , Taylor Jack A. , Sandler Dale P.
Published: May 2019

Prostaglandin E2 (PGE2) induces aromatase expression in adipose tissue leading to increased estrogen production that may promote the development and progression of breast cancer. However, few studies have simultaneously investigated systemic levels of PGE2 and estrogen in relation to postmenopausal breast cancer risk. In a case-cohort study of postmenopausal women (295 cases and 294 subcohort) we previously reported that high levels of PGE-M, a major metabolite of PGE2, were associated with an increased risk of breast cancer among postmenopausal women who did not regularly use nonsteroidal anti-inflammatory drugs (NSAIDs). Here we determined urinary estrogen metabolites (EMs) using mass spectrometry in the same case-cohort set and using linear regression estimated the effect of PGE-M on EMs. Hazard ratios (HRs) for the risk of developing breast cancer in relation to PGE-M and EMs were evaluated in Cox regression models with and without mutual adjustment. PGE-M was a significant predictor of estrone (E1), but not estradiol (E2) levels in multivariable analysis. Elevated E2 levels were associated with an increased risk of developing breast cancer (HRQ5vs.Q1 =1.54, 95% CI: 1.01-2.35), and this association remained unchanged after adjustment for PGE-M (HRQ5vs.Q1 =1.52, 95% CI: 0.99-2.33). Similarly, elevated levels of PGE-M were associated with increased risk of developing breast cancer (HRQ4vs.Q1 =2.01, 95% CI: 1.01-4.29), and this association was only nominally changed after consideration of E1 or E2 levels. Urinary levels of PGE-M and parent estrogens were independently associated with future risk of developing breast cancer among these postmenopausal women. Increased breast cancer risk associated with PGE-M might be attributable both to PGE2-mediated increases in estrogens, and to additional effects related to inflammation.

Note: This abstract was not presented at the conference.

Citation Format: Sangmi Kim, Jeff Campbell, Wonsuk Yoo, Jack A. Taylor, Dale P. Sandler. Urinary levels of PGE-M and estrogens are independently associated with postmenopausal breast cancer risk. [abstract]. In: Proceedings of the AACR Special Conference: Improving Cancer Risk Prediction for Prevention and Early Detection; Nov 16-19, 2016; Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(5 Suppl):Abstract nr A12.
Abstract B02: Recreational physical activity, sedentary time and the incidence of colorectal polyps in a screening population for colon cancer
Authors: Brenner Darren R. , Yannitsos Demetra H. , Warkentin Matthew , Shaw Eileen , Brockton Nigel T. , McGregor S. Elizabeth , Town Susanna , Hilsden Robert J.
Published: May 2019

Background: Despite the consistent association between regular recreational moderate to vigorous physical activity (rMVPA) and reduced risk of colorectal cancer (CRC), few studies have examined the effect of physical activity on carcinogenic development by examining colorectal adenomas (polyps). Furthermore, even fewer studies have examined the impact of sedentary behavior/time (ST) on the development of polyps. In this study we examined the associations between rMVPA and ST and the presence, number and type of colorectal polyps in a population undergoing screening for colorectal cancer in Calgary, Alberta, Canada.

Methods: A cross-sectional study of 2,499 individuals undergoing colonoscopy at the Forzani & MacPhail Colon Cancer Screening Centre in Calgary, Canada was conducted. Physical activity levels and ST were characterized using hours of rMVPA, meeting cancer prevention recommendations (≥150 mins/wk of rMVPA) and hours of ST using self-reported data from the Long Form International Physical Activity Questionnaire. Unconditional logistic regression models were used to estimate the crude and adjusted odds ratios (OR) for presence of polyps associated with rMVP and ST.

