bluuebunny/crossref_metadata_2025 huggingface dataset:
Atypical Hepatic Hemangioma: A Case Study
Authors: Blumhagen Nicholas , Fisher Kelsy L.
Published: March 2017

Hemangiomas are benign vascular tumors caused by an increase of blood vessels lined with endothelium. Diagnostic imaging such as sonography, computed tomography (CT), and contrast-enhanced magnetic resonance imaging (CE-MRI) can be used to detect hepatic hemangiomas, which are typically noted as incidental findings. However, in cases where hepatic hemangiomas demonstrate atypical appearances, this may suggest a possible malignancy. In such instances, a liver biopsy may be necessary for pathologic confirmation. A case is provided of a large hepatic mass that was initially detected on CT and further evaluated with sonography. Sonographic evaluation revealed characteristics suspicious for possible malignancy, including highly enlarged size, heterogeneous echotexture, and lobular contour. A biopsy ultimately determined the mass to be a cavernous hepatic hemangioma. The atypical sonographic appearance of the hepatic hemangioma in this case is worthy of consideration such that sonographers and the interpreting physician are aware of various presentations of this pathology.
Mineralogical and geochemical characterisation of warm-water, shallow-marine glaucony from the Tertiary of the London Basin
Authors: Huggett Jennifer , Adetunji Jacob , Longstaffe Fred , Wray David
Published: March 2017

Glaucony is present in the Palaeocene sediments of the London Basin, from the Thanet Sand Formation to the gravel beds at the base of the Lower Mottled Beds of the Reading Formation. The Upnor Formation glaucony is a rare example of formation in warm, shallow, brackish water and this, combined with the ready availability of fresh material from boreholes, make this study important in developing our understanding of this mineral. Glaucony comprises up to 50% of the Upnor Formation, a grey to green sandstone, of variable thickness and composition, which was deposited in awarm, shallow, marine to estuarine environment, ∼55.6–56.2 Ma. Using morphological criteria, X-ray diffraction data and K+abundance, the Upnor glaucony may be defined as evolved. The underlying shallow marine Thanet Sand contains <5% of nascent to slightly evolved glaucony. The rare earth element (REE) data for the Upnor Formation suggest more than one source for the sediment from which the Upnor glaucony formed, while the ThanetREEdata are consistent with a large detrital clay component.

In the Upnor Formation, the large proportion of glaucony that occurs as granule fragments rather than whole granules, and the high-energy estuarine to shallow-marine environment of deposition, are indicative of reworking. The Upnor glaucony is inferred to be intraformationally reworked, rather than derived from the Thanet Sand Formation. The glaucony may have formed in sediments deposited away from the main estuarine channel, and been subsequently reworked into higher-energy sediments.Warm seas with freshwater mixing are more typically characteristic of verdine formation than of glaucony. The shallow, brackish environment of deposition suggests that there is not a clear distinction between the environmental requirements of verdine (or odinite) and glaucony (or glauconite), as is often proposed. The highly fractured, delicate nature of some granules indicates that they have experienced somematurationin situ, after reworking.

The oxygen and hydrogen isotopic compositions of Upnor Formation shark teeth and glaucony point to formation in low-salinity water at ∼23 ± 3°C, also consistent with formation in the Upnor Formation, rather than in a fully marine sediment and subsequent reworking. A higher than normal temperature of formation may have increased the rate of evolution of glaucony.

Our multidisciplinary study considers many of the factors relating to depositional environment that must be considered when glaucony-rich facies are encountered in comparable palaeo-environmental settings elsewhere in the geological record.
Tetrahedral charge and Fe content in dioctahedral smectites
Authors: Kaufhold S. , Stucki J.W. , Finck N. , Steininger R. , Zimina A. , Dohrmann R. , Ufer K. , Pentrák M. , Pentráková L.
Published: March 2017

Natural aluminosilicates can contain Fe in tetrahedral or octahedral coordination. Amongst smectites, tetrahedral iron is known to occur in Fe-rich nontronites but few indications exist for the presence of tetrahedral Fe in smectites of the montmorillonite–beidellite series. A set of 38 different bentonites showed a correlation of tetrahedral charge and Fe content in their smectites. All materials with large tetrahedral charge were rich in Fe. This could be explained by a general tendency of Fe to enter the tetrahedral sheet. To investigate this correlation, nine materials were selected and investigated by Mössbauer, UV-Vis, Fe K pre-edge and EXAFS spectroscopy with respect to tetrahedral Fe (Fe[IV]). The latter two methods were at the detection limit but Mössbauer and UV-Vis spectroscopy provided consistent results indicating the significance of both methods in spite of some scatter caused by the overall small amount of tetrahedral Fe. The results indicate the absence of any relation between Fe content and tetrahedral Fe. Tetrahedral Fe can be present in Fe-poor smectites and absent in the case of Fe-rich materials. This means that Fe-rich montmorillonites have a larger tetrahedral charge which is not caused by Fe[IV]but by Al[IV]. A possible explanation for this indirect relation is based on: the coordination of Al3+in the weathering/smectite-forming solutions determines the coordination in the precipitates; and the Al[IV/VI]ratio increases with increasing pH. The correlation could thus be explained if the pH of weathering solutions generally was higher in Fe-rich parent smectite rocks than in more acidic smectite parent rocks. The relation between tetrahedral charge and Fe content can probably be explained by different geochemical contexts throughout the formation of smectites which affect the coordination of dissolved Al.
Adsorption studies of hydrogen and ethylene on cation-exchanged bentonite
Authors: Alver Burcu Erdoğan
Published: March 2017

