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The overall objective of the Land surface Interactions with the Atmosphere over the Iberian Semi-arid Environment (LIAISE) project is to improve the understanding of land-atmosphere and hydrology interactions in a semi-arid region characterized by strong surface heterogeneity owing to contrasts between the natural landscape and intensive, irrigated agriculture. It is known that irrigation can potentially impact the local atmospheric boundary layer (ABL) characteristics, thereby modifying near surface atmospheric conditions within and downwind of irrigated areas (e.g., Lawston et al., 2020) and potentially the recycling of precipitation. The understanding of the impact of anthropization and its representation in models have been inhibited due to a lack of consistent and extensive observations. In recent years, land surface and atmospheric observation capabilities have advanced while irrigated surfaces have been increasing, leading to a renewed need for dedicated field campaigns over contrasting (climate) regions.We present a summary of the LIAISE field campaign intensive phase between July 15–29 2021, which took place over the Catalan counties of Urgell and Pla d'Urgell within the Ebro basin in north-eastern Spain. LIAISE is located in a semi-arid hot, dry Mediterranean climate, with a very sharp delineation between a vast, nearly continuous intensively-irrigated region and the generally much more dry rain-fed zone to the east of the study domain. Intensive, spatially distributed surface-based and airborne measurements of the atmospheric boundary layer were made, along with intensive eco-physiological observations and remotely-sensed high spatial resolution mesoscale measures of surface variables from aircraft and unmanned aerial vehicles (UAVs). Two energy budget sites were extended with a network of soil moisture sensors since they were used to evaluate remote sensing data from aircraft. More than 30 institutions took part in the campaign covering a wide range of expertise and spatiotemporal scales in the methods involved, be it through modelling or measurements.In this contribution we will elaborate on the spatial and temporal scales involved in the processes of evapotranspiration. We will make a strong case for integrated approaches combining observation and modelling techniques to further develop our understanding of evapotranspiration. This will be illustrated with a case study using a mixed layer column model heavily guided and constrained by measurements.

Background & Aims Microvascular invasion (MVI) is a critical prognostic factor for operable hepatocellular carcinoma (HCC). This study aimed to explore the performance of circulating tumour DNA (ctDNA) in evaluating MVI status preoperatively. Methods Seventy‐three HCC patients were enrolled and randomly divided into a training cohort and a validation cohort in a 2:1 ratio, and preoperative blood and surgical tissue samples were obtained. Genomic alterations were analysed using targeted deep sequencing with a 1021‐gene panel. Results In training cohort, 260 somatic mutations were identified in 40 blood samples (81.6%). CtDNA mutation was verified in paired tissue sample in 39 patients (97.5%). In univariate analysis, ctDNA allele frequency (AF) and largest tumour diameter were associated with the presence of MVI, but ctDNA AF was the only independent risk factor in multivariate analysis. With the cut‐off value of 0.83%, ctDNA AF determined the presence of MVI with the sensitivity of 89.7% and specificity of 80.0% in the training cohort, and the sensitivity of 78.6% and the specificity of 81.8% in the validation cohort. In preoperative evaluation, ctDNA AF, AFP level and BCLC staging were associated with recurrence‐free survival in both univariate and multivariate analysis. Conclusions CtDNA can serve as an independent risk factor of MVI for operable HCC and help determining precise treatment strategies. The integration of ctDNA in the management of operable HCC may achieve better clinical outcomes.