Results: Crude estimates for meeting cancer prevention guidelines (ORunadj=0.83, 95% CI: 0.70-0.98) and increasing rMVPA (ORunadj=0.75, 95% CI: 0.60-0.93 for 1-3 hrs/wk vs. 0) were associated with lower odds of having ≥1 polyp at screening. Effect estimates were attenuated in adjusted models. Threshold effects were observed for ST with significant associations observed for up to 20 hours/week of sitting time (ORadj per hour sitting=1.05, 95% CI: 1.01-1.09). Associations were strongest for rMVPA among females (ORadj=0.68, 95% CI: 0.48-0.97 for 1-3 hrs/wk vs. 0) and for ST among males (ORadj=1.74, 95% CI: 1.06-2.86 for 14-35hrs/wk of ST vs. 0-14 hrs/wk)

Conclusions: In this large population undergoing colonoscopy screening for colorectal cancer, rMVPA was associated with reduced prevalence of polyps at screening, particularly among females. Even low amounts of regular ST (2-5hrs/day) were associated with the presence of polyps, particularly among males. Strategies aimed at reducing the amount of pre-carcinogenic colon lesions should combine increasing rMVPA and reducing ST.

Citation Format: Darren R. Brenner, Demetra H. Yannitsos, Matthew Warkentin, Eileen Shaw, Nigel T. Brockton, S. Elizabeth McGregor, Susanna Town, Robert J. Hilsden. Recreational physical activity, sedentary time and the incidence of colorectal polyps in a screening population for colon cancer. [abstract]. In: Proceedings of the AACR Special Conference: Improving Cancer Risk Prediction for Prevention and Early Detection; Nov 16-19, 2016; Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(5 Suppl):Abstract nr B02.
Abstract B10: Development of a cancer risk prediction tool for use in the Risk Estimation For Lifestyle Enhancement Combined Trial (REFLECT)
Authors: Lophatananon Artitaya , Alajmi Kawthar , Thorpe Emma , Hughes John , Blodgett Joanna , Fisher Bernadette , Rogers Simon , Waters Erika K. , Muir Kenneth R.
Published: May 2019

This abstract is being presented as a short talk in the scientific program. A full abstract is printed in the Proffered Abstracts section (PR14) of the Conference Proceedings.

Citation Format: Artitaya Lophatananon, Kawthar Alajmi, Emma Thorpe, John Hughes, Joanna Blodgett, Bernadette Fisher, Simon Rogers, Erika K. Waters, Kenneth R. Muir. Development of a cancer risk prediction tool for use in the Risk Estimation For Lifestyle Enhancement Combined Trial (REFLECT). [abstract]. In: Proceedings of the AACR Special Conference: Improving Cancer Risk Prediction for Prevention and Early Detection; Nov 16-19, 2016; Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(5 Suppl):Abstract nr B10.
Abstract B11: Projecting individualized absolute risk of developing gastric cancer in Koreans
Authors: Song Minkyo , Yang Jae Jeong , Sung Hyuna , Kong Seong-Ho , Lee Hyuk-Joon , Kim Hyung-Ho , Kim Sang Gyun , Yang Han-Kwang , Sawada Norie , Tsugane Shoichiro , Inoue Manami , Kang Daehee
Published: May 2019

This abstract is being presented as a short talk in the scientific program. A full abstract is printed in the Proffered Abstracts section (PR15) of the Conference Proceedings.

Citation Format: Minkyo Song, Jae Jeong Yang, Hyuna Sung, Seong-Ho Kong, Hyuk-Joon Lee, Hyung-Ho Kim, Sang Gyun Kim, Han-Kwang Yang, Norie Sawada, Shoichiro Tsugane, Manami Inoue, Daehee Kang. Projecting individualized absolute risk of developing gastric cancer in Koreans. [abstract]. In: Proceedings of the AACR Special Conference: Improving Cancer Risk Prediction for Prevention and Early Detection; Nov 16-19, 2016; Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(5 Suppl):Abstract nr B11.
Abstract B14: Modulating effects of green and black tea on biomarkers of chronic inflammation by gender and smoking status
Authors: Hakim Iman A. , Aldaham Sami A. , Foote Janet , Chow H-H Sherry
Published: May 2019