The adsorption of C2H4 and H2 gases by bentonite from the Ünye region, Turkey both as raw (B) and as K+-, Li+-, Ag+- and Mg2+-exchanged forms, was investigated using automated volumetric equipment and pressures up to 100 kPa at 273 K and 77 K, respectively. X-ray powder diffraction (XRD) and specific surface area measurement (BET) methods were employed to characterize the bentonite samples. The C2H4and H2gas adsorption capacities of the original and modified forms were in the ranges 1.817–0.201 mmol g−1and 0.522–0.388 mmol g−1, respectively. The influence of salt modifications on the gas adsorption properties of bentonite is discussed.
Intracranial hemorrhage in patients with atrial fibrillation receiving anticoagulation therapy
Authors: Lopes Renato D. , Guimarães Patrícia O. , Kolls Bradley J. , Wojdyla Daniel M. , Bushnell Cheryl D. , Hanna Michael , Easton J. Donald , Thomas Laine , Wallentin Lars , Al-Khatib Sana M. , Held Claes , Gabriel Melo de Barros e Silva Pedro , Alexander John H. , Granger Christopher B. , Diener Hans-Christoph
Published: March 2017

Key Points

Nearly 80% of the warfarin-treated patients with ICH had an INR within or below therapeutic range around 2 weeks before the event. We can reduce ICH by using apixaban rather than warfarin and by avoiding concomitant aspirin, especially in patients with older age.
Correlates of child undernutrition in Yemen
Authors: De Souza Laetícia R.
Published: March 2017

Malnutrition is part of a vicious cycle involving biological and social aspects. Some factors are directly associated with malnutrition, such as inadequate dietary intake and incidence of disease, while others (socio-economic in nature) are more distant but no less important. This paper aims at identifying the main correlates of stunting among Yemeni children through a logistic regression model. The results are based on the fourth round of the National Social Protection Monitoring Survey conducted in 2013; which makes this study a baseline assessment of Yemeni child undernutrition before the ongoing civil war. Primarily addressing the most significant factors associated with stunting in Yemen is urgent especially if one considers the country’s constant public budget shortages. There are significant differences—in prevalence of child stunting— between regions of residence that could be reduced by putting in place local policies aimed at increasing population access to adequate water and good hygiene practices. The Social Welfare Fund (SWF) programme is also important since this benefit is the only source of income for some families. However, if corruption, regional and civil conflict continues, improvements in the SWF will probably not matter. Such interventions, together with policies for changing attitudes towards women’s education, would also help to promote proper child feeding practices. Likewise, cultural aspects can explain the aetiology of children’s poor growth. Examples include feeding taboos that influence early initiation and duration of breastfeeding. With so many steps to be taken to prevent child malnutrition, it cannot remain an invisible problem.
Elastic least-squares one-way wave-equation migration
Authors: Stanton Aaron , Sacchi Mauricio D.
Published: March 2017

Least-squares migration seeks a reflectivity model that fits the observed data. It is used to compensate for acquisition noise, poor sampling of sources and receivers on the surface, as well as poor illumination of the subsurface. To date, least-squares migration has been mainly restricted to the imaging of acoustic wavefields. We have developed an extension of one-way wave-equation least-squares migration for elastic wavefields in isotropic media. Least-squares migration is an iterative method that requires a forward and an adjoint operator. In elastic least-squares one-way wave-equation migration, the forward operator generates data components from multiparameter images by recursive wavefield decomposition, extrapolation, and recomposition. Conversely, the adjoint operator generates multiparameter images from data components by recursively applying the adjoint of the wavefield recomposition, extrapolation, and wavefield decomposition operators. We use an extended imaging condition and regularize the inversion by applying a smoothing filter on the depth-angle axes of each common image point gather to reduce the effect of source/receiver sampling, noise, and crosstalk artifacts. Elastic least-squares migration is able to compensate for irregular subsurface illumination in elastic imaging and provides an alternative approach to interpolation and wavefield separation of multicomponent seismic data.
Understanding reservoir heterogeneity through water-saturation prediction via neural network — A case study from offshore Nile Delta
Authors: Mohamed Islam Ali , Shenkar Omar , Mahmoud Hossam
Published: March 2017

In complex geologic settings with a great degree of heterogeneity in reservoir properties, such as submarine channel complexes as in the Nile Delta province, we face the challenge of characterizing the reservoir based on availability of different seismic attributes. Amplitude variation with offset (AVO) analysis and prestack inversion techniques show impressive results in delineating the gas-bearing reservoirs, especially in clastic systems. However, a shortage of available wells and/or seismic data leads to a challenge in applying AVO and any prestack seismic inversion approaches. In addition, quantitative prediction of water saturation (Sw) from seismic is ambiguous because of its independent nonlinear relationship with conventional seismic attributes and inversion products. Water-saturation prediction away from the well is essential in order to characterize the reservoirs effectively. Therefore, probabilistic neural network (PNN) analysis has been implemented to predict Sw 3D volume using full-stack seismic data and Sw logs. In this case study, we applied the proposed neural network workflow over one of the late-Pliocene gas-sandstone reservoirs, Sequoia Field, in the West Delta Deep Marine (WDDM) concession, offshore Nile Delta, Egypt. The resulting volume then was tested using two blind wells that haven't been used in the analysis. The predicted Sw volume contains fine details that were used with variance and spectral-decomposed volumes to understand the reservoir's internal architecture in terms of sand body geometries and connectivity. The resulting volumes were used to better define the reservoir and optimize a new development well location.
Use of multibeam echo sounder backscatter and bathymetry data to reveal new insights into the Campeche Escarpment
Authors: McBee Jayme , Brumley Kelley , Mitchell Garrett , Gharib Jamshid
Published: March 2017

