Detection Of Early-stage Tumors Research Articles

Location of Early Stage Tumor Detection using Microwave Imaging in the Breast Phantom.

Universally, the most predominant cause of female mortality is mainly due to breast cancer. Owing to numerous constraints in the existing imaging technique, researchers are trying out an alternative tool to detect the tumor before going to the miserable stage. This article presents a novel method to detect the mean value system for detecting the location of the tumor in different depths by shifting the antenna anywhere in the breast tissue. In addition, an algorithm to reconstruct the breast image, namely Delay-Multiply-and-Sum (DMAS) is followed to identify the tumor implanted in the breast tissue. The analysis shows that the maximum mean value occurs while the antenna moves very near to the tumor while the mean value reduces while the antenna shifts apart from the tumor location. The mean value in different locations is converted into a microwave image. The high intensity in the image exhibits the precise position of the tumor. This technique can identify the location of early-stage tumor of size 3mm. Multiple tumors of sizes 6mm and 7mm can identify at a depth of 12mm and 18mm in the homogeneous breast phantom. DMAS can provide better imaging results in the early stage tumor of size 3mm embedded in the breast phantom. Microwave imaging is an efficient technique to differentiate healthy and malignant tissue in the breast. Antenna plays a major role in identifying tumors in the breast in the early stage. Hence a high-performance Ultra Wideband Dielectric Resonator Antenna (DRA-UWB) is used to identify the tumor in the breast. An antenna is sketched in different locations of the breast phantom. On account of the hemispherical structure, the mean value of the reflected signal is high at the center than at the edge. Hence, the difference in mean value is calculated with and without breast phantom for identifying the tumor location. The overall efficiency of this technique can be improved by using a high-performance UWB antenna. The image of the breast is reformed by the DMAS beamforming algorithm.

A compact ultrawideband slotted patch antenna for early stage breast tumor detection applications

AbstractThis paper presents a compact ultrawideband slotted patch antenna for early stage tumor detection applications using microwave breast imaging systems. In order to reduce any reflections between the antenna and breast, the antenna is designed and optimized inside a coupling medium with electrical properties similar to that of normal breast tissue as a coupling medium. The wideband performance of the antenna is obtained by adding a rectangular slit and L-shaped sleeves on the ground plane. While the added rectangular slit mainly improves the matching, the L-shaped sleeves improve both the matching and the bandwidth. The antenna operates from 0.9 to 9.6 GHz with a fractional bandwidth of ~165$\%$, providing a good penetration and resolution. In addition, the proposed antenna has a very compact size of 16 × 16 mm2. Furthermore, an antenna array consisting of 31 antennas is formed around a realistic breast phantom in the simulation environment to demonstrate the imaging of a spherical tumor with a diameter of 5 mm inside the breast. The results confirm that the proposed antenna can be used for early stage breast tumor detection purposes.

Clinical Characteristics and Outcomes of Nonalcoholic Fatty Liver Disease–Associated Hepatocellular Carcinoma in the United States

The extent to which nonalcoholic fatty liver disease (NAFLD) contributes to hepatocellular carcinoma (HCC) prevalence in contemporary practices and whether there are any etiologic differences in surveillance receipt, tumor stage, and overall survival (OS) remain unclear. We aimed to estimate the burden of NAFLD-related HCC and magnitude of associations with surveillance receipt, clinical presentation, and outcomes in a contemporary HCC cohort. In a cohort of HCC patients from the Surveillance, Epidemiology and End Results-Medicare database between 2011 and 2015, we used multivariable logistic regression to identify factors associated with surveillance receipt, early-stage tumor detection, and curative treatment. Cox regression was used to identify factors associated with OS. Among 5098 HCC patients, NAFLD was the leading etiology, accounting for 1813 cases (35.6%). Compared with those with hepatitis C-related HCC, NAFLD was associated with lower HCC surveillance receipt (adjusted odds ratio, 0.22; 95% confidence interval [CI], 0.17-0.28), lower early-stage HCC detection (adjusted odds ratio, 0.49; 95% CI, 0.40-0.60), and modestly worse OS (adjusted hazard ratio, 1.20; 95% CI, 1.09-1.32). NAFLD subgroup analysis showed that early-stage HCC, absence of ascites/hepatic encephalopathy, surveillance, and curative treatment receipt were associated with improved OS. NAFLD patients with coexisting liver disease were more likely to have surveillance, early-stage detection, curative treatment, and improved OS than NAFLD patients without coexisting liver diseases. NAFLD is the leading etiology of HCC among Medicare beneficiaries. Compared with other etiologies, NAFLD was associated with lower HCC surveillance receipt, early-stage detection, and modestly poorer survival. Multifaceted interventions for improving surveillance uptake are needed to improve prognosis of patients with NAFLD-related HCC.

