A spatio-temporal analysis of environmental fate and transport processes of pesticides and their transformation products in agricultural landscapes dominated by subsurface drainage with SWAT.

Pesticides are detected in surface water and groundwater, endangering the environment. In lowland regions with subsurface drainage systems, drained depressions become hotspots for transport of pesticides and their transformation products (TPs). This study focuses on detailed modelling of the degradation and transport of pesticides with different physico-chemical properties. The objective is to analyse complex hydrological transport processes, to understand the temporal and spatial dynamics of the degradation and transport of pesticides. The ecohydrological model SWAT+ simulates hydrological processes as well as agricultural management and pesticide degradation, and can therefore be used to develop pesticide loss reduction strategies. This study focuses on modelling of three pesticides (pendimethalin, diflufenican, and flufenacet), and two TPs, flufenacet-oxalic acid (FOA) and flufenacet sulfonic acid (FESA). The study area is a 100-hectare farmland in the northern German lowlands of Schleswig-Holstein that is characterized by an spacious drainage network of 6.3 km and managed according to common conventional agricultural practice. SWAT+ modelled streamflow with very good agreement between observed and simulated data during calibration and validation. Regarding pesticides, the model performance for highly mobile substances is better than for non-mobile pesticides. While the transport of the moderately to very mobile substances via tile drains played an important role in both wet and dry conditions, no transport via tile drains was modelled for the highly sorptive and non-mobile pendimethalin. In conclusion, the model can reliably represent the degradation of moderately to very mobile pesticides in small-scale tile drainage-dominated catchments, as well as surface runoff-induced peak loads. However, it has weaknesses in accounting for the subsurface transport of non-mobile substances, which can lead to an underestimation of the subsequent delivery after precipitation events and thus underestimates the total load.

Examining characteristics and sampling methods of phosphor dynamics in lowland catchments.

Despite over two decades since the EU Water Framework Directive have passed, achieving the desired water quality in German surface waters remains challenging, regardless of efforts to reduce phosphorus inputs and associated environmental impacts. This study aims at analyzing the characteristics governing the concentrations of four key water quality parameters (total phosphorus, orthophosphate, particulate phosphate, and suspended solids) in two lowland catchments: the 50 km2 catchment of the Kielstau, Germany, and its 7 km2 tributary, the Moorau, which are dominated by agricultural land use. To this end, different sampling methods, particularly high-resolution precipitation event-based sampling and daily mixed samples, are conducted and evaluated, and their effectiveness is compared. The identification of sources and characteristics that affect phosphorus and suspended sediment dynamics, both in general and specifically during heavy precipitation events, is one focus of the study. Over a 15-year period, increasing concentrations of these parameters were observed in daily mixed samples, exhibiting distinct seasonal patterns-higher in summer and lower in winter-consistent with lowland catchment behavior. Particularly during heavy precipitation events, the smaller catchment exhibits a more complex and less predictable response to chemical concentrations compared with the dilution effect observed in the larger catchment. The results underline the complexity of phosphorus dynamics in small catchments and emphasize the importance of event-based sampling for capturing short-term concentration peaks for all four parameters, particularly beneficial regarding measuring suspended solids. While daily mixed samples capture average phosphorus concentrations, event-based sampling is crucial for detecting short-term spikes, providing a more comprehensive understanding of phosphorus dynamics.

PreCancer Atlas: Present and Future.

Precancer atlases have the potential to revolutionize how we think about the topographic and morphologic structures of precancerous lesions in relation to cellular, molecular, genetic, and pathophysiologic states. This mini review uses the Human Tumor Atlas Network (HTAN), established by the National Cancer Institute (NCI), to illustrate the construction of cellular and molecular three-dimensional atlases of human cancers as they evolve from precancerous lesions to advanced disease. We describe the collaborative nature of the network and the research to determine how and when premalignant lesions progress to invasive cancer, regress or obtain a state of equilibrium. We have attempted to highlight progress made by HTAN in building precancer atlases and discuss possible future directions. It is hoped that the lessons from our experience with HTAN will help other investigators engaged in the construction of precancer atlases to crystallize their thoughts on logistics, rationale, and implementation.