Multibeam echo sounder (MBES) bathymetry and backscatter data from the 2013 R/V Falkor survey are used to define the Cretaceous–Paleogene (K-Pg) boundary deposit outcropping on the Campeche Escarpment and to characterize large-scale erosional processes on the Campeche shelf. We delineate the escarpment into four geomorphic provinces based on submarine canyon density and morphology, as well as pronounced geomorphological differences formed in response to erosional processes along strike of the Campeche Escarpment. Large-scale, retrogressive-appearing mass wasting has left high-angle scarps where large slabs of sediment have eroded the escarpment edge, giving the slope a terraced appearance. This erosion reveals higher backscatter intensity material overlain with remnants of lower backscatter intensity sediments within the slide scar. We infer this high-intensity backscatter material to be predominantly carbonate layers on which erosion occurred. The most prominent high-intensity backscatter layer is interpreted to identify the K-Pg boundary deposit (KPBD) that was reported previously based on a steep bathymetric change and constrained by cores from Deep Sea Drilling Project (DSDP) Sites 86 and 94. Given its proximity to the impact crater, the KPBD is likely to be composed of a massive impact breccia. Upslope, high-intensity backscatter layers are inferred to represent postimpact carbonates that progressively infilled the basin flank after the Chicxulub bolide impact. Lower intensity backscatter material is inferred to be fine-grained Cenozoic sediment drape. The stark contrast observed in MBES backscatter data between high-intensity carbonate material and lower-intensity sediments refines and constrains the location of the K-Pg boundary deposit exposed along the Campeche escarpment and provides new insights into the carbonate platform's postbolide impact evolution as observed in the erosional styles of the Campeche escarpment.
Monitoring the stability of tailings dam walls with ambient seismic noise
Authors: Olivier Gerrit , Brenguier Florent , de Wit Tjaart , Lynch Richard
Published: March 2017

Tailings dams are massive structures designed to contain the waste slurry remaining after processing ore at open pit and underground mines. These structures fail far more regularly than normal water-storage dams. In recent years, catastrophic tailings dam failures have occurred, causing significant damage to the environment and even loss of life. To mitigate these catastrophic events in the future, there is an urgent need to develop cost-effective methods to monitor the structural stability of these constructions over time. The lack of current cost-effective monitoring methods prompted us to investigate whether ambient seismic noise can be used to detect internal changes in a tailings dam wall during a period of heavy rainfall. We recorded three weeks of continuous seismic data with 10 short-period geophones at a tailings dam in Tasmania, Australia. Seismic interferometry was used on ambient noise to create virtual seismic sources. With these virtual source signals, small changes in seismic velocity were measured daily and compared to rainfall, seepage flow rates, and fluid pore pressure. The observed velocity changes were driven by fluid saturation, ground water level, increased loading from increased dam water level, and a sudden increase in fluid pore pressure in a section of the dam wall. The results suggest that this relatively inexpensive method can be used to monitor and locate small changes in the interior of the tailings dam wall, providing a valuable tool to remotely monitor the structural stability of tailings dam walls over time.
Getting started with controlled-source electromagnetic 1D modeling
Authors: Werthmüller Dieter
Published: March 2017

Forward modeling is an important part of understanding controlled-source electromagnetic (CSEM) responses. The diffusive term in the electromagnetic wave equation is dominant over the displacement term at these frequencies. It is the diffusive behavior that makes it difficult to imagine the actual propagation of the signal. An important tool in gaining experience therefore is forward modeling, and lots of it. The advantage of one-dimensional (1D) forward modeling, besides its speed, is to study isolated effects (see for instance Key, 2009): What is the influence of resistivity anisotropy, or of fine-scale resistivity variations? What is the influence of the airwave? With 1D modeling you can quickly study these effects in isolation before you go on to more complex models in higher dimensions. For an introduction to CSEM for hydrocarbon exploration see, for instance, Constable (2010).
Autophagic cell death with hydroxychloroquine in patients with hormone-dependent prostate-specific antigen progression after local therapy for prostate cancer.
Authors: George Mridula Annette , Mayer Tina M. , Moore Dirk , Chen Chunxia , White Eileen , DiPaola Robert S. , Jeyamohan Chandrika , Stein Mark N.
Published: March 2017