It is known that irrigation can impact the local atmospheric boundary layer characteristics, thereby modifying near surface atmospheric conditions within and downwind of irrigated areas and potentially the recycling of precipitation. The understanding of the impact of anthropization and its representation in models have been inhibited due to a lack of consistent and extensive observations, but in recent years, land surface and atmospheric observation capabilities have advanced. The overall objective of the Land surface Interactions with the Atmosphere over the Iberian Semi-arid Environment (LIAISE) project is to improve the understanding and prediction of land-atmosphere-hydrology interactions in a semi-arid region characterized by strong surface heterogeneity between the natural landscape and intensive agriculture. The study region is located over the Pla d’Urgell region within the Ebro basin in NE Spain. This area was selected since it is a breadbasket region: there are discussions underway to further expand this irrigated zone owing to its economic importance, but consensus of current climate projections predicts a significant warming and drying over this region in upcoming years. Thus there is an urgent need to improve the prediction of the potential changes to the regional water cycle since water resources are limited. Here we present an overview of the intense phase of the LIAISE observational campaign, which is part of the HYdrological cycles in the Mediterranean Experiment (HyMeX) phase 2, that took place in July, 2021 when land surface heterogeneity was at a maximum. A network of 7 stations provided continuous measurements of the surface energy and water budget components for multiple representative land cover types, including irrigated surfaces, along with detailed surface biophysical measurements from the leaf to field scale. Surface fluxes at the field scale were made using scintillometer configurations over 3 of the sites. Lower atmospheric measurements were obtained from tethered balloons, lidar, UHF profilers, frequent radio-sounding releases, UAVs and several aircraft. Finally, airborne instruments measured solar induced florescence, surface temperature over several spectral bands and soil moisture over a transect cutting across the rain-fed and irrigated areas. The main outcome of this project is to provide the underpinnings for improved models leading to better water resource impact studies for both the present and under future climate change.

Land surface-atmosphere interactions determine the atmospheric boundary layer (ABL) features, and in the case of semi-arid regions the water availability in the upper ground strongly conditions the surface energy balance and in general the observed dominant processes. In the Land surface Interactions with the Atmosphere over the Iberian Semi-arid Environment project (LIAISE, Boone et al. 2021), an observational campaign took place in the eastern Ebro river sub-basin between spring and fall 2021 to study the land/atmosphere interactions and the effect of the surface heterogeneities on the ABL in a semi-arid environment, enclosing a large irrigated area in summer. The combined analysis of the ground-based observations, ABL atmospheric measurements (including aircraft and remote-sensing data) and modelling is expected to improve the understanding of processes affecting exchange fluxes between the surface and the atmosphere, especially evapotranspiration, and to allow exploring the local and mesoscale circulations induced by the surface heterogeneities.A first mesoscale modelling inter-comparison for a summer event in the LIAISE area is intended to evaluate the performance of the participating models compared to the observations and explore the differences between them. Participant models are run at their standard configurations to evaluate the representation of the surface features in the numerical models and its impact in the organisation of the flow at lower levels. Besides, some sensitivity tests are made (initial and lateral boundary conditions, resolution or representation of the surface features, among others) to identify the importance of some model parameters in the model results.Four models participate in the inter-comparison: MesoNH, WRF, UKMO Unified Model and MOLOCH. They are run with similar horizontal (2km x 2km and 400m x 400m for the outer and inner domains) and vertical (2m at lower levels and stretched above) grid meshes. A 48-h integration is made between 16 and 18 July 2016 for a case under a high-pressure system centred over NW France, with well-developed thermally-driven circulations in the Ebro Basin. Sea breezes are found at the coast and seem to reach the basin after surmounting the mountain coastal range.Model results are validated using data from the surface stations of the Servei Meteorològic de Catalunya network (very dense in the studied region). It is found that each model has a different representation of the surface heterogeneities affecting the grid values of the surface fluxes. Nevertheless, the mesoscale circulations generated by the models are very close being the differences lying mostly at smaller scales, namely the ABL characteristics, the values of the exchange fluxes at the surface or the state of the surface and the soil. The challenge at this point is to relate the model biases to the particularities of the parameterisations and of the physiographic data bases used by each model. This model inter-comparison is expected to point improvements in the definitions of the setup of each model for a later phase, when the model simulations will be validated using observations from the recent LIAISE experimental field campaign.