Oncoguía de carcinoma hepatocelular 2020

Hepatocellular carcinoma (HCC) represents the most common primary liver cancer, approximately 80-85% of the cases. It is the fourth most frequent cause of death, and it ranks sixth in incidence worldwide. HCC develops in patients with underlying liver disease, mainly due to a hepatitis B or C virus infection (HBV or HCV) or alcohol abuse. The increase in nonalcoholic fatty liver disease has augmented the liver cancer risk in the last few years and soon will become one of the main causes in West countries. Barcelona Clinic Liver Cancer Group (BCLC) staging is the primary clinical algorithm to define the patient’s disease stage according to the prognosis and treatment. Surveillance programs allow the detection of early-stage tumors that are susceptible to receiving curative therapies as resection, liver transplant, or local ablation. Transarterial chemoembolization (TACE) is the standard treatment for intermediate stages (BCLC staging). Such a stage is considered unresectable, even in a macroscopic vascular invasion, except for portal vein tumor thrombus. TACE may help select patients as candidates for a liver transplant but not candidates for resection or another ablative method. Systemic therapies for patients with advanced-stage liver cancer are changing fast, and now we have four new agents showing clinical efficacy in phase-III trials.

Chemoresistive Nanostructured Metal-Oxide Sensors for Human Tumor Tissue and Blood Exhalations Analysis

Early-stage tumor detection is one of the most coveted goals for the world research community. An effective prevention, associated to reliable screening protocols, is crucial to favor a early diagnosis, allowing doctors and surgeons to intervene with high probabilities of success on tumor affected patients. The main purpose of this study is cancer detection, exploiting the volatile organic compounds (VOCs) produced by cancer cells as tumor biomarkers [1][2], by investigating tumor tissue and blood samples. Tumor biomarkers exhalation is attributed to two main cell involving biological mechanisms: altered metabolism and cellular membrane peroxidation [3]. This experimental work was carried on using an innovative, fast-responding and reliable patented device, named SCENT B1 [4], entirely designed and assembled in the Sensor Laboratory of the University of Ferrara. It hosts an array of four specific metal-oxide (MOX) sensors able to detect gases in low concentration (up to 10 ppm) with high stability and repeatability, chosen after many tests on different types of biological samples (feces, blood, cell cultures, etc.) [5,6]; the chosen sensors are based on different mixtures of tin, titanium, tungsten, niobium, tantalum and vanadium oxides (ST25Au, W11, STN, TiTaV). Moreover, SCENT B1 is gifted of a power supply and sensor signal transduction electronic boards, a pneumatic air system (necessary to direct the VOCs contaminated air from the sample chamber to the sensors) and an ad hoc management and data acquisition software (LSS4) [6]. The sensor output signal is a voltage directly proportional to the sensor conductance, depending on the chemical redox reactions taking place on the surface of the sensor sensing material. The sensor response is: R=Vgas/Vair , where Vgas and Vair are the sensor voltage in gas presence and in dry air after the steady state achievement respectively [6].Sensor responses were further elaborated, using different statistical approaches as principal component analysis and receiver operating characteristics methods.Measurements have been performed on colorectal cancer and healthy tissues surgically removed from the same operatory piece (directly and far enough from tumor mass respectively) (Figure 1a), and on blood samples collected from tumor affected subjects and healthy ones as controls (Figure 1b). with the future aim of extending the study to other tumor types. All four sensors gave larger responses (although with different amplitudes) to the tumor tissue with respect to the healthy one. Smaller and reproducible responses were given by the breeding ground (DMEM) only, confirming that it does not alter the measurements. The results are consistent with the stronger and altered metabolism of tumor cells, leading them to emit a larger amount of volatile biomarkers with respect to the healthy ones;.All the four sensors hosted by SCENT B1 proved to be capable of distinguishing between healthy and tumor tissue and blood samples, although with different discrimination power. The encouraging results of this feasibility study are the basis of a new in-depth study, which includes also a follow-up protocol based on post surgery blood monitoring of patients. Our future aims foresee the extension of this study to other tumor types and the obtainment of the SCENT B1 clinical validation as oncologic screening device. Figure 1

Chemoresistive Nanostructured Sensors for the Analysis of Human Tumor Tissue Exhalations