102

Background: For patients who have a rising prostate-specific antigen value after definitive local therapy, androgen deprivation is a commonly employed option. However, immediate hormonal therapy has not been shown to alter the progression of the disease. Prior studies showed the dependence of early tumor growth and progression on anaerobic metabolism through glycolysis. Autophagy is conserved, genetically controlled catabolic response to starvation and stress whereby cells self-digest intracellular proteins and organelles by targeting them for degradation in lysosomes to generate energy and mitigate damage, thereby supporting cancer cell survival. Our hypothesis was that the autophagic inhibitor, hydroxychloroquine, when utilized in prostate cancer, would interfere with defective autophagy such that tumor growth will be slowed or stopped. Methods: Patients had rising PSA after primary therapy for PC, no radiographic evidence of metastasis, no (neo)adjuvant ADT within 3 months of enrollment and testosterone > 150 ng/dL. Hydroxychloroquine was dosed at 400 mg/day (cohort 1) or 600 mg/day (cohort 2). Endpoints were PSA response (change in slope of PSA rise by at least 25%, when log (PSA) is plotted vs. time). Results: 64 patients (36 cohort 1; 28 patients cohort 2) with median age 71(55-94) and baseline PSA was 3.25ng/ml (0.24- 45.69ng/ml) were enrolled in the study. 39 patients completed 6 months of hydroxychloroquine therapy and 44 patients completed 5 months of treatment. Out of 64 patients, 52 had at least 5 PSA measurements after the start of treatment, and we restrict our analysis to these patients. In 33 patients of these 52 (63%), the doubling time decreased after treatment began. In 12 of these 52 (23%), the “doubling time” turned negative, consistent with decreasing PSA value. Most common adverse events were diarrhea (26%), nausea (12%) and rash (12%). Conclusions: Hydroxychloroquine appears to have some activity in PSA progression after localized therapy with minimal toxicity. Given that hydroxychloroquine has limited side effects, this drug has the potential to augment responses to hormonal therapy or chemotherapy. Clinical trial information: NCT00726596.
National survey of practice patterns employing MRI-guided prostate biopsy for diagnosis of prostate cancer.
Authors: Tooker Graham , Pinto Peter A. , Siddiqui Mohummad Minhaj
Published: March 2017

104

Background: Targeted MRI/Ultrasound (MR/US) guided biopsy is an emerging technology that has the potential to change standard of care for the diagnosis and management of prostate cancer. It is believed that this new technology is rapidly proliferating, however quantitative analysis to describe these trends is not available. The primary objective of this study was to assess nationwide urologist opinions and efforts to implement MR/US imaging into their prostate cancer practices. Methods: A questionnaire was generated and distributed using REDCap to 7341 practicing urologists within the United States. The twenty question survey was designed to gather information regarding demographics, current and recent changes in MRI use, opinions on targeted MR/US guided biopsy, and barriers to implementation. The survey results were then analyzed with ANOVA. Results: 291 practicing urologists completed the survey. Respondents were primarily trained in general urology (60%) or urologic oncology (22%) and well distributed across practice type and geographic location. 86% of respondents currently employ MRI in some capacity in their practice, and 60% report using MR/US guided biopsy. 67% of respondents report increased use of MR/US guided biopsy over the past 5 years and 81% believe it is appropriate to use MR/US guided biopsy for the diagnosis of prostate cancer. Academic centers had the greatest utilization of targeted biopsy (72%) and solo practitioners had the least (38%, p = 0.003). The northeast region also demonstrated greatest use of targeted biopsy (68%) and western region had the least (44%, p = 0.02). 24% of respondents feel there is sufficient evidence to employ MR/US as standard of care in all prostate biopsies, while 65% believe MR/US should be reserved for select cases such as men with prior negative biopsies. Of those not performing biopsies, 69% of respondents cited cost as a barrier to implementation. Conclusions: While there are some reservations about employing MR/US guided biopsy, the data suggests urologists support its use, and are making efforts to introduce targeted MR/US guided biopsy into their practice. Regional and practice setting variations exist in adaptation of this technology.
Defining the index lesion for salvage partial gland ablation after radiation therapy for localized prostate cancer.
Authors: Sivaraman Arjun , Takaeda Toshikazu , Vargas Hebert Alberto , Fine Samson , Eastham James Andrew , Ehdaie Behfar
Published: March 2017

105

Background: Our objective was to evaluate the impact of MRI and systematic biopsy characteristics to identify the index lesion for salvage partial gland ablation using tumor maps from whole mount slides of salvage radical prostatectomy (sRP) specimen. Methods: We identified 225 patients who underwent sRP between 2000 and 2014 and a tumor map was created from whole-mount slides in 77 patients. Among these patients, we selected men with a priori pre-treatment criteria considered eligible for PGA, including, biopsy proven unilateral disease concordant with a region of interest (ROI) on MRI, and excluding men with imaging suspicious for extra-capsular extension (ECE), seminal vesicle Invasion (SVI) or lymph node involvement (LNI). We describe the correlation between pre-treatment clinical characteristics and final radical prostatectomy whole mount specimen to select men eligible for PGA defined as hemi-gland ablation. Results: Among 77 patients with a tumor map of entirely-submitted and whole-mounted specimens, 15 patients were determined to be eligible for partial gland ablation based on pre-treatment clinical characteristics. The mean age was 60 years and median time from primary RT was 48 months. The median (IQR) tumor volume of the index lesion was 0.3 (0.4) cc. The location of the index lesion was determined to be the apex, mid-gland and base in 77%, 100% and 15% of patients, respectively. The median distance of the index tumor to the urethra was 0.5 (0.2) cm. The index tumor was confined to one lobe and concordant to the biopsy pathology and MRI data in all 15 patients (100%). There was no ECE, LNI or SVI identified in the sRP specimens. To account for those patients who did not have a tumor map of the whole-mount specimen, a sensitivity analysis was performed and determined that the clinical characteristics of the 77 patients with tumor maps were comparable to the entire 225 sRP cohort. Conclusions: Clinical characteristics guided by biopsy findings and MRI data can be used to select men for PGA with recurrent localized prostate cancer after radiation therapy and based on tumor maps from sRP specimen, we propose that salvage hemi-gland ablation including periurethral tissue is feasible.
Satisfying the fatty acid demand of prostate cancer: De novo synthesis versus uptake as alternative and potentially cooperative prostate cancer phenotypes.
Authors: Gaston Sandra Marlene , Kearns James , Adams George W. , Rais-Bahrami Soroush , Nix Jeffrey , Kolettis Peter N , Bryant James E , Otali Dennis , Grizzle William E.
Published: March 2017