Integrated modeling of global change impacts on land and water resources.

There is a common scientific understanding that global change impact analysis, mitigation, and adaptation require interdisciplinary work. Integrated modeling could help to address the challenges associated with the impacts of global change. Particularly, integrated modeling that takes feedback effects into account will allow for the derivation of climate resilient land use and land management. Here, we call for more of such integrated modeling work focusing on the interdisciplinary subject of water resources and land management. As a proof-of-concept, we tightly couple a hydrologic (SWAT) and a land use model (CLUE-s) and illustrate the benefits of this coupled land and water modeling framework (LaWaCoMo) with a scenario on cropland abandonment induced by water stress. As compared to standalone model runs of SWAT and CLUE-s for the past, LaWaCoMo performs slightly better regarding measured river discharge (PBIAS: +0.8% and +1.5% compared at two gauges) and land use change (figure of merit: +6.4% and +2.3% compared to land use maps at two points in time). We show that LaWaCoMo is suitable for global change impact analysis as it is sensitive to climate and land use inputs as well as to management decisions. Our results shed light on the importance of feedback effects between land use and hydrology to assess impacts of global change on land and water resources accurately and consistently. To facilitate that the developed methodology can serve as a blueprint for integrated modeling of global change impacts, we used two freely available models that belong to the most widely used models in their respective disciplines.

Spatial and temporal assessment of human-water interactions at the Inle Lake, Myanmar: a socio-hydrological DPSIR analysis.

Freshwater resources as a key aspect of socio-economic development, provide a large number of services in human and environmental systems. Nevertheless, human appropriation of these water resources and the modification of landscapes lead to potential threats on water availability and quality from local to global scales. The Inle Lake in Myanmar is an economically, traditionally, and ecologically important freshwater ecosystem that faced severe degradation from the 2000s. In its catchment area, a Driver-Pressure-State-Impact-Response (DPSIR) framework is applied for an assessment period of 30 years from 1990 to 2020. The analysis results are complemented with a socio-hydrological survey, water quality assessment, a land use classification based on ground truth and satellite data, and hydrologic models. The resulting land use changes, - 13% forest, + 13% agriculture, and + 5% urban areas, lead to increased water yield, decreased evapotranspiration, and increased sediment yield. Together with other drivers and pressures such as climate change and anthropogenic pollution, these human activities are major threats for freshwater resources and the ecosystem. However, the existing awareness of the local population for the environmental degradation is obstructed by national and international crises and responses to negative developments can accelerate degradation if they are unplanned and short-term solutions. Our study shows that environmental degradation processes have a complex nature and can only be tackled in a coordinated way with a long-term perspective. DPSIR is a suitable approach to assess human-water dynamics and disentangle the complex interconnectedness of social and environmental systems in freshwater ecosystems, even in data-scarce regions.

Land use change and climate dynamics in the Rift Valley Lake Basin, Ethiopia.

Land use and climate dynamics have a pronounced impact on water resources, biodiversity, land degradation, and productivity at all scales. Thus, in this study, we present the spatio-temporal dynamics of land use change and climate aiming to provide a scientific evidence about gains and losses in major land use categories and associated drivers and significancy and homogeneity of climate change. To this end, Landsat images and historical climate data have been used to determine the dynamics. In addition, population census data and land use policy have been considered to assess the potential drivers of land use change. The spatio-temporal land use dynamics have been evaluated using transition matrix and dynamics index. Likewise, shifts in the climate data were analyzed using change point analysis and three homogenous climate zones have been identified using principal component analysis. The results show that, from 1989 to 2019, the areal percentage of agricultural land increased by 27.5%, settlement by 0.8%, and barren land 0.4% while the natural vegetation, wetland, water body, and grass land decreased by 24.5%, 1.6%, 0.5%, and 2.1%, respectively. The land use dynamics have been stronger in the first decade of the study period. An abrupt shift of climate has occurred in the 1980s. In the last four decades, rainfall shows a not significant decreasing trend. However, a significant increasing trend has been observed for temperature. Rapid population growth, agricultural expansion policy, and climate variability have been identified as the underlying drivers of land use dynamics.