Background/Purpose: Epidemiologic data implies that there are gender differences in lung cancer pathogenesis and possibly increased susceptibility to lung cancer in women. Chronic inflammation has been implicated as important modulator of human health by playing a significant role in both disease prevention and disease development. Several studies have demonstrated increased interleukin 6 (IL-6) and C-reactive protein (CRP) in the blood of smokers. The overall goal of this study was to develop a feasible tea intervention that will serve as a model for the chemoprevention of a wide range of tobacco-related diseases. Our immediate goal, that was addressed over a 4-year study period, was to determine the effects of high tea consumption on biological markers of chronic inflammation that mediate lung cancer risk, including, IL-6, CRP and antioxidant enzyme activities.

Methods: We completed a 6-month randomized, controlled, double-blinded trial in a group of current and former smokers. Participants were stratified on smoking status and gender, and were randomized to green or black tea preparations or a control intervention (matching placebo). Levels of urinary iIL-6 and CRP are used to measure chronic inflammation and levels of superoxide dismutase (SOD) in red blood cells are used to measure antioxidant enzymes.

Results: The study protocol was approved by all parties. A total of 138 participants (78 females and 60 males) completed the study. Our data show that il6 is significantly correlated with years of smoking and pack/year among smokers and former smokers. At the end of the 6-month intervention, female smokers in the green tea group showed a significant decrease in IL-6 (P=0.036) while male former smokers in the black tea group showed a significant decrease in CRP levels (P=0.012). There were no significant changes in dietary and serum antioxidant levels between the different groups.

Conclusion: This data implies that smokers are more likely to benefit from green tea intake while the beneficial effects of black tea are observed among former smokers.

Note: This abstract was not presented at the conference.

Citation Format: Iman A. Hakim, Sami A. Aldaham, Janet Foote, H-H Sherry Chow. Modulating effects of green and black tea on biomarkers of chronic inflammation by gender and smoking status. [abstract]. In: Proceedings of the AACR Special Conference: Improving Cancer Risk Prediction for Prevention and Early Detection; Nov 16-19, 2016; Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(5 Suppl):Abstract nr B14.
Abstract B15: Communicating information about personalised genomic risk of melanoma to family, friends, and health professionals
Authors: Cust Anne E. , Smit Amelia K. , Espinoza David , Louise Keogh , Butow Phyllis N. , Dunlop Kate , Kirk Judy , Newson Ainsley J.
Published: May 2019

Background: It is anticipated that cancer risk prediction tools, including those with genomic risk information, will increasingly be used to communicate personalised cancer risk to the public. Receiving information on personal genomic risk of cancer might encourage conversations about cancer prevention and early detection with family, friends and health professionals, but few studies have examined this.

Aims: To explore participant communication about personal genomic risk of melanoma to family, friends and health professionals, using a mixed-methods approach, and to examine results according to participants' genomic risk category (low, average, high).

Methods: We conducted a study examining the impact of giving information on personalised genomic risk of melanoma to the public. Participants (n=101) received a personalised booklet presenting their melanoma genomic risk based on variants in 21 genes, together with telephone-based genetic counselling and generic educational materials. They completed a questionnaire 3-months after receiving their personal genomic risk of melanoma. To further contextualise these data, we conducted semi-structured qualitative interviews with 30 participants.

Results: Participants' communication with health professionals according to melanoma genomic risk category was 41% for high-risk, 16% for average-risk and 13% for low-risk (P=0.02). Communication with family was 83% for high-risk, 65% for average-risk, 79% for low-risk participants (P=0.19); and communication with friends was 55% for high-risk, 43% for average-risk, 54% for low-risk participants (P=0.49). Preliminary thematic analysis found that preventive behaviours and early detection were raised by participants in discussions with family and doctors. Reasons for not communicating genomic risk included: concern about causing worry and not feeling a need to share the information.

Conclusions: Genomic risk information prompted conversations about melanoma risk and prevention, most frequently with family. When stratified by genomic risk, comparable numbers of participants discussed their genomic risk with family and friends, but communication with health professionals was more frequent among participants in a high-risk category.