107

Background: Malignant transformation increases cellular demand for fatty acids (FA). Many cancers show increased expression of fatty acid synthase (FASN); FASN catalyzes the de novo synthesis of the FA palmitate. While research has focused on FASN and de novo tumor FA synthesis, observations suggest that alternate mechanisms for FA acquisition are also important, including studies showing that cancer cells can be rescued from FASN inhibition by exogenous palmitate. Using a biopsy-based approach, we identified a PrCa subtype with outlier (>10 fold) overexpression of fatty acid binding protein 5 (FABP5). FABP5 facilitates the utilization of palmitate and other FAs from outside the cell; a FABP5 overexpression phenotype may confer a selective advantage when dietary FAs are abundant or when FASN is targeted as a therapy. Methods: 244 prostate biopsy patients were prospectively enrolled. Tissue prints were collected from each core for RNA and DNA preparation. mRNA was analyzed using Affymetrix arrays and TaqMan qrtPCR assays. Immunohistochemistry (IHC) was performed using archival radical prostatectomy (RP) specimens. Results: mRNA analyses revealed a PrCa subtype with >10 x overexpression of FABP; this phenotype was observed in 7% of 268 cores with Gleason sum (GS) 7-10 PrCa. We also observed a second subtype with >10 x overexpression of FASN in 9% of GS 7-10 cores. With few exceptions these two PrCa subtypes showed an “either-or” pattern with top-quartile overexpression of FABP5 or FASN but not both (Spearman r = - 0.385; P < 0.0001). IHC confirmed variable expression, including “patchwork” PrCas with high Gleason pattern (GP) areas overexpressing FABP5 next to low GP areas overexpressing FASN. The net result may be a selective advantage for the high grade cancer if FABP5 allows it to exploit the FA being synthesized by the adjacent low grade focus Conclusions: Identification of a PrCa subtype with high levels of FABP5 overexpression suggests a previously unrecognized mechanism by which some PrCas can increase FA supply without de novo synthesis; such a PrCa subtype might be particularly sensitive to dietary interventions and relatively insensitive to FASN inhibitors.
A metastatic biology gene expression assay to predict the risk of distant metastases in patients with localized prostate cancer treated with primary radical treatment.
Authors: Jain Suneil , Lyons Ciara , Walker Steven M. , McQuaid Stephen , Hynes Sean , Mitchell Darren M. , Pang Brendan , Logan Gemma E , McCavigan Andrena , O'Rourke Declan , Davidson Catherine Joan , Knight Laura A , Berge Viktor , Neal David , Pandha Hardev S. , Harkin Paul D , James Jacqueline , Kennedy Richard D. , O'Sullivan Joe M. , Waugh David J.
Published: March 2017

11

Background: Approximately 20% of patients with organ confined prostate cancer (PCa) will develop disease recurrence following radical treatment (surgery or external beam radiotherapy (EBRT)). We hypothesized that a molecular subgroup of early PCa may have metastatic potential at presentation, resulting in disease recurrence. Methods: Using unsupervised hierarchical clustering of gene expression from a PCa dataset we identified a novel molecular subgroup with a transcriptional profile similar to metastatic disease. We developed a 70 gene expression assay to prospectively identify patients within the subgroup from formalin fixed and paraffin embedded tissue (FFPE). Initial assessment found the assay to be prognostic in three independent publicly available prostatectomy datasets. We therefore assessed the prognostic value of the assay in FFPE clinical samples collected from multiple international sites. FFPE tumor resections and tumor biopsy specimens were obtained from 322 surgical patients and 248 patients treated with EBRT. Regions of highest Gleason grade were identified for macrodissection, RNA extraction and gene expression analysis. Samples were dichotomized as metastatic biology assay positive or negative using a pre-specified cut-off. The association of assay results with biochemical failure (BF) and distant metastases (DM) was tested on multivariate (MVA). Results: The assay was significantly associated with BF on MVA (HR 1.67 [1.16-2.38]; p = 0.0059), (HR 2.26 [1.26-4.04]; p = 0.0062) and DM on MVA (HR 3.39 [1.88-6.12]; p = 0.0001), (HR 3.26 [1.27-8.30]; p = 0.0137) for surgery and EBRT cohorts respectively. Importantly, in a combined model, the assay demonstrated additional information to the commonly used CAPRA clinical tool for prediction of DM, HR 2.72 [2.10-3.51]; p < 0.0001, and HR 2.72 [1.42-5.20]; p = 0.0026 (Prostate Metastatic Assay combined with CAPRA-S and CAPRA respectively). Conclusions: The metastatic biology assay predicts BF and DM in PCa patients treated with surgery or EBRT. The assay may help to select patients at risk of metastatic disease for additional treatment aimed at preventing disease recurrence.
Informed decision making (IDM) for prostate cancer (PCa) screening in a high-risk population.
Authors: Dhillon Puneet , Grivas Petros , Raska Paola , Hickman Devon , Elson Paul , Awadalla Ann , Abraham Jame , Smolenski Kathy N. , Zhu Hui , Schalcosky Thomas , Modlin Charles , Bell Kimberly , Abraksia Samir
Published: March 2017