A method for detecting the non-stationarity during high flows under global change.

The sustainability of existing water resources is influenced by extreme streamflow, and climate variability and human activities are generally the major factors controlling these dynamics. However, most of previously proposed methods to determine the effects of these factors have only been developed under the assumption of stationarity. Therefore, to overcome the existing research gap, an innovative method was proposed in this study to analyze and distinguish the effects of climate variability and human activities on extreme streamflow based on the non-stationarity theory. Accordingly, a rainfall-runoff model was developed using long-term hydrological data in the watersheds of Southeast China, which cover >75,000 km2. The model proposed in this study showed an acceptable performance, as indicated by the Nash-Sutcliffe efficiency coefficient (NSE), the Kling-Gupta efficiency (KGE), and percent bias (PBIAS). The NSE, KGE, and |PBIAS| were 0.67-0.75, 0.57-0.74, and 1.22-16.79 during the calibration periods, respectively. And the NSE, KGE, and |PBIAS| were 0.69-0.77, 0.65-0.76, and 0.98-17.51 during the calibration periods, respectively. The trends of the extreme streamflow were analyzed for these watersheds at different time scales. The streamflow extremes at short time scales were found to be more sensitive to changing environment than those at longer time scales. The major factor controlling streamflow extremes at short time scales was human activities and climate change may be the dominant factor influencing streamflow extremes at long time scales. The findings of this study could provide useful insights into water management under global change conditions.

Impacts of hydrological alteration on ecosystem services changes of a large river-connected lake (Poyang Lake), China.

Large lakes provide various types of ecosystem services (ESs), of which stocks and variations induced by hydrological alterations are largely unquantified. The present study investigates the long-term changes of five key ESs (i.e., flood regulation, water supply, fish production, nutrient retention and biodiversity conservation) in a large river connected lake (Poyang Lake), with special attention to impacts of hydrological alteration induced by the Three Gorges Dam (TGD). Hydrological data series, hydrodynamic model, the nutrient balance, fishery statistics, and wetland winter waterbird survey data from 1980 to 2016 were employed. Results showed that Poyang Lake provide significant ESs, with long-term average flood regulation, water supply and nutrient retention services of 167.7 × 108 m3, 31.53 × 108 m3, and 15.12% of total phosphorus load, respectively. The fish production service ranged from 1.74 × 104t to 7.19 × 104t, with an average value of 3.12 × 104t. All five key ESs exhibited a downward trend since the 2000s, especially for water supply, fish production and nutrient retention services (p < 0.05), which might be largely attributed to the hydrological condition changes induced by TGD operation. Nevertheless, more detailed monitoring data and biophysical models are required to further acknowledge the changes in biodiversity conservation and fish production services and their linkages with the TGD. The present study sheds light on long-term ES changes in large lakes and their possible linkages with human influences through hydropower projects.

Twenty years of change: Land and water resources in the Chindwin catchment, Myanmar between 1999 and 2019.

Since 2011, Myanmar has undergone a more rapid socio-economic development, which may substantially have affected land use and land cover (LULC) and water resources. This study investigates the changes in land and water resources of the Chindwin River catchment (114,686.9 km2) in Myanmar over a twenty-year timespan from 1999 to 2019. The main aim of this study is to assess LULC change and evaluate its effects on the water balance and the people in the region. To this end, interviews were conducted, LULC classifications based on multi-temporal multi-spectral satellite data and in-situ ground truth data were created, and a hydrologic model was built. The hydrologic model shows a reasonable performance for daily discharge simulation at the catchment outlet (percent bias between -2 and 13.2, Kling-Gupta Efficiency between 0.75 and 0.76, Nash-Sutcliffe Efficiency between 0.57 and 0.61, RMSE-observations standard deviation between 0.63 and 0.66). The LULC changes detected include a decrease in forest area of about 2%, an increase in shrubland area indicating increased degradation of the forest, an increase in mining areas of 0.38%, an overall decrease in agricultural area (2.1%), but also the presence of new agricultural land pointing toward relocation of agricultural areas and an indication of an increase in settlement areas (1.5%). With the help of the hydrologic model, the most significant hydrologic impacts detected were a decrease in evapotranspiration and an increase in water yield which is correlated with the decrease of forest at the sub-catchment scale (R2 = 0.72 and 0.46, respectively). Moreover, an increase of mining areas contributed to the increase in water yield (R2 = 0.62). Interviews confirm that the identified LULC changes deforestation and increased mining activities contribute to major issues, e.g., water pollution, sedimentation, and changes in the river course.