One of the greatest goals in medicine is early-stage tumor detection. An effective prevention is crucial to allow physicians and surgeons to intervene on tumor affected patients with the available therapies and surgical techniques with a high probability of success. The purpose of this research relies on the identification of cancer presence by detecting the volatile organic biomarkers directly produced by cancer cells. Cancer cells produce different biomarkers with respect to healthy cells, mainly due to the altered metabolism and cellular membrane peroxidation. This difference can be recognized by using an innovative device manufactured in the Sensor Laboratory of the University of Ferrara, hosting a specific sensor array chosen for biological sample investigation. The sensor array is composed by four chemoresistive metal-oxide nanostructured sensors, able to detect gases in low concentration (up to 1 ppm) with excellent stability and repeatability. In this study, a fast-responding, reliable and reproducible sensing device, named SCENT B1[1], showed to be capable of discriminating cancerous cells from healthy ones, proving to be an efficient and low-invasive screening system.The device combines a specific electronic and pneumatic system to a specifically selected sensor array. The sample is inserted inside a sample box through a support composed by Petri dishes, while a stabilized ambient airflow conveys the exhalations to sensors. Sensor responses are then statistically analyzed by principal component analysis (PCA).Measurements have been performed on cancer and healthy tissues, extracted during surgery from human colon and rectum, with the future aim of extending the study to the other tumor types.Sensors chosen are the following: a mixture of tin and titanium oxides with addition of gold (ST25Au), tungsten oxide (W11), a mixture of tin, titanium and niobium oxides (STN) and a solid solution of titanium oxide, tantalum and vanadium (TiTaV). Sensors have been selected after a feasibility study performed on immortalized cells of diverse types, where sensors responses have been correlated with cell type and cell initial plating concentration of the samples; the measures have been performed after 24, 48, 72 hours of incubation.The sensor output signal is a voltage directly proportional to the sensor conductance; it depends on the chemical redox reactions taking place on sensor surface [2,3]. In Figure (a) the response R=ÄG/G for each sensor is reported, where ÄG is the difference between the sensor conductance with and without the metabolites expelled by the cells of a tissue. All four sensors gave larger responses (although with different amplitudes) to the tumor tissue with respect to the healthy one. Smaller and reproducible responses were given by the breeding ground (DMEM) only, confirming that it does not alter the measurement.The results are consistent with the stronger metabolism of tumor cells with respect to the healthy ones, because the former emits larger amounts of volatile biomarkers [4,5]. Other tests proved also that different initial plating concentrations (250k, 500k and 1M) of cell give increasing responses, as shown in Figure (b). From this study what emerges is that the device is capable of distinguishing different cell samples basing on their health status and concentrations. The encouraging results of this study are the basis of a deepen study for the clinical validation of the device as a oncologic screening device.

Chemoresistive Nanostructured Sensors for the Analysis of Tumor Tissues Exhalations