112

Background: PCa incidence and mortality in African Americans (AA) is higher than in Caucasians. Health-education programs and culturally appropriate outreach to high-risk groups in accordance with American Cancer Society IDM guidelines can reduce disparities. Data show that it is hard to provide comprehensive unbiased education about screening to patients (pts). This study aims to examine whether IDM guidelines in a large high risk group setting can improve knowledge on PCa and screening decision, and whether such education program is overall beneficial to pts. Methods: Pts were included in one-day outreach event and were given a 15-question pre and post- test focused on standard informative educational PowerPoint and then were offered screening (PSA + DRE). Components of IDM were reviewed during this educational intervention. Demographics and family history was collected and UCSF 10-year mortality index was assessed to help IDM. Pre- and post- test number of correct answers were compared (Wilcoxon signed rank); pts were surveyed on their opinion on the program. The decision regarding screening after the intervention was tracked as well as the % of PCa diagnosed. Pts were tracked via an established navigation system to ensure follow up care. Results: 106 pts were included in the current analysis. Median number of correct answers at pre and post test was 8 and 11 (p < 0.001). Overall, 86% responded that they wanted screening. Of those, 92% were AA and 21% had family history of PCa; 21 pts had PSA only, 60 had PSA + DRE. 13 pts (16%) had abnormal PSA per NCCN guidelines, 5 (8%) had abnormal DRE. 5 PCa were biopsy-diagnosed, 4 had abnormal DRE + PSA; 1 had only abnormal DRE. Overall, 82% pts favored IDM before screening, 18% would prefer screening without IDM. 75% of all pts found the information “very helpful” in decision-making (within a 5-point Likert scale). Conclusions: Our education-based IDM led to significant improvement in knowledge about PCa screening. Most pts preferred education prior to screening. Our approach paired with the use of navigation program is feasible and was positively received by a large high risk group. Project is ongoing with more pts and follow up, and further validation is pending. Clinical trial information: NCT02419846.
Effect of heparin bridged transrectal prostate biopsy on the risk of hemorrhage in patients requiring temporary discontinuation of warfarin.
Authors: Hamano Itsuto , Hatakeyama Shingo , Yoneyama Tohru , Tobisawa Yuki , Soma Osamu , Matsumoto Teppei , Yamamoto Hayato , Imai Atsushi , Yoneyama Takahiro , Hashimoto Yasuhiro , Koie Takuya , Ohyama Chikara
Published: March 2017

125

Background: Safety of heparin bridging therapy for transrectal ultrasound-guided prostate (TRUS) biopsy in patients requiring temporary discontinuation of antithrombotic therapy is unknown. This study aimed to assess the relationship between heparin bridging therapy and the incidence of complications after TRUS biopsy. Methods: From January 2005 to November 2015, we performed 1307 consecutive TRUS biopsies on 1134 patients in our hospital. The patients were assigned to two groups: those without heparin bridging (the control group) and those with temporary discontinuation of antithrombotic agents with heparin bridging therapy (the bridging group). A 10–12-core TRUS biopsy was performed; the patients were evaluated for bleeding-related complications. Results: Of 1134 patients, 1109 (1281 biopsies) and 25 (26 biopsies) were assigned to the control and bridging group, respectively. Patient background did not significantly differ between the control and bridging groups, except for age, history of diabetes, cardiovascular diseases, and CHADS2 scores. Compared with the control group, the bridging group showed a significantly higher rate of complication for any complication (35% vs. 8.3%, P < 0.001), bleeding-related complications (27% vs. 4.4%), and urinary tract infection (7.7% vs. 1.2%). No thromboembolic event was observed in the present study. Multivariate logistic analysis showed that heparin bridging therapy was a significant risk factor for the incidence of any complication and bleeding-related complications. Conclusions: Heparin bridging therapy with temporal discontinuation of antithrombotic agents may increase the risk of complications after TRUS biopsy. Further, large-scale studies are required to clarify the safety of heparin bridging therapy.
Single cell phenogenomic subtyping of circulating tumor cells (CTCs) identify intercellular tumor heterogeneity (het) and multiple resistance mechansisms in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Scher Howard I. , Graf Ryon , Jendrisak Adam , Schreiber Nicole A. , McLaughlin Brigit , Greene Stephanie , Rodriguez Angel , Fleisher Martin , Lee Jerry , Kelvin James , Wang Yipeng , Landers Mark Andrew , Dittamore Ryan Vance
Published: March 2017