The Early Detection Research Network: A National Infrastructure to Support the Discovery, Development, and Validation of Cancer Biomarkers.

In 2000, the NCI (Rockville, MD) established the Early Detection Research Network (EDRN) to identify, develop, and validate biomarkers to improve the detection of early-stage cancers and risk assessment. This consortium of more than 300 investigators at academic institutions and in the private sector is working collaboratively to bring biomarkers and imaging methods to clinical fruition. Although significant roadblocks have hindered the field of biomarker discovery and validation, the EDRN has helped overcome many of them by setting well-defined strategies and milestones focused on solving defined unmet clinical needs. The EDRN has implemented measures to improve biomarker discovery and validation, such as data sharing, use of common data elements, generating multidisciplinary and multi-institutional collaborations within a cohesive and productive team environment, and putting emphasis on quality control and data replication for all candidate biomarkers for reaching a "go" or "no go" decision. A measure of the success of the EDRN is the number of biomarkers tests or devices approved by the FDA to which EDRN investigators have made significant contributions and the number of biomarkers tests developed by EDRN investigators that are available in Clinical Laboratory Improvement Amendments laboratories.See all articles in this CEBP Focus section, "NCI Early Detection Research Network: Making Cancer Detection Possible."

Cancer overdiagnosis: a biological challenge and clinical dilemma.

For cancer screening to be successful, it should primarily detect cancers with lethal potential or their precursors early, leading to therapy that reduces mortality and morbidity. Screening programmes have been successful for colon and cervical cancers, where subsequent surgical removal of precursor lesions has resulted in a reduction in cancer incidence and mortality. However, many types of cancer exhibit a range of heterogeneous behaviours and variable likelihoods of progression and death. Consequently, screening for some cancers may have minimal impact on mortality and may do more harm than good. Since the implementation of screening tests for certain cancers (for example, breast and prostate cancers), a spike in incidence of in situ and early-stage cancers has been observed, but a link to reduction in cancer-specific mortality has not been as clear. It is difficult to determine how many of these mortality reductions are due to screening and how many are due to improved treatments of tumours. In cancers with lower incidence but high mortality (for example, pancreatic cancer), screening has focused on high-risk populations, but challenges similar to those for general population screening remain, particularly with regard to finding lesions with difficult-to-characterize malignant potential (for example, intraductal papillary mucinous neoplasms). More sensitive screening methods are detecting smaller and smaller lesions, but this has not been accompanied by a comparable reduction in the incidence of invasive cancers. In this Opinion article, we focus on the contribution of screening in general and high-risk populations to overdiagnosis, the effects of overdiagnosis on patients and emerging strategies to reduce overdiagnosis of indolent cancers through an understanding of tumour heterogeneity, the biology of how cancers evolve and progress, the molecular and cellular features of early neoplasia and the dynamics of the interactions of early lesions with their surrounding tissue microenvironment.

Validation of Biomarkers for Early Detection of Pancreatic Cancer: Summary of The Alliance of Pancreatic Cancer Consortia for Biomarkers for Early Detection Workshop.