One of the greatest goals in medicine is early-stage tumor detection. An effective prevention is crucial to allow physicians and surgeons to intervene on patients with the available therapies, usually successful on small volume cancers only. The purpose of this research relies on the identification of cancer presence by detecting the volatile organic biomarkers directly produced by cancer cells. Cancer cell biomarkers are different by the ones exhaled by healthy cells and this difference can be recognized by means of a specific chemoresistive sensor array. In this study, a fast-responding, reliable and reproducible sensing technique proved to discriminate cancerous from healthy cells, making it an efficient low invasive screening system. The device employed, named SCENT B1 [1] combines a specific electronic and pneumatic system to a sensor core made of four nanostructured chemoresistive metal-oxide sensors (nanograins with average size of 40-50 nm) manufactured in the Sensor Laboratory of the University of Ferrara. The sample is inserted inside a specific sample box in a specific support composed by Petri dishes, while an ambient airflow, humidity stabilized, conveys the exhalations to sensors. Sensors responses are then analyzed by principal component analysis (PCA). Measurements have been performed on cancer and healthy tissues extracted during surgery from human colon and rectum, with the future aim of extending the study to the other type of tumors. Neoplastic tissues exhibit altered metabolic processes with respect to the metabolism of healthy cells, therefore the chemicals (metabolites) expelled during cellular respiration depend upon the cell health status. Sensors chosen to compose the array have been selected after a feasibility study performed on immortalized cells of diverse types, correlating also sensors responses with cell concentration inside the Petri dish (after 24, 48, 72 hours of incubation). Sensors chosen are: a mixture of tin and titanium oxides with addition of gold (ST25Au), tungsten oxide (W11), a mixture of tin, titanium and niobium oxides (STN) and a solid solution of titanium oxide, tantalum and vanadium (TiTaV). The voltage output of each sensor is directly proportional to its conductance, that depends on the chemical reactions happening on sensor surface [2,3]. In Figure (a) the response R=DG/G for each sensor is reported, where DG is the difference between the sensor conductance with and without the metabolites expelled by the cells of a tissue. All four sensors gave larger responses (although with different amplitudes) to the tumor tissue with respect to the healthy one. Smaller responses were given by the breeding ground (DMEM) only, confirming that it does not alter the measurement. Results are consistent with the stronger metabolism of tumor cells with respect to the healthy ones, because the former emits larger amounts of volatile biomarkers [4,5]. Other tests proved also that different initial plating concentrations (250k, 500k and 1M) of cell give increasing responses, as shown in Figure (b). From this study what emerges is that the the device is capable of distinguishing different cell samples basing on their health status and concentrations, laying the foundation for a deepen study for the clinical validation of the device as a oncologic screening device. References SCENT B1, Italian Patent Number: 102015000057717; Zonta, G. Anania, B. Fabbri, A. Gaiardo, S. Gherardi, A. Giberti, V. Guidi, N. Landini, C. Malagù; “Detection of colorectal cancer biomarkers in the presence of interfering gases”; Sensors and Actuators B 218 (2015), 289–295; Zonta, G. Anania, B. Fabbri, A. Gaiardo, S. Gherardi, A. Giberti, N. Landini, C. Malagù, L. Scagliarini, V. Guidi, Preventive screening of colorectal cancer with a device based on chemoresistive sensors. Sensors and Actuators B, 238, 1098–110, 2016.F. Altomare, M. Di Lena, F. Porcelli, L. Trizio, E. Travaglio, M. Tutino, S. Dragonieri, V. Memeo, G. de Gennaro; “Exhaled volatile organic compounds identify patients with colorectal cancer”; British Journal of Surgery 100 (2013), 144-150;Chan, E.C.Y., Koh, P.K., Mal, M., Cheah, P.Y., Eu, K.W., Backshall, A., Cavill, R., Nicholson, J.K., Keun, H.C., 2009. “Metabolic Profiling of Human Colorectal Cancer Using High-Resolution Magic Angle Spinning Nuclear Magnetic Resonance (HR-MAS NMR) Spectroscopy and Gas Chromatography Mass Spectrometry (GC/MS)”, Journal of Proteome Research 8(1), 352–361; Figure 1

A comprehensive review on multi-organs tumor detection based on machine learning

Tumor is comprised of abnormally growing regions that is dangerous for human survival. Therefore, early stage tumor detection is useful for increase of survival rate although it is challenging because of numerous prolific image factors including poor contrast, complex background, brightness issues, shape of infected region and fuzzy borders. Practically in recent times, numerous computerized aided systems (CAD) perform better for the detection of various sorts of tumors in brain, breast, skin and lung. These body organs are analyzed through different modalities for exampple magnetic resonance imaging (MRI), computed tomography (CT), dermoscopic, mammography and positron emission tomography (PET) etc. The major objective is to extensively analyze existing methodologies for brain, breast, skin and lung cancer/tumor detection. The survey is organized in terms of computer vision employed for cancer/tumor detection. The deep learning approaches are also discussed.

Hepatocellular Carcinoma Screening Is Associated With Increased Survival of Patients With Cirrhosis

Hepatocellular carcinoma (HCC) screening of patients with cirrhosis is recommended by professional societies to increase detection of early stage tumors and survival, but is underused in clinical practice. We conducted a retrospective cohort study of 13,714 patients diagnosed with HCC from 2003 through 2013 included in the Surveillance, Epidemiology, and End Results Program-Medicare database. We characterized receipt of HCC screening in the 3 years before HCC diagnosis using mutually exclusive categories (consistent vs inconsistent vs no screening) and the proportion of time covered with screening. Correlates for screening receipt were assessed using a multivariable 2-part regression model. We examined the association between screening receipt and early detection of tumors using multivariable logistic regression. We evaluated associations between screening receipt and overall survival using a Cox proportional hazards model, after adjustments for effects of lead-time bias and length-time bias on survival rate estimators. Most patients with cirrhosis (51.1%) did not receive any screening in the 3 years before a diagnosis of HCC, and only 6.8% of patients underwent consistent annual screening. The proportion with consistent screening increased from 5.4% in 2003 to 2006 to 8.8% in 2011 to 2013 (P < .001). The mean proportion of time covered was 13.4% overall, which increased from 11.7% in 2003 to 2006 to 15.2% in 2011 to 2013. Receipt of consistent screening was associated with detection of early stage tumors (odds ratio, 1.98; 95% CI, 1.68-2.33) and a reduced risk of death after correction for lead-time bias (hazard ratio, 0.76; 95% CI, 0.70-0.83). Inconsistent screening was associated with a slightly smaller increase in early detection of HCC (odds ratio, 1.31; 95% CI, 1.20-1.43) and a reduced risk of death (hazard ratio, 0.86; 95% CI, 0.83-0.90). After correction for lead- and length-time biases, higher proportions of patients with consistent (23%; 95% CI, 21%-25%) and inconsistent screening (19%; 95% CI, 19%-20%) survived for 3 years compared with patients without screening (13%; 95% CI, 12%-14%). In an analysis of the Surveillance, Epidemiology, and End Results Program-Medicare database, we found HCC screening to be underused for patients with cirrhosis. This contributes to detection of liver tumors at later stages and shorter times of survival. However, the proportion of patients screened for HCC has increased over time.