Citation Format: Anne E. Cust, Amelia K. Smit, David Espinoza, Keogh Louise, Phyllis N. Butow, Kate Dunlop, Judy Kirk, Ainsley J. Newson. Communicating information about personalised genomic risk of melanoma to family, friends, and health professionals. [abstract]. In: Proceedings of the AACR Special Conference: Improving Cancer Risk Prediction for Prevention and Early Detection; Nov 16-19, 2016; Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(5 Suppl):Abstract nr B15.
Abstract B29: Terahertz spectral imaging and scanning for early detection of skin cancer
Authors: Rahman Anis , Rahman Aunik K. , Rao Babar
Published: May 2019

A terahertz diagnosis tool has been developed to identify early stage skin cancer at the cellular level. Here, three different techniques are used where each technique independently identifies a given disease condition compared to healthy skin specimen; thus, collectively forms a diagnostic procedure with minimal falls alarm. Namely, terahertz sub-surface spectral imaging, terahertz absorbance spectroscopy and skin thickness profiling have been used. Terahertz radiation is non-ionizing, therefore, save for in-vivo investigations. It is also more sensitive than other forms of probing energies. In the present work, biopsies from three skin disease conditions have been compared with a healthy skin sample. It was found that the terahertz images clearly visualize healthy skin cells where a regular cellular pattern is visible. In contrast, cancerous skin specimen images exhibit deterioration from regular cellular pattern indicating abnormal conditions. For example, the skin specimen excised by Mohs microsurgery and diagnosed for basal cell carcinoma exhibits cell agglomeration indicating the onset of tumor formation. Similarly, other skin conditions such as squamous cell carcinoma and lentigo maligna exhibit their characteristic images without a regular cell pattern. Since the skin is a layered structure, a thickness profile of the healthy skin clearly exhibits this layering pattern while the layering is significantly diminished for cancerous skin samples. Thus a diminished layering profile is an indication of skin abnormalities. In addition, spectral analyses also exhibit distinguishable differences between different cancer conditions compared to healthy skin spectrum. Details of the methodology and results will be discussed.

Note: This abstract was not presented at the conference.

Citation Format: Anis Rahman, Aunik K. Rahman, Babar Rao. Terahertz spectral imaging and scanning for early detection of skin cancer. [abstract]. In: Proceedings of the AACR Special Conference: Improving Cancer Risk Prediction for Prevention and Early Detection; Nov 16-19, 2016; Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(5 Suppl):Abstract nr B29.
Abstract IA02: A brief overview of building and validating absolute risk models
Authors: Pfeiffer Ruth
Published: May 2019

Statistical models that predict disease incidence, disease recurrence or mortality following disease onset have broad public health and clinical applications. Of great importance are models that predict absolute risk, namely the probability of a particular outcome, e.g. breast cancer, in the presence of competing causes of mortality. Although relative risks are useful for assessing the strength of risk factors, they are not nearly as useful as absolute risks for making clinical decisions or establishing policies for disease prevention. That is because such decisions or policies often weigh the favorable effects of an intervention on the disease of interest against the unfavorable effects that the intervention might have on other health outcomes. The common currency for such decisions is the (possibly weighted) absolute risk for each of the health outcomes in the presence and absence of intervention. First, I discuss various approaches to building absolute risk models from various data sources and illustrate them with absolute risk models for breast cancer and thyroid cancer.