Pancreatic cancer is the third leading cause of cancer death in the United States, and the 5-year relative survival for patients diagnosed with pancreatic cancer is less than 10%. Early intervention is the key to a better survival outcome. Currently, there are no biomarkers that can reliably detect pancreatic cancer at an early stage or identify precursors that are destined to progress to malignancy. The National Cancer Institute in partnership with the Kenner Family Research Fund and the Pancreatic Cancer Action Network convened a Data Jamboree on Biomarkers workshop on December 5, 2016, to discuss and evaluate existing or newly developed biomarkers and imaging methods for early detection of pancreatic cancer. The primary goal of this workshop was to determine if there are any promising biomarkers for early detection of pancreatic cancer that are ready for clinical validation. The Alliance of Pancreatic Cancer Consortia for Biomarkers for Early Detection, formed under the auspices of this workshop, will provide the common platform and the resources necessary for validation. Although none of the biomarkers evaluated seemed ready for a large-scale biomarker validation trial, a number of them had sufficiently high sensitivity and specificity to warrant additional research, especially if combined with other biomarkers to form a panel.

Dynamic integration of land use changes in a hydrologic assessment of a rapidly developing Indian catchment.

Rapid land use and land-cover changes strongly affect water resources. Particularly in regions that experience seasonal water scarcity, land use scenario assessments provide a valuable basis for the evaluation of possible future water shortages. The objective of this study is to dynamically integrate land use model projections with a hydrologic model to analyze potential future impacts of land use change on the water resources of a rapidly developing catchment upstream of Pune, India. For the first time projections from the urban growth and land use change model SLEUTH are employed as a dynamic input to the hydrologic model SWAT. By this means, impacts of land use changes on the water balance components are assessed for the near future (2009-2028) employing four different climate conditions (baseline, IPCC A1B, dry, wet). The land use change modeling results in an increase of urban area by +23.1% at the fringes of Pune and by +12.2% in the upper catchment, whereas agricultural land (-14.0% and -0.3%, respectively) and semi-natural area (-9.1% and -11.9%, respectively) decrease between 2009 and 2028. Under baseline climate conditions, these land use changes induce seasonal changes in the water balance components. Water yield particularly increases at the onset of monsoon (up to +11.0mm per month) due to increased impervious area, whereas evapotranspiration decreases in the dry season (up to -15.1mm per month) as a result of the loss of irrigated agricultural area. As the projections are made for the near future (2009-2028) land use change impacts are similar under IPCC A1B climate conditions. Only if more extreme dry years occur, an exacerbation of the land use change impacts can be expected. Particularly in rapidly changing environments an implementation of both dynamic land use change and climate change seems favorable to assess seasonal and gradual changes in the water balance.

Evaluation of two mitochondrial DNA biomarkers for prostate cancer detection.

BACKGROUND: A 3.4kb deletion (3.4kbΔ ) in mitochondrial DNA (mtDNA) found in histologically normal prostate biopsy specimens has been reported to be a biomarker for the increased probability of prostate cancer. Increased mtDNA copy number is also reported as associated with cancer. OBJECTIVE: Independent evaluation of these two potential prostate cancer biomarkers using formalin-fixed paraffin-embedded (FFPE) prostate tissue and matched urine and serum from a high risk cohort of men with and without prostate cancer. METHODS: Biomarker levels were detected via qPCR. RESULTS: Both 3.4kbΔ and mtDNA levels were significantly higher in cancer patient FFPE cores (p= 0.045 and p= 0.070 respectively at > 90% confidence). Urine from cancer patients contained significantly higher levels of mtDNA (p= 0.006, 64.3% sensitivity, 86.7% specificity). Combining the 3.4kbΔ and mtDNA gave better performance of detecting prostate cancer than either biomarker alone (FFPE 73.7% sensitivity, 65% specificity; urine 64.3% sensitivity, 100% specificity). In serum, there was no difference for any of the biomarkers. CONCLUSIONS: This is the first report on detecting the 3.4kbΔ in urine and evaluating mtDNA levels as a prostate cancer biomarker. A confirmation study with increased sample size and possibly with additional biomarkers would need to be conducted to corroborate and extend these observations.

New paradigms in translational science research in cancer biomarkers.