98 Background: Salvage treatments for refractory mCRC are an unmet need. This study determined the safety and Recommended Phase 2 Dose (RP2D) of the multi-kinase inhibitor Cabo in combination with FDT/TPI in mCRC. Methods: Single institution investigator-initiated phase 1 study using 3+3 design. Patients (pts) with mCRC previously treated with a fluoropyrimidine, oxaliplatin, irinotecan and appropriate biologics were eligible. Cabo was given orally (p.o.) at 20 mg (dose level [DL] 0) or 40 mg (DL 1) daily on days 1-28, and FTD/TPI p.o. at 35 mg/m2 on days 1-5 and 8-12 every 28 days. Prophylactic growth factors were allowed. The primary endpoint was Dose Limiting Toxicity (DLT) at 28 days. Secondary endpoints included overall survival (OS), progression-free survival (PFS), objective response rate and CEA response. Results: 12 pts were enrolled. Median age 57 years (31-80), male (9/12), ECOG 0/1 = 7/5, Caucasian/Hispanic/Asian = 7/4/1. 3 pts were treated at DL 0 with no observed DLT. Another 9 pts (n = 6 pts to determine RPD2 and additional n = 3 pts in expansion) were treated at DL 1, none exhibiting a DLT. The most common any grade (G) treatment related adverse events (TRAE) were diarrhea (50%), nausea (42%), neutropenia (42%), fatigue (33%) and rash (25%). G3-4 TRAE in > 5% of patients were neutropenia (25%) and thrombocytopenia, hypokalemia, weight loss (each 8%). No serious TRAE or G5 were reported. The RP2D was determined to be DL 1. Median PFS and OS were 4.1 (95% CI 1.9-6.8) and 6.7 (95% CI 2.2-not evaluable) months, respectively. The disease control rate was 75%. 5/12 (42%) pts had a CEA decline > 30%. Conclusions: The combination of Cabo and FTD/TPI is feasible and tolerable and showed encouraging clinical activity in refractory mCRC. Additional pts are being enrolled at DL 1 and will be presented at the meeting. Clinical trial information: NCT04868773 .

Land surface-atmosphere interactions determine the atmospheric boundary layer (ABL) features, and in the case of semi-arid regions the water availability in the upper ground strongly conditions the surface energy balance and in general the observed dominant processes. LIAISE (Land surface Interactions with the Atmosphere over the Iberian Semi-arid Environment, eastern Ebro sub-basin) is an observational campaign planned between spring and fall 2021 designed to study the land/atmosphere interactions and the effect of the surface heterogeneities on the ABL in a semi-arid environment enclosing a large irrigated area in summer.The combined analysis of the ground-based observations and ABL atmospheric measurements, including aircraft and remote-sensing data, is expected to improve the understanding of processes affecting exchange fluxes between the surface and the atmosphere, especially evapotranspiration, and to allow exploring the local and mesoscale circulations induced by the surface heterogeneities. In this sense, mesoscale simulations will be performed over the eastern Ebro sub-basin to contribute to this understanding while evaluating the representation of the surface features in the numerical models and its impact in the organisation of the flow at lower levels.A first mesoscale modelling inter-comparison for a 2016 summer event in the LIAISE area, is under progress, intended to evaluate the performance of the participating models compared to the observations and explore the differences between them, trying to understand the reasons behind them. In this initial phase the models are run at their standard configurations and the comparison is expected to allow improvements in the definitions of the setup of each model for a later phase.Four models participate in the inter-comparison: MesoNH, WRF, UKMO Unified Model and MOLOCH. They are run with similar horizontal (2km x 2km and 400m x 400m for the outer and inner domains) and vertical (2m at lower levels and stretched above) grid meshes and, in this first phase, using their default setup. A 48-h integration is made between 16 and 18 July 2016 for a case under a high-pressure system centred over NW France, with well developed thermally-driven circulations in the Ebro Basin. Sea breezes are found at the coast and seem to reach the basin after surmounting the mountain coastal range.Preliminary results show that each model has a different representation of the surface heterogeneities affecting the grid values of the surface fluxes. Nevertheless, the mesoscale circulations generated by them do not differ significantly between models, the differences lying mostly at smaller scales, namely the ABL characteristics, the values of the exchange fluxes at the surface or the state of the surface and the soil. The challenge at this point is to relate the observed differences to the particularities of the parameterisations and of the physiographic data bases used by each model.