139

Background: Genomic profiling of metastatic tumors can identify mCRPC pts w/ “actionable” targets. However, responses from this approach are infrequent and not durable, broadly attributed to intra-tumor and intrer-cellular het. We sought to understand relationships between single CTC phenotypic and genomic patterns present when starting ARSi or taxane therapy (Tx) to develop more effective biomarker-directed treatment approaches. Methods: 9225 CTCs from 319 blood samples from 179 mCRPC pts were detected and digital phenotypically profiled using the Epic Sciences platform. Unsupervised clustering revealed 15 phenotypic CTC subtypes based on digital pathology features (Type ‘A’-‘O’). Phenotypic diversity was determined by a Shannon index of these subtypes in pt samples. Next, 856 CTCs representing each subtype were individually whole genome sequenced for copy number variation and genomic instability, to define phenogenomic single cell profile and taxonomy. Tx outcomes were associated with CTC profiles. Results: Pre-therapy identification of certain CTC phenotypic subtypes was associated with poor overall survival (OS) following ARSi and/or taxanes. 5/15 subtypes existed primarily in pts w/ high CTC het (84-94%, Bonferroni adjusted p < 0.05, permutation test), and linked to amp of AR and cMYC, and loss of TP53 and PTEN. Clusters of genomic events were linked to phenotypic features (i.e. small cell CTC w/AuroraK & nMYC amp) and provide single cell phenogenomic associations with pathways such as AR/PTEN feedback and DNA repair machinery. Conclusions: Presence ofspecific CTC subtypes was associated w/ poor survival on ARSi and/or taxanes and may inform Tx selection. Identifying CTC subtypes present in high het samples can provide insight into individual pt disease evolution and potential approaches to maximize benefit. Longitudinal monitoring of CTC phenogenomics is being studied in novel Tx trials.[Table: see text]
Rapid, ultra-low coverage copy number profiling of cell-free DNA as a precision oncology screening strategy in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Hovelson Daniel H. , Liu Chia-Jen , Wang Yugang , Kang Qing , Haakenson Christine , Langmore John , Kamberov Emmanuel , Ramnath Nithya , Krauss John C. , Talpaz Moshe , Chugh Rashmi , Hyland David , Tuck Missy , Herman Kirk , Husain Hatim , Tewari Muneesh , Chinnaiyan Arul M. , Mills Ryan , Morgan Todd Matthew , Tomlins Scott A. ,   Rubicon Genomics
Published: March 2017

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Background: Although cell free DNA (cfDNA) profiling by next generation sequencing (NGS) holds great promise for precision oncology, the inability to estimate tumor content a priori typically results in ultra-deep sequencing (e.g. 10,000x) based approaches—often at limited loci—to ensure accurate assessment of cfDNA samples where tumor content can be < 0.1%. However, a large subset of patients with advanced cancers, where most precision oncology is applied, have much greater cfDNA tumor content. Methods: Here we demonstrate the utility of a pan-cancer, rapid, inexpensive, whole genome NGS of cfDNA approach (PRINCe) on benchtop sequencers as a precision medicine screening strategy based on ultra-low coverage (~0.005x) tumor content determination through genome-wide copy number alteration (CNA) profiling using 48 plasma cfDNA samples from patients with advanced cancer. Results: Using this approach, we identified therapeutically relevant focal CNAs in 13 of 48 (27%) cfDNA samples from patients with metastatic cancer, including 11 of 36 (31%) from patients with mCRPC. We further show that PRINCe is effective at whole genome coverages as low as 0.005x. Combining PRINCe with targeted multiplexed-PCR NGS of the same cfDNA enables mutation and CNA assessment using effective coverage as low as 25x based on calibrating sequencing depth to cfDNA tumor content. Lastly, PRINCe identifies pre-treatment cfDNA copy number profiles that can be used for inexpensive disease monitoring. Conclusions: Taken together, our screening approach enables broadly applicable cfDNA based precision oncology for patients with advanced cancer through rapid, inexpensive identification of therapeutically relevant CNAs and pre-treatment genomic profiles for disease monitoring, while also guiding additional cfDNA profiling approaches to reserve costly ultra-deep approaches for patients with very low cfDNA tumor content.
Estimating the incidence of oligorecurrent and potentially salvageable prostate cancer on 18F-Choline PET-CT: Screening phase of the STOMP randomized phase II trial.
Authors: Ost Piet , De Bruycker AurÃ©lie , Claeys Tom , Delrue Louke , De Meerleer Gert , De Vos Filip , Decaestecker Karel , De Man Kathia , Fonteyne Valerie , Lumen Nicolaas , Ameye Filip , Billiet Ignace , Joniau Steven , Lambert Bieke
Published: March 2017

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Background: To identify sites and patterns of prostate cancer (PCa) recurrence following primary PCa treatment with 18F-choline PET/CT and estimate the number of patients potentially eligible for metastasis-directed therapy (MDT, defined as patients with up to 3 metastatic lesions). Methods: Between 7/7/2011 and 7/6/2016, 229 patients underwent a 18F-choline PET/CT for a biochemical PCa recurrence for potential inclusion in a randomized phase II-trial (STOMP). The trial randomizes patients with oligorecurrent (Orec) PCa between active surveillance (AS) and MDT. Patients were eligible for the trial in case of biochemical recurrence following primary prostate cancer treatment, up to 3 extracranial metastases and testosterone > 50 ng/ml. Patterns of recurrence were classified as local (prostate or prostate bed), distant (N1, M1a/b/c) or a combination of both. The number of lesions were counted per scan and patients with up to 3 distant lesions with or without a local recurrence were considered as ORec vs > 3 lesions as polyrecurrent (PRec). Results: A total number of 229 patients underwent 277 choline PET-CTs, resulting in 208 patients (91%) with a recurrence and 21 patients (9%) without any detectable recurrence. Twenty-two men (10%) had a local recurrence and 186 men (81%) had a distant recurrence, which was combined with a local recurrence in 17 men. Of the 186 patients, 131 (57%) were considered as ORec and 55 (24%) as PRec at median PSA values of 3.4 and 5.4 ng/ml, respectively (p < 0.003). ORec were categorized as N1: 16%, M1a: 8%, M1b: 13%, M1c: 2% or a combination of sites: 17% (Figure 1). Fifty-eight patients had 1 lesion (25%), 39 2 lesions (17%) and 34 3 lesions (15%). Men with ORec PCa were treated with AS, MDT or palliative ADT in respectively 27%, 27% and 1% of the cases. Sixty-two of ORec men (27%) agreed to be randomized in the STOMP-trial. PRec were categorized as N1: 2%, M1a: 1%, M1b: 3%, M1c: 1% or a combination: 17% (Figure 1). Thirteen patients had 4 lesion (6%), 9 5 lesions (4%) and 33 > 5 lesions (18%) Conclusions: Two out of three PCa recurrences on 18F-choline PET-CT are potentially salvageable with local therapy and/or metastasis-directed therapy. Clinical trial information: NCT01558427.
First-line chemotherapy (CT) versus anti-androgen therapy (AT) for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): Individual patient analysis of the Veterans Health Administration (VHA) dataset.
Authors: Sonpavde Guru , Huang Ahong , Wang Li , Baser Onur , Miao Raymond
Published: March 2017