Despite significant investments in basic science by the US National Institutes of Health, there is a concern that the return on this investment has been limited in terms of clinical utility. In the field of biomarkers, translational research is used to bridge the gap between the results of basic research that identify biomolecules involved in or the consequence of carcinogenesis and their incorporation into medical application. The cultural separation between different scientific disciplines often makes it difficult to establish the multidisciplinary and multi-skilled teams that are necessary for successful translational research. The field of biomarker research requires extensive interactions between academic researchers and industrial developers, and clinicians are needed to help shape the research direction that can be addressed only by a multidisciplinary, multi-institutional approach. In this article, we provide our perspective on the relatively slow pace of cancer biomarker translation, especially those for early detection and screening.

Standards for immunohistochemical imaging: a protein reference device for biomarker quantitation.

We are developing a reference device to be used in the validation of immunohistochemical imaging of biomarkers by microscopy. The prototype device consists of p53 protein immobilized at various concentrations on a glass slide. The device is designed as a reference control to be used with assays that incorporate commercially available anti-p53 antibodies. p53 protein was characterized by mass spectrometry and covalently immobilized through amide linkage to the (3-aminopropyl)trietoxysilane-modified glass surface. This procedure is reproducible and provides a chemically stable product in high yield. The surface-bound protein was shown to be immunoreactive by its specific interaction with anti-p53 antibody (Ab) and detection by absorbance and fluorescence spectroscopy. Also, comparison was made with microscopic images of Ab-stained tissue samples, known to stain positive for p53. Further development will be required to establish accurate surface protein concentrations in the range required for specific clinical applications.

Molecular markers for early detection.

A common belief is that the earlier that cancer is detected, the better the chance exists for reduced mortality and morbidity. The advent of new and emerging molecular, genetic, and imaging technologies has broadened the possible strategies for early detection and prevention, but a beneficial impact on mortality needs to be supported by clinical evidence. Molecular markers are being identified that are enhancing our ability to predict and detect cancer before it develops and at the earliest signs of impending carcinogenic transformation. Of the innumerable molecular markers in development, a standalone early detection marker with acceptable sensitivity and specificity is available for bladder cancer, although for most cancer sites there are promising avenues of research that will likely produce results in the next decade. The perfect molecular marker would be one that is inherently related to the disease, specifically to the processes of malignant tumorigenesis or to the defense mechanisms of the individual. For example, mutations associated with increased cancer risk often produce gene products that interfere with tumor-suppressor pathways (eg, DNA repair or cell-cycle control) or support oncogenic pathways (eg, through genetic instability or silencing the apoptotic pathway). Finding molecular markers associated with these processes, and where in the process they produce their actions, can lead to interventions based on maintaining support for the normal process and interrupting the action of the products of the mutation. The search for molecular markers for cancer prevention and early detection presents a formidable challenge that requires a systematic and scientifically sound validation process. The search encompasses a broad range of scientific disciplines, including biochemistry, genetics, histology, immunology, informatic technologies, and epidemiology; strategies to identify and understand molecular markers are approached with multidisciplinary teams focused on understanding the mechanistic basis of cancer and the processes and pathways that underlie carcinogenesis.

Anti-HER2 IgY antibody-functionalized single-walled carbon nanotubes for detection and selective destruction of breast cancer cells.

BACKGROUND: Nanocarrier-based antibody targeting is a promising modality in therapeutic and diagnostic oncology. Single-walled carbon nanotubes (SWNTs) exhibit two unique optical properties that can be exploited for these applications, strong Raman signal for cancer cell detection and near-infrared (NIR) absorbance for selective photothermal ablation of tumors. In the present study, we constructed a HER2 IgY-SWNT complex and demonstrated its dual functionality for both detection and selective destruction of cancer cells in an in vitro model consisting of HER2-expressing SK-BR-3 cells and HER2-negative MCF-7 cells. METHODS: The complex was constructed by covalently conjugating carboxylated SWNTs with anti-HER2 chicken IgY antibody, which is more specific and sensitive than mammalian IgGs. Raman signals were recorded on Raman spectrometers with a laser excitation at 785 nm. NIR irradiation was performed using a diode laser system, and cells with or without nanotube treatment were irradiated by 808 nm laser at 5 W/cm2 for 2 min. Cell viability was examined by the calcein AM/ethidium homodimer-1 (EthD-1) staining. RESULTS: Using a Raman optical microscope, we found the Raman signal collected at single-cell level from the complex-treated SK-BR-3 cells was significantly greater than that from various control cells. NIR irradiation selectively destroyed the complex-targeted breast cancer cells without harming receptor-free cells. The cell death was effectuated without the need of internalization of SWNTs by the cancer cells, a finding that has not been reported previously. CONCLUSION: We have demonstrated that the HER2 IgY-SWNT complex specifically targeted HER2-expressing SK-BR-3 cells but not receptor-negative MCF-7 cells. The complex can be potentially used for both detection and selective photothermal ablation of receptor-positive breast cancer cells without the need of internalization by the cells. Thus, the unique intrinsic properties of SWNTs combined with high specificity and sensitivity of IgY antibodies can lead to new strategies for cancer detection and therapy.