The Saharan Air Layer (SAL) in the summertime eastern Atlantic is typically well mixed and 3–4 km deep, overlying the marine boundary layer (MBL). In this paper, we show experimental evidence that at times a very different structure can be observed. During the AERosol properties – Dust (AER-D) airborne campaign in August 2015, the typical structure described above was observed most of the time, and was associated with a moderate dust content yielding an aerosol optical depth (AOD) of 0.3–0.4 at 355 nm. In an intense event, however, an unprecedented vertical structure was observed close to the eastern boundary of the basin, displaying an uneven vertical distribution and a very large AOD (1.5–2), with most of the dust in a much lower level than usual (0.3–2 km). Estimated dust concentrations and column loadings for all flights during the campaign spanned 300–5500 and 0.8–7.5 g m−2, respectively. The shortwave direct radiative impact of the intense dust event has been evaluated to be as large as -260±30 and -120±15 W m−2 at the surface and top of atmosphere (TOA), respectively. We also report the correlation of this event with anomalous lightning activity in the Canary Islands. In all cases, our measurements detected a broad distribution of aerosol sizes, ranging from ∼0.1 to ∼80 µm (diameter), thus highlighting the presence of giant particles. Giant dust particles were also found in the MBL. We note that most aerosol models may miss the giant particles due to the fact that they use size bins up to 10–25 µm. The unusual vertical structure and the giant particles may have implications for dust transport over the Atlantic during intense events and may affect the estimate of dust deposited to the ocean. We believe that future campaigns could focus more on events with high aerosol load and that instrumentation capable of detecting giant particles will be key to dust observations in this part of the world.

Purpose: Determination of microsatellite instability (MSI) by PCR is the gold standard; however, IHC of mismatch repair (MMR) proteins is frequently performed instead. The reliability of these methods on postneoadjuvant therapy specimens is unknown. We examined the effect of neoadjuvant therapy on MSI results by PCR and IHC. Experimental design: A total of 239 colorectal cancers resected after neoadjuvant therapy were assessed for MSI with PCR and IHC. PCR and IHC results for matched paired pre- and posttreatment specimens were compared. In parallel, 2 isogenic cell lines conditioned for MMR functioning and 2 different patient-derived xenografts (PDXs) were exposed to chemotherapy, radiation, or both. We also examined whether establishment of PDXs induced MSI changes in 5 tumors. IHC and MSI were tested after treatment to assess for changes. Results: We identified paired pre- and posttreatment specimens for 37 patients: 2 with PCR only, 34 with IHC only, and 1 with both. All 3 patients with PCR had microsatellite stable pre- and posttreatment specimens. Of the 35 patients with IHC, 30 had intact MMR proteins in pre- and posttreatment specimens, 1 had equivocal MLH1 staining in the pretreatment and loss in the posttreatment specimen, and 4 had intact pretreatment MSH6 but variable posttreatment staining. In the experimental setting, no changes in MSI status were detected after treatment or tumor implantation in animals. Conclusions: Our findings show that the expression of MMR proteins, commonly MSH6, can change after neoadjuvant therapy and confirm PCR as the gold-standard test for MSI after neoadjuvant therapy. Clin Cancer Res; 23(17); 5246–54. ©2017 AACR.