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Background: The outcomes of pts receiving first-line CT vs AT for mCRPC are unclear. Using the VHA dataset, we compared outcomes with first-line CT vs AT in pts with mCRPC and assessed the impact of prior androgen deprivation therapy (ADT) duration and known prognostic factors. Methods: Pts with mCRPC initiating first-line AT (abiraterone, enzalutamide) or CT (taxane) from Oct 2012 to Sept 2014 were identified. The impact of AT vs CT on overall survival (OS) and time to discontinuation (TTD) was assessed using Cox proportional hazard models, adjusting for prior ADT duration, known prognostic factors (hemoglobin [Hb], albumin [alb], alkaline phosphatase [ALP], prostate-specific antigen [PSA]), Charlson Comorbidity Index (CCI) and chronic disease score (CDS). Results: Overall, 1445 pts were evaluable; 1108 received AT (abiraterone 996, enzalutamide 112) and 337 received CT (docetaxel). The overall median duration of prior ADT was 464 days. On multivariable analysis, prior ADT duration, CCI, CDS, Hb, Alb, ALP and PSA were associated with OS, but AT vs CT was not (HR: 1.041 [95% CI: 0.853–1.270], p = 0.6943). PSA levels, prior ADT duration, and ALP was associated with TTD, and TTD was shorter for CT vs AT (HR: 2.339 [95% CI: 1.969–2.779], p < 0.0001). Longer prior ADT duration was associated with longer OS (HR: 0.566, p < 0.0001) and TTD (HR: 0.831, p = 0.0363) in the AT cohort, but not in the CT cohort. Treatment-free interval (TFI) (between first- and second-line treatment) was longer for CT vs AT (mean: 53 vs 39 days; p = 0.0303). Conclusions: To our knowledge, this is one of the largest mCRPC datasets analyzed at the individual pt level comparing first-line CT vs AT. OS was not significantly different for first-line CT vs AT after adjusting for key prognostic factors, despite shorter TTD with CT and longer TFI after first-line CT. Prior ADT duration ≤ 464 days was associated with shorter OS and TTD in the AT cohort, but not the CT cohort, suggesting that such pts may benefit from receiving CT over AT. The results are hypothesis-generating and prospective validation is required. Funding: Sanofi Genzyme
Multisite experience of fluciclovine (18F) PET/CT imaging in biochemically recurrent prostate cancer: Impact of clinical factors and intersite variation.
Authors: Zanoni Lucia , Nanni Christina , Bach-Gansmo Tore , Bogsrud Trond V , Nieh Peter , Kieboom Jesse , Korsan Katrine Andersen , Sletten Heidi , Tade Funmilayo I , Odewole Oluwaseun , Ward Penny , Chau Albert , Goodman Mark , Fanti Stefano , Schuster David M. , Willoch Frode
Published: March 2017

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Background: Fluciclovine (18F) is an FDA-approved positron emission tomography/computerized tomography (PET/CT) tracer in clinical use for the detection and localization of biochemically recurrent (BCR) prostate cancer. Here, we report the impact of clinical factors and study site on its performance. Methods: In total, 596 subjects with BCR prostate cancer underwent fluciclovine (18F) PET/CT scanning at four sites in Italy, Norway and USA. Detection Rates (DR), including region level analyses, were stratified by prostate specific antigen (PSA) levels, PSA doubling time (PSAdt), Gleason score (GS), and by investigator/site. Extra-prostatic disease was defined as all positivity outside of residual prostate, prostate bed and seminal vesicles. Results: Fluciclovine (18F) PET/CT was positive in 67.7% (403/595) of subjects. Positive findings were detected in the prostate/bed and pelvic lymph node regions in 38.7% (232/599) and 32.6% (194/596) of scans, respectively. Metastatic involvement outside the pelvis was found in 26.2% (155/591) of scans. Generally, DR increased with increasing baseline PSA (Table 1). While subject level DR did not vary significantly with PSAdt (DR = 60-69% across all categories), a positive extra-prostatic scan was more likely in patients with shorter PSAdt (DR = 52%, 48%, 37% and 28% for PSAdt <3, 3-<6, 6-<12 and >12 months, respectively). Among 361 subjects for whom baseline GS was available, scores ≥9 were associated with the highest extra-prostatic DR (55%) compared with 23% in patients with GS ≤6. Inter-site variations in acquisition protocols may have impacted DR at low baseline PSA values; with subject level DR at PSA >0.2-0.5 ng/ml = 20%, 38%, 46% and 73% at site A, B, C and D, respectively. Conclusions: Fluciclovine (18F) can detect and localize BCR prostate cancer in a wide range of subjects and, with appropriate imaging protocols, has a clinically useful DR at PSA <0.5 ng/ml. Clinical trial information: NCT02443571. [Table: see text]