Primary Care Provider Practice Patterns and Barriers to Hepatocellular Carcinoma Surveillance

Low rates of hepatocellular carcinoma (HCC) surveillance are primarily due to provider-related process failures. However, few studies have evaluated primary care provider (PCP) practice patterns, attitudes, and barriers to HCC surveillance at academic tertiary care referral centers. We conducted a web-based survey of PCPs at 2 tertiary care referral centers (133 providers) from June 2017 through December 2017. The survey was adapted from pretested surveys and included questions about practice patterns, attitudes, and barriers to HCC surveillance. We used the Fisher exact and Mann-Whitney rank-sum tests to identify factors associated with adherence to HCC surveillance recommendations, for categoric and continuous variables, respectively. We obtained a provider-level response rate of 75% and clinic-level response rate of 100% (133 providers). Whereas most PCPs performed HCC surveillance themselves, one-third deferred surveillance to subspecialists and referred patients to a hepatology clinic. Providers believed the combination of ultrasound and α-fetoprotein analysis to be highly effective for early stage tumor detection and reported using the combination for assessment of most patients. However, PCPs were more likely to use computed tomography- or magnetic resonance imaging-based surveillance for patients with nonalcoholic steatohepatitis or decompensated cirrhosis. Most providers believed HCC surveillance to be efficacious for early tumor detection and increasing survival. However, they desired increased high-quality evidence to characterize screening benefits and harms. Providers expressed notable misconceptions about HCC surveillance, including the role for measurement of liver enzyme levels in HCC surveillance and cost effectiveness of surveillance in patients without cirrhosis. They also reported barriers, including not being up to date on HCC surveillance recommendations, limited time in the clinic, and competing clinical concerns. In a web-based survey, PCPs reported misconceptions and barriers to HCC surveillance. This indicates the need for interventions, including provider education, to improve HCC surveillance effectiveness in clinical practice.

FAKTOR YANG BERHUBUNGAN DENGAN PERILAKU IBU RUMAH TANGGA MELAKUKAN PEMERIKSAAN PAYUDARA SENDIRI (SADARI)

Breast cancer is cancer with the number of new cases and deaths highest in Indonesia. According to the Data Center and Information Ministry of a health Indonesia in the year 2013, the number of new cases of breast cancer of 819 and the number of deaths amounted to 217. In general, breast cancer known after stepping on an advanced stage. So the methods of early detection of breast cancer are focused on the detection of early stage tumors that are usually small with self-breast examination (SADARI). The purpose of this research is to predict the factors related to the behavior of self-breast examination (SADARI) the housewives aged 40–50 years. This research is an observational study with cross sectional approach. Sample research totaling 100 people housewife in Kelurahan Sidotopo Wetan Kenjeran Subdistrict Surabaya. The measurement was done by providing a questionnaire to obtain information about the research variables. Variable independent research is k nowledge, attitudes, information accessibility, support health providers and descent with breast cancer. The results of this research showed the variables that are associated with the SADARI behavior of the housewifes is attitude (p = 0.000), accessibility of information (p = 0.000), and health care providers support (p = 0.010). The majority of housewives in Kelurahan Sidotopo Wetan Kenjeran Sub-district Surabaya showed a good attitude and support toward SADARI. In the area surrounding the residence h ousewife get access information easily. There are no support for doing SADARI from health care providers.

P3.05-002 The Effect of Nodule Size on the Sensitivity of the LuCED® Test for Lung Cancer

The LuCED® test is based on analysis of sputum by the Cell-CT® platform that computes 3D images of cells with isometric resolution, allowing orientation-independent measurements of 704 3D structural biomarkers to generate a probabilistic score to identify abnormal cells. that was consistent by tumor histology and stage. Early stage tumors are generally smaller in size. One view is that smaller tumors might exfoliate fewer abnormal cells into sputum, making early stage tumor detection less likely.