Before a risk prediction model can be recommended for clinical or public health applications, one needs to assess how good the predictions are. I will give an overview over various criteria for assessing the performance of a risk model. I assume that we have developed a risk model on training data and assess the performance of the model on independent test or validation data. This approach, termed external validation, provides a more rigorous assessment of the model than testing the model on the training data (internal validation); even though cross-validation techniques are available to reduce the over-optimism bias that can result from testing the model on the training data. I present general criteria for model assessment, such as calibration, predictive accuracy and classification accuracy, and discriminatory accuracy. Calibration measures how well the numbers of events predicted by a model agree with the observed events that arise in a cohort. Calibration is the most important general criterion, because if a model is not well calibrated, other criteria, such as discrimination, can be misleading. Discriminatory accuracy measures how well separated the distributions of risk are for cases and non-cases. Another approach is to tailor the criterion to the particular application. I will also present novel criteria for screening applications or high risk interventions. If losses can be specified in a well-defined decision problem, I will show how models can be assessed with respect to how much they reduce expected loss.

Citation Format: Ruth Pfeiffer. A brief overview of building and validating absolute risk models. [abstract]. In: Proceedings of the AACR Special Conference: Improving Cancer Risk Prediction for Prevention and Early Detection; Nov 16-19, 2016; Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(5 Suppl):Abstract nr IA02.
Abstract IA07: Using genetic information in screening and prevention: Perspective of clinicians and policy-makers
Authors: Ransohoff David F.
Published: May 2019

How can genetic information be effectively used in screening and prevention?

The conceptual framework and rules of evidence for answering this question - widely used by clinicians, policy-makers, and payors - has been developed over decades in the field of Evidence-Based Medicine, exemplified by the approach of the USPSTF (US Preventive Services Task Force) and EGAPP (Evaluation of Genomic Applications in Practice and Prevention). The framework's principles include using the best evidence (clinical trials where available, and observational data where necessary) assessed in systematic searches that consider quality of each study using specific rules of evidence. Outcomes are projected quantitatively to assess net benefit (benefits vs harms) of prevention and screening strategies.

In this framework, genetic data may provide information about the magnitude of lifetime risk of developing a specific cancer, while other data (including genomic data) may provide information about the current risk that a cancer is present. Risks of appropriate magnitude may direct interventions that can prevent cancer (for example chemoprevention or preventive surgery) or that can detect the presence of early curable cancer or an important precursor.

This talk will describe the quantitative conceptual framework and its rationale, along with the implications, challenges, and opportunities for the use of genetic and genomic information for cancer prevention and screening.

Citation Format: David F. Ransohoff. Using genetic information in screening and prevention: Perspective of clinicians and policy-makers. [abstract]. In: Proceedings of the AACR Special Conference: Improving Cancer Risk Prediction for Prevention and Early Detection; Nov 16-19, 2016; Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(5 Suppl):Abstract nr IA07.
Abstract PR14: Development of a cancer risk prediction tool for use in the Risk Estimation For Lifestyle Enhancement Combined Trial (REFLECT)
Authors: Lophatananon Artitaya , Alajmi Kawthar , Thorpe Emma , Hughes John , Blodgett Joanna , Fisher Bernadette , Rogers Simon , Waters Erika K. , Muir Kenneth R.
Published: May 2019

Exposure to modifiable lifestyle and environmental risk factors accounts for approximately 40% of all cancers in the UK. Therefore, primary prevention is of growing importance and an effective and engaging strategy that encourages long-term adoption of healthy lifestyle behaviours is required.

Several multivariable risk prediction models have been developed to assess an individual's risk of developing specific cancers. Such models can be used in a variety of settings for prevention, screening, and guiding investigation and treatment. Models aimed at predicting future disease risk that contains modifiable factors may be of particular use for targeting health promotion activities at an individual level. We have therefore developed a UK version of the well-established U.S. derived “YourDiseaseRisk” model which allow users to quantify their individual risk of developing individual cancers relative to the population average risk.

The UK-Manchester version of “YourDiseaseRisk” computes 10 year cancer risk for 11 cancer types utilising UK figures for prevalence of risk factors and cancer incidence. The model can be used to estimate cancer risk for use in community settings.

Using a variety of qualitative and quantitative methods we have assessed the impact of the REFLECT risk model on public understanding of cancer risk factors and UK NHS Cancer Screening programs. We have also explored public opinion and perceptions regarding the provision of information on of genetic susceptibility to aid in further personalising cancer risk information.