// Jennifer B. Goldstein 1 , Chad Tang 2 , Kenneth R. Hess 3 , David Hong 4 , Vivek Subbiah 4 , Filip Janku 4 , Siqing Fu 4 , Daniel D. Karp 4 , Aung Naing 4 , Apostolia Maria Tsimberidou 4 , Jennifer Wheler 4 , Ralph Zinner 4 , Milind Javle 5 , Gauri R. Varadhachary 5 , Robert A. Wolff 5 , David R. Fogelman 5 , Funda Meric-Bernstam 4 and Sarina A. Piha-Paul 4 1 Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 2 Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 3 Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 4 Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 5 Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Correspondence to: Jennifer B. Goldstein, email: jbgoldstein@mdanderson.org Keywords: pancreatic cancer, phase I trial, biomarker, chemotherapy, targeted therapy Received: November 02, 2016 Accepted: July 17, 2017 Published: August 03, 2017 ABSTRACT Background: In 2011, we reported the outcomes of pancreatic cancer (PC) patients enrolled in phase I trials at our institution from 2004 through 2009. At the time, gemcitabine and erlotinib were the only Food and Drug Administration-approved drugs for PC and median overall survival (OS) from consultation in the phase I clinic was 5 months. We sought to determine the impact of novel therapeutics on PC patients in phase I trials. Methods: We reviewed records of PC patients treated in phase I trials at our institution from January 2009 through December 2014. Survival was analyzed using the Kaplan-Meier method. Results: Ninety-five patients were identified. The median age was 61 years (range, 40-84), 59% were men, and 41% had stage IV disease. The median OS from consultation in the phase I clinic was 5.8 months (95% confidence interval [CI], 4.5-6.8), and the 1-year OS rate was 9% (95% CI, 4%-17%). Three patients had partial responses and 18 had stable disease ≥ 4 months. Conclusion: We observed no improvement in OS between PC patients enrolled in phase I trials in 2004-2009 and 2009-2015. To substantially improve OS in this challenging disease, improved patient selection and science-driven, innovative trial designs will be key.

Background Mucoepidermoid pancreatic cancer is a rare entity with only 8 cases reported in the literature. On review of the literature, the authors found that cutaneous metastases in pancreatic cancer are rare and have not been associated with the mucoepidermoid subtype. The authors present the first reported case of cutaneous metastasis in a patient with mucoepidermoid carcinoma of the pancreas. Case presentation A 50-year old white male with a metastatic invasive poorly differentiated mucoepidermoid carcinoma of the pancreas was found to have a slow growing lesion in the skin over his left upper quadrant while undergoing active therapy. The lesion was biopsied and the pathology was consistent with pancreatic origin sharing similar morphologic features when compared with the primary pancreactectomy specimen. Conclusions Mucoepidermoid pancreatic cancer is an exceedingly rare subtype of pancreatic cancer, with very little information regarding its diagnosis, treatment, and patterns of metastases. Here, the authors present the first reported case of cutaneous metastases of mucoepidermoid pancreatic cancer.

Purpose: Family history of BRCA-related tumors may correlate with response to chemotherapy and overall survival (OS) in pancreatic cancer. The frequency of germline mutations has been reported in patients predominantly under the age of 60 or with strong family history. We examine the incidence of deleterious germline mutations and compare the chemotherapy responses and OS in an unselected group of patients with metastatic pancreatic cancer. Experimental Design: Patients with metastatic pancreatic cancer, who were seen at a single cancer center between 2010 and 2016, were included. Germline DNA was sequenced using a 263-gene panel to identify novel mutations (N = 133 MD Anderson cohort, N = 127 TCGA cohort). Chemotherapy response and OS were determined by review of medical records. Results: Deleterious germline mutations were identified in 26 of 133 patients (19.5%). Patients with DNA damage repair (DDR) gene mutations (ATM, BRCA1/2, CDKN2A, CHEK2, ERCC4, PALB2, n = 15) had an improved OS as compared with patients without (16.8 vs. 9.1 months, P = 0.03). Conversely, patients with other deleterious mutations had a trend toward worse OS. However, survival in the latter group was longer (P = NS) in those mutants initially treated with gemcitabine/nab-paclitaxel. A family history of multiple breast, ovarian, and pancreatic cancers was associated with DDR gene mutations and better survival. Conclusions: We have identified novel germline mutations that are prognostic for survival in patients with pancreatic cancer. We observe improved survival in patients with DDR gene mutations and worsened survival in patients with deleterious mutations in non-DDR genes.