A multicenter, double-blinded validation study of methylation biomarkers for progression prediction in Barrett's esophagus.

Esophageal adenocarcinoma risk in Barrett's esophagus (BE) is increased 30- to 125-fold versus the general population. Among all BE patients, however, neoplastic progression occurs only once per 200 patient-years. Molecular biomarkers are therefore needed to risk-stratify patients for more efficient surveillance endoscopy and to improve the early detection of progression. We therefore performed a retrospective, multicenter, double-blinded validation study of eight BE progression prediction methylation biomarkers. Progression or nonprogression were determined at 2 years (tier 1) and 4 years (tier 2). Methylation was assayed in 145 nonprogressors and 50 progressors using real-time quantitative methylation-specific PCR. Progressors were significantly older than nonprogressors (70.6 versus 62.5 years; P < 0.001). We evaluated a linear combination of the eight markers, using coefficients from a multivariate logistic regression analysis. Areas under the ROC curve (AUC) were high in the 2-year, 4-year, and combined data models (0.843, 0.829, and 0.840; P < 0.001, <0.001, and <0.001, respectively). In addition, even after rigorous overfitting correction, the incremental AUCs contributed by panels based on the 8 markers plus age versus age alone were substantial (Delta-AUC = 0.152, 0.114, and 0.118, respectively) in all 3 models. A methylation biomarker-based panel to predict neoplastic progression in BE has potential clinical value in improving both the efficiency of surveillance endoscopy and the early detection of neoplasia.

Alpha-fetoprotein, des-gamma carboxyprothrombin, and lectin-bound alpha-fetoprotein in early hepatocellular carcinoma.

BACKGROUND & AIMS: Alpha-fetoprotein (AFP) is widely used as a surveillance test for hepatocellular carcinoma (HCC) among patients with cirrhosis. Des-gamma carboxy-prothrombin (DCP) and lectin-bound AFP (AFP-L3%) are potential surveillance tests for HCC. The aims of this study were to determine performance of DCP and AFP-L3% for the diagnosis of early HCC; whether they complement AFP; and what factors affect DCP, AFP-L3%, or AFP levels. METHODS: We conducted a large phase 2 biomarker case-control study in 7 academic medical centers in the United States. Controls were patients with compensated cirrhosis and cases were patients with HCC. AFP, DCP, and AFP-L3% levels were measured blinded to clinical data in a central reference laboratory. RESULTS: A total of 836 patients were enrolled: 417 (50%) were cirrhosis controls and 419 (50%) were HCC cases, of which 208 (49.6%) had early stage HCC (n = 77 very early, n = 131 early). AFP had the best area under the receiver operating characteristic curve (0.80, 95% confidence interval [CI]: 0.77-0.84), followed by DCP (0.72, 95% CI: 0.68-0.77) and AFP-L3% (0.66, 95% CI: 0.62-0.70) for early stage HCC. The optimal AFP cutoff value was 10.9 ng/mL leading to a sensitivity of 66%. When only those with very early HCC were evaluated, the area under the receiver operating characteristic curve for AFP was 0.78 (95% CI: 0.72-0.85) leading to a sensitivity of 65% at the same cutoff. CONCLUSIONS: AFP was more sensitive than DCP and AFP-L3% for the diagnosis of early and very early stage HCC at a new cutoff of 10.9 ng/mL.