Contrast-enhanced ultrasound with a novel nanoparticle contrast agent for clinical diagnosis in patients with non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) initiates in the non-small cells of the lung and is one of the most common types of human cancer. It is known for its rapid growth, easy migration, invasion and reoccurrence, and has the highest incidence rate of all types of cancer. Early detection of NSCLC is difficult to achieve and this is the primary reason for low survival rates in NSCLC. Contrast-enhanced ultrasound is the most common application for evaluating patients diagnosed with NSCLC. In the present study, a contrast-enhanced ultrasound combined with nanoparticles was performed with the aim of identifying patients with NSCLC at an early stage. The present study evaluated the effectiveness of administering a nanoparticle contrast agent through respiration in combination with enhanced ultrasound at improving image quality compared with traditional ultrasound. This maybe a novel method of detecting early-stage tumors in patients. There are numerous benefits to conducting diagnoses of NSCLC using contrast-enhanced ultrasound. It is a non-invasive imaging modality, induces little pain, has a low cost, an extensive range and produces high-resolution images. This means that it is safer and more beneficial to use in patients with NSCLC than conventional imaging examinations, including X-ray and bronchoscopy. Furthermore, the nanoscale microbubble contrast agent containing liposome-encapsulated epidermal growth factor receptor was inhaled by nebulization, which may lead to an enhanced ultrasound image. The sensitivity of contrast-enhanced ultrasound was investigated in mice with early stage NSCLC. The results indicated that ultrasound administrated with nanoscale microbubble enhanced sensitivity and improved image quality compared with simple ultrasound. Furthermore, enhanced ultrasound resulted in a reliable and sensitive assessment of tumor mass in early-stage tumors. Altogether, contrast-enhanced ultrasound facilitated the efficient detection of NSCLC in patients in situ at an early stage. This protocol improved the understanding of the pathophysiology of NSCLC and may be applied in the detection of early-stage tumors in patients suspected of having cancer.

Effective Screening and Classification of Cervical Precancer Biopsy Imagery.

Microscope images of biopsy samples of cervical precancers conventionally discriminated by histopathology, the current "gold standard" for cancer detection, showed that their correlation properties are segregated into different classes. The correlation domains clearly indicate increasing cellular clustering in different grades of precancer compared with their normal counterparts. This trend indicates the probability of pixel distribution of the corresponding tissue images. Because the cell density is not uniform in the higher grades, the skewness (asymmetry of a distribution), kurtosis (sharpness of a distribution), entropy (randomness), and standard deviation are affected. A combination of these parameters effectively improves the diagnosis and quantitatively classifies the normal and all the three grades of precancerous cervical tissue sections significantly. Thus, the statistical analysis of microscope images is a promising approach for early stage tumor detection and quantitative classification of precancerous grades; this can effectively supplement the qualitative analysis by the pathologist.

Abstract LB-246: Detection of circulating tumor DNA in early stage cancers

Abstract Early detection is a major goal for reducing mortality of human cancer. However, non-invasive detection of early stage tumors has remained a challenge. We have developed an approach called Targeted Error Correction Sequencing (TEC-Seq) for ultra-sensitive analyses of circulating cell-free tumor DNA (ctDNA). This methodology involves in-solution targeted capture of multiple regions of the genome and deep sequencing (~30,000x) of cell-free DNA fragments. Laboratory and bioinformatic methods were optimized to enrich for rare ctDNA molecules and to reduce potential amplification, sequencing, and contamination errors. We have used this approach to examine 58 cancer related genes, and demonstrated a limit of detection of mutant to wild-type DNA of 0.05% and a specificity &amp;gt;99.999% across targeted regions of interest. We applied this method to analyze plasma from healthy individuals as well as over 200 individuals with breast, lung, colorectal and ovarian cancers. Analysis of plasma from 44 healthy individuals revealed no tumor-related somatic mutations and identified alterations in genes related to myelodysplasia in a subset of cases. Among patients with cancer, we detected measurable ctDNA in 56%, 71%, 57%, and 56% of patients with early stage (I and II) breast, colorectal, lung and ovarian cancer. Over three quarters of patients with late stage (III and IV) disease had detectable ctDNA among all cases analyzed. Analyses of mutations in the circulation revealed a high concordance with alterations in the independently analyzed tumors of these patients. These analyses provide a widely applicable, ultra-sensitive, and non-invasive method for detection of ctDNA, and have important implications for detection of early stage disease and management of patients with cancer. Citation Format: Jillian A. Phallen, Mark Sausen, Vilmos Adleff, Alessandro Leal, Jacob Fiksel, Carolyn Hruban, Savannah Speir, Eniko Papp, Valsamo Anagnostou, Mai-Britt W. Orntoft, Thomas Reinert, Brian D. Woodward, Derek Murphy, Sonya Parpart-Li, David Riley, Monica Nesselbush, Naomi Sengamalay, Andrew Georgiadis, Rob Scharpf, Qing K. Li, Sian Jones, Samuel Angiuoli, Joost Huiskens, Cornelis Punt, Nicole van Grieken, Remond Fijneman, Gerrit Meijer, Hatim Husain, Luis Diaz, Torben Ørntoft, Hans J. Nielsen, Claus L. Anderson, Victor E. Velculescu. Detection of circulating tumor DNA in early stage cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-246. doi:10.1158/1538-7445.AM2017-LB-246