This abstract is also being presented as Poster B10.

Citation Format: Artitaya Lophatananon, Kawthar Alajmi, Emma Thorpe, John Hughes, Joanna Blodgett, Bernadette Fisher, Simon Rogers, Erika K. Waters, Kenneth R. Muir. Development of a cancer risk prediction tool for use in the Risk Estimation For Lifestyle Enhancement Combined Trial (REFLECT). [abstract]. In: Proceedings of the AACR Special Conference: Improving Cancer Risk Prediction for Prevention and Early Detection; Nov 16-19, 2016; Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(5 Suppl):Abstract nr PR14.
Abstract A10: Epigenetic mechanisms in liver tumors: Gene expression analysis of epigenetic machinery in hepatoblastomas
Authors: Rivas Maria , Costa Cecília da , Toledo Silvia , Cypriano Monica , Caires Luiz , Goulart Ernesto , Carraro Dirce , Werneck Isabela , Rosenberg Carla , Zatz Mayana , Krepischi Ana
Published: May 2019

Liver tumors in children are rare and account for only 1-4% of all pediatric solid tumors. While hepatocellular carcinoma is predominant in adults, the most common liver cancer in children is hepatoblastoma, an embryonal tumor. The prognosis of patients with advanced tumor stages remains poor as well as surviving children often face severe effects following aggressive chemotherapy.

Hepatoblastomas carry a low mutational burden, and the impairment of epigenetic mechanisms, which are the core of embryogenesis and development, stands out as an alternative route for tumorigenesis.

The main objective of this study was to explore the role of genes associated with methylation and hydroxymethylation in hepatoblastomas. The expression of seven genes of the epigenetic machinery (DNMT1, DNMT3A, DNMT3L, UHRF1, TET1, TET2, and TET3) was analyzed by qPCR (Taqman). The cohort of tumors consisted of 21 hepatoblastomas and a control group of 8 non-tumor differentiated liver tissues. Additionally, a 5hmC quantification assay (Quest 5-hmC DNA ELISA Kit) was applied to assess the level of 5hmC in tumors.

TET1 and TET2 genes, whose proteins are responsible for the active demethylation of 5-methylcytosine (5mC), and consequent production of 5-hydroxymethylcytosine (5hmC), were found to be upregulated. A significant increase in the 5hmC levels was also evident in tumor samples when compared to nontumoral tissues.

We have shown in hepatoblastomas an upregulated profile of TET1 and TET2 enzymes with a resulting elevation of 5hmC level in tumors. Our data suggest that hepatoblastomas could present a pluripotency pattern of gene expression when compared to differentiated livers; to address this issue, the expression levels of three genes associated with pluripotency (POU5F1, SOX2 and NANOG) were evaluated, with no significant alteration.

Therefore, although hepatoblastomas have a more undifferentiated molecular profile than mature hepatocytes, our results indicate that tumor cells are already commited with the differentiation process. Altogether, these data suggest that the development of hepatoblastomas is associated with a blockage in the stages of hepatoblasts.

Citation Format: Maria Rivas, Cecília da Costa, Silvia Toledo, Monica Cypriano, Luiz Caires, Ernesto Goulart, Dirce Carraro, Isabela Werneck, Carla Rosenberg, Mayana Zatz, Ana Krepischi. Epigenetic mechanisms in liver tumors: Gene expression analysis of epigenetic machinery in hepatoblastomas [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr A10.
Abstract A25: Intragroup genomic, transcriptional, and epigenomic variability is higher in sporadic than in BRCA1-associated hereditary triple-negative breast tumors
Authors: Nakamura Kivvi Duarte de Mello , Ramalho Rodrigo Fernandes , Brianese Rafael Canfield , Krepischi Ana , Barros Bruna D. F. , Carraro Dirce Maria
Published: May 2019