A limitation of the Met Office operational data assimilation scheme is that surface-sensitive infrared satellite sounding channels cannot be used during daytime periods where Numerical Weather Prediction (NWP) model background land surface temperature (LST) biases are greater than 2 K. The Met Office Unified Model (UM) has a significant cold LST bias in semi-arid regions when compared with satellite observations. UM LST biases were evaluated at global resolution and in a Limited Area Models (LAM) at 2.2 km resolution over the SALSTICE (Semi-Arid Land Surface Temperature and IASI Calibration Experiment) experimental domain in southeastern Arizona. This validation is in conjunction with eddy-covariance flux tower measurements. LST biases in the Global Atmosphere/Land 3.1 (GA/L3.1) configuration were largest in the mid-morning with respect to Terra (−13.6 ± 2.8 K at the Kendall Grassland site). The diurnal cycle of LST in Global Atmosphere/Land 6.1 (GA/L6.1) showed a significant improvement relative to GA/L3.1. The higher resolution LAM showed added value over the global configurations. The spatial distribution of the LST biases relative to Moderate Resolution Imaging Spectroradiometer (MODIS) and the modelled bare soil cover fraction were found to be moderately correlated (0.61 ± 0.08) during the daytime, which suggests that regions of cold LST bias are associated with low bare soil cover fraction. Coefficients of correlation with the shrub surface fractions followed the same trend as the bare soil cover fraction although with a less significant correlation (0.36 ± 0.09), and indicate that the sparse vegetation canopies in southeastern Arizona are not well represented in UM ancillary datasets. The x-component of the orographic slope was positively correlated with the LST bias (0.35 ± 0.06) and identified that regions of cold model LST bias are found on easterly slopes and regions of warm model LST bias are found on westerly slopes. An overestimate in the modelled turbulent heat and moisture fluxes at the eddy-covariance flux sites was found to be coincident with an underestimate in the ground heat flux.

The Saharan Air Layer (SAL) in the summertime Eastern Atlantic is typically well-mixed and 3–4 km deep, overlying the marine boundary layer (MBL). In this paper, we show experimental evidence that at times a very different structure can be observed. During the AER-D airborne campaign in August 2015, the typical structure described above was observed most of the times, and was associated with a moderate dust content yielding an Aerosol Optical Depth (AOD) of 0.3–0.4 at 355 nm. In an intense event, however, an unprecedented vertical structure was observed close to the Eastern boundary of the basin, displaying an uneven vertical distribution and a very large AOD (1.5–2), with most of the dust in a much lower level than usual (0.3–2 km). Estimated dust concentrations and column loadings spanned 300–5500 μg m−3 and 0.8–7.5 g m−2, respectively. The shortwave direct radiative impact of the intense dust event has been evaluated to be as large as −260 ± 30 and −120 ± 15 W m−2 at the surface and top of atmosphere, respectively. This event was also correlated with anomalous lightning activity in the Canary Islands. In all cases, our measurements detected a broad distribution of aerosol sizes, ranging from ~ 0.1 to ~ 80 μm (diameter), thus highlighting the presence of giant particles. Giant dust particles were also found in the MBL. We note that most aerosol models may miss the giant particles due to the fact that they use size bins up to 10–25 μm. The unusual vertical structure and the giant particles may have implications for dust transport over the Atlantic during intense events, and may affect the estimate of dust deposited to the Ocean. We believe that future campaigns should focus more on events with high aerosol load, and that instrumentation capable of detecting giant particles will be key to dust observations in this part of the world.