Upconversion optical/magnetic resonance imaging-guided small tumor detection and invivo tri-modal bioimaging based on high-performance luminescent nanorods.

In this work, we demonstrated multifunctional NaYbF4: Tm3+/Gd3+ upconversion (UC) nanorods (UCNRs) with near-infrared (NIR)-to-NIR emission and controlled phase and size for UC optical and T1/T2 dual-weighted magnetic resonance (MR) imaging-guided small tumor detection and tri-modal bioimaging. Cell toxicity and post-injection histology results revealed that our designed UCNRs present low biotoxicity and good biocompatibility in living animals. Real-time tracking based on UCNRs in living mice demonstrated that the UCNRs were mainly accumulated in the reticuloendothelial system (RES) and excreted through the hepatic pathway. Additionally, the UCNRs exhibited high X-ray absorption coefficient and large K-edge value, resulting in efficient invivo CT imaging. A new type of binary (Yb3+/Gd3+) MR contrast agent for simultaneous T1/T2 dual-weighted MR imaging was achieved by doping Gd3+ into NaYbF4 host. Importantly, a small tumor (5mm in diameter) could be detected invivo by intravenously injecting UCNRs under UC optical and MR imaging modalities. Therefore, these multifunctional nanoprobes based on NaYbF4:Tm3+/Gd3+ UCNRs with remarkable NIR-to-NIR emission provide potential applications for tri-modal UC optical, CT, binary T1/T2 MR imaging, and early-stage tumor detection in nanomedicine.

Biomarkers of genome instability and cancer epigenetics

Tumorigenesis is a multistep process involving genetic and epigenetic alterations that drive somatic evolution from normal human cells to malignant derivatives. Collectively, genetic and epigenetic alterations might be combined into biomarkers for the assessment of risk, the detection of early stage tumors, and accurate tumor characterization before and after treatment. Recent efforts have provided systematic approaches to cancer genomics through the application of massive sequencing of specific tumor types. Here, we review biomarkers of genome instability and epigenetics. Cancer evolvability and adaptation emerge through genetic and epigenetic lesions of a variety of sizes and qualities-from point mutations and small insertions/deletions to large-scale chromosomal rearrangements, alterations in whole chromosome copy number, preferential allelic expression of cancer risk alleles, and mechanisms that increase tumor mutation rates. We also review specific epigenetic mechanisms that facilitate or hinder tumor adaptation, including DNA methylation, histone modification, nucleosome remodeling, transcription factor activity, and small non-coding RNAs. Given the complexity of the carcinogenic process, the challenge ahead will be to interpret disparate signals across hundreds of genes and summarize these signals into a single actionable diagnosis that translates into specific treatments. Another challenge is to refine preventive efforts through the identification of epigenetic processes that mediate increased cancer rates in individuals exposed to sources of toxic environmental stress and pollution, specially through development and early childhood.

Circulating RNAs as new biomarkers for detecting pancreatic cancer.