Intra-tumor genetic heterogeneity is a possible cause of therapy resistance and has consequences in the disease progression and patient survival. Triple-negative breast cancer (TNBC) is associated with rapid growth, early metastasis, and worse prognosis than other breast cancer subtypes. Close association has been identified between TNBC and germline loss-of-function mutations in BRCA1 gene which trigger the tumorigenic process in hereditary TNBC. Although at genomic level, TNBC was previously characterized as more heterogeneous than other breast cancer subtypes, the difference in genomic, epigenomic, and transcriptional variability between two groups of TNBC—sporadic (BRCA1-proficent) and hereditary (BRCA1-associated)—remains unclear. Here, we investigated both sporadic and hereditary TNBC, by using data from copy-number alterations (CNAs) array, methylation array, and RNA-Seq. A total of 80 samples, 40 TNBC BRCA1-proficient (classified as sporadic), 18 TNBC with BRCA1 germline mutation (classifed as hereditary) and 22 normal breast tissues used as controls, were used. Data from methylation and CNA arrays were analyzed with the RnBeads and snapCGH softwares, respectively. RNA-seq data was analyzed mainly with the STAR aligner, Bioconductor-GenomicFeatures and DESeq2 softwares. To assess the intragroup genomic, transcriptional, and epigenomic variability we used the inter-quantile difference between patients of the same group. Our results clearly demonstrated that the TNBC BRCA1-proficient group has a higher intragroup heterogeneity than the BRCA1-mutated group regarding (i) global pattern of gene expression, (ii) number and intensity of CNAs (copy number alterations), and (iii) level of promoter methylation. Moreover, normal breast samples showed the lowest intra-group heterogeneity for the last two features. Then, our results show higher genomic, transcriptional, and epigenomic variability in sporadic than hereditary TNBC and motivates further molecular subtyping of the sporadic TNBCs, which may reveal new targets to improve TNBC treatment.

Citation Format: Kivvi Duarte de Mello Nakamura, Rodrigo Fernandes Ramalho, Rafael Canfield Brianese, Ana Krepischi, Bruna D. F. Barros, Dirce Maria Carraro. Intragroup genomic, transcriptional, and epigenomic variability is higher in sporadic than in BRCA1-associated hereditary triple-negative breast tumors [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr A25.
Abstract A42: Prenatal role of medical radiation in children diagnosed with a blood cancer: Single-institution study, 2006-2016
Authors: Rohrer Robin L.
Published: May 2019

Background: Prenatal exposure to medical radiation is an identified risk for childhood cancers, but is difficult to document. The author developed a family questionnaire and interview form to identify possible exposures in children diagnosed from 2006-2016 with a blood cancer at a single institution. The Children's Hospital of Pittsburgh historically in this ten-year period has seen 180-200 new cases of a pediatric cancer each year with approximately 35-40% of these cancers being a blood cancer, notably an acute leukemia, chronic leukemia, Hodgkins's lymphoma, or a non-Hodgkin's lymphoma.

Method: Each converted family (approximately 30% of the cohort) has been interviewed at hospital, clinic, or through phone conversation who were diagnosed with a type of acute or chronic leukemia or lymphoma. All children were diagnosed/treated at the Children's Hospital of Pittsburgh (CHP). CHP is the tristate regional referral center which sees about 180-200 new cases of a pediatric cancer each year. Medical staff and psychosocial staff referred patient families for interview with the author.

Results: Among the families interviewed, at least one medical radiation prenatally has been identified in over one-third of families. These exposures prominently included sinus, chest or abdominal x-rays, or CT in either patient.

Conclusion: Exposures to medical radiation for a child later diagnosed with cancer may occur pre-conception, in utero, or in early childhood. These exposures may be part of the “perfect storm” which eventually results in a blood or other cancer in children. Documenting these exposures may possibly in future lead to more preventive measures pre-conception similar to the “image gently” initiative to limit the number of diagnostic procedures and radiation doses in CT imaging of children today.

Citation Format: Robin L. Rohrer. Prenatal role of medical radiation in children diagnosed with a blood cancer: Single-institution study, 2006-2016 [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr A42.