Pancreatic cancer remains difficult to treat and has a high mortality rate. It is difficult to diagnose early, mainly due to the lack of screening imaging modalities and specific biomarkers. Consequently, it is important to develop biomarkers that enable the detection of early stage tumors. Emerging evidence is accumulating that tumor cells release substantial amounts of RNA into the bloodstream that strongly resist RNases in the blood and are present at sufficient levels for quantitative analyses. These circulating RNAs are upregulated in the serum and plasma of cancer patients, including those with pancreatic cancer, compared with healthy controls. The majority of RNA biomarker studies have assessed circulating microRNAs (miRs), which are often tissue-specific. There are few reports of the tumor-specific upregulation of other types of small non-coding RNAs (ncRNAs), such as small nucleolar RNAs and Piwi-interacting RNAs. Long ncRNAs (lncRNAs), such as HOTAIR and MALAT1, in the serum/plasma of pancreatic cancer patients have also been reported as diagnostic and prognostic markers. Among tissue-derived RNAs, some miRs show increased expression even in pre-cancerous tissues, and their expression profiles may allow for the discrimination between a chronic inflammatory state and carcinoma. Additionally, some miRs and lncRNAs have been reported with significant alterations in expression according to disease progression, and they may thus represent potential candidate diagnostic or prognostic biomarkers that may be used to evaluate patients once detection methods in peripheral blood are well established. Furthermore, recent innovations in high-throughput sequencing techniques have enabled the discovery of unannotated tumor-associated ncRNAs and tumor-specific alternative splicing as novel and specific biomarkers of cancers. Although much work is required to clarify the release mechanism, origin of tumor-specific circulating RNAs, and selectivity of carrier complexes, and technical advances must also be achieved, such as creating a consensus normalization protocol for quantitative data analysis, circulating RNAs are largely unexplored and might represent novel clinical biomarkers.

Perspectives in the treatment of pancreatic adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is an incurable lethal disease whose incidence rate is growing. There is no effective screening for detection of early stage tumors and, in most cases, PDAC is diagnosed at advanced disease stages, when radical pancreatic resection is not possible. The aggressive nature of pancreatic tumor cells lies in the complex genetic mechanisms behind their uncontrolled capability to grow and metastasize, which involve essential adaptive changes in cellular metabolism, signaling, adhesion and immunoediting. In addition, PDAC cells promote a dense functional stroma that facilitates tumor resistance to chemotherapy and radiation. During the last two decades, gemcitabine has been the reference for the systemic treatment of PDAC. However, recently, a regimen combining fluorouracil, irinotecan, oxaliplatin, and leucovorin (FOLFIRINOX) and another combining albumin-bound paclitaxel with gemcitabine have shown clear therapeutic advantage in advanced PDAC, with survival outcomes of 11.3 and 8.5 mo on phase III trials, respectively, over single-agent gemcitabine. With the pending issue of their higher toxicities, these regimens set the reference for ongoing and future clinical studies in advanced PDAC. In addition, the efficacy of oral fluoropyrimidine (S-1) has been well documented in Asiatic PDAC patients. The development of therapeutic approaches other than cytotoxic drugs has proven difficult in the past, with only one drug (erlotinib) approved to date. Besides, a number of agents targeting signaling pathways in tumor or stroma cells are being investigated. Likewise, immunotherapies that target PDAC in various ways are the subject of a number of clinical trials. The search for reliable biomarkers with diagnostic and prognostic value using genomics and mass spectrometry methods may facilitate monitoring and refinement of therapies. This review focuses on current understanding of the pathogenesis of PDAC and the latest developments in the treatment of advanced PDAC.

Early detection, curative treatment, and survival rates for hepatocellular carcinoma surveillance in patients with cirrhosis: a meta-analysis.

Surveillance for hepatocellular carcinoma (HCC) has level I evidence among patients with hepatitis B but only level II evidence in patients with cirrhosis. This lack of randomized data has spurred questions regarding the utility of HCC surveillance in this patient population; however, lack of randomized data does not equate to a lack of data supporting the efficacy of surveillance. The aim of our study was to determine the effect of HCC surveillance on early stage tumor detection, receipt of curative therapy, and overall survival in patients with cirrhosis. We performed a systematic literature review using Medline from January 1990 through January 2014 and a search of national meeting abstracts from 2009-2012. Two investigators identified studies that reported rates of early stage tumor detection, curative treatment receipt, or survival, stratified by HCC surveillance status, among patients with cirrhosis. Both investigators independently extracted data on patient populations, study methods, and results using standardized forms. Pooled odds ratios, according to HCC surveillance status, were calculated for each outcome using the DerSimonian and Laird method for a random effects model. We identified 47 studies with 15,158 patients, of whom 6,284 (41.4%) had HCC detected by surveillance. HCC surveillance was associated with improved early stage detection (odds ratio [OR] 2.08, 95% CI 1.80-2.37) and curative treatment rates (OR 2.24, 95% CI 1.99-2.52). HCC surveillance was associated with significantly prolonged survival (OR 1.90, 95% CI 1.67-2.17), which remained significant in the subset of studies adjusting for lead-time bias. Limitations of current data included many studies having insufficient duration of follow-up to assess survival and the majority not adjusting for liver function or lead-time bias. HCC surveillance is associated with significant improvements in early tumor detection, receipt of curative therapy, and overall survival in patients with cirrhosis. Please see later in the article for the Editors' Summary.