Introduction: We aimed to determine the prevalence and landscape of germline mutations among patients with young-onset pancreatic ductal adenocarcinoma (PDAC) as well as their influence in prognosis. Methods: Patients from two cohorts were studied, the high-risk cohort (HRC), which included 584 PDAC patients who received genetic counseling at The University of Texas MD Anderson Cancer Center, and a general cohort (GC) with 233 metastatic PDAC patients. We defined germline DNA sequencing on 13 known pancreatic cancer susceptibility genes. The prevalence and landscape of mutations were determined, and clinical characteristics including survival were analyzed. Results: A total of 409 patients underwent genetic testing (277 from HRC and 132 from GC). As expected, the HRC had higher prevalence of germline mutations compared with the GC: 17.3% versus 6.81%. The most common mutations in both cohorts were in BRCA1/2 and mismatch-repair (MMR) genes. Patients younger than 60 years old had significantly higher prevalence of germline mutations in both the HRC [odds ratios (OR), 1.93 ± 1.03–3.70, P = 0.039] and GC (4.78 ± 1.10–32.95, P = 0.036). Furthermore, PDAC patients with germline mutations in the GC had better overall survival than patients without mutations (HR, 0.44; 95% CI of HR, 0.25–0.76, P = 0.030). Discussion: Germline mutations are highly prevalent in patients with PDAC of early onset and can be predictive of better outcomes. Considering emerging screening strategies for relatives carrying susceptibility genes as well as impact on therapy choices, genetic counseling and testing should be encouraged in PDAC patients, particularly those of young onset. Cancer Prev Res; 11(11); 679–86. ©2018 AACR.

OBJECTIVES The aim of this study was to examine tumor-infiltrating lymphocytes (TILs) and their prognostic value in patients with pancreatic ductal adenocarcinoma (PDAC) after neoadjuvant therapy. METHODS Intratumoral CD4, CD8, and FOXP3 lymphocytes were examined by immunohistochemistry using a computer-assisted quantitative analysis in 136 PDAC patients who received neoadjuvant therapy and pancreaticoduodenectomy. The results were correlated with clinicopathological parameters and survival. RESULTS High CD4 TILs in treated PDAC were associated with high CD8 TILs (P = 0.003), differentiation (P = 0.04), and a lower frequency of recurrence (P = 0.02). Patients with high CD4 TILs had longer disease-free survival and overall survival (OS) than did patients with low CD4 TILs (P < 0.01). The median OS of patients with a high CD8/FOXP3 lymphocyte ratio (39.5 [standard deviation, 6.1] months) was longer than that of patients with a low CD8/FOXP3 lymphocyte ratio (28.3 [standard deviation, 2.3] months; P = 0.01). In multivariate analysis, high CD4 TILs were an independent prognostic factor for disease-free survival (hazard ratio, 0.49; 95% confidence interval, 0.30-0.81; P = 0.005) and OS (hazard ratio, 0.54; 95% confidence interval, 0.33-0.89; P = 0.02). CONCLUSIONS High level of CD4 lymphocytes is associated with tumor differentiation and lower recurrence and is an independent prognostic factor for survival in PDAC patients treated with neoadjuvant therapy.

The microsatellite instability-high (MSI-H) phenotype, present in 15% of early colorectal cancer (CRC), confers good prognosis. MSI-H metastatic CRC is rare and its impact on outcomes is unknown. We describe survival outcomes and the impact of chemotherapy, metastatectomy, and BRAF V600E mutation status in the largest reported cohort of MSI-H metastatic colorectal cancer (CRC).A retrospective review of 55 MSI-H metastatic CRC patients from two institutions, Royal Melbourne Hospital (Australia) and The University of Texas MD Anderson Cancer Center (United States), was conducted. Statistical analyses utilized Kaplan-Meier method, Log-rank test, and Cox proportional hazards models.Median age was 67 years (20-90), 58% had poor differentiation, and 45% had stage IV disease at presentation. Median overall survival (OS) from metastatic disease was 15.4 months. Thirteen patients underwent R0/R1 metastatectomies, with median OS from metastatectomy 33.8 months. Thirty-one patients received first-line systemic chemotherapy for metastatic disease with median OS from the start of chemotherapy 11.5 months. No statistically significant difference in progression-free survival or OS was seen between fluoropyrimidine, oxaliplatin, or irinotecan based chemotherapy. BRAF V600E mutation was present in 14 of 47 patients (30%). BRAF V600E patients demonstrated significantly worse median OS; 10.1 versus 17.3 months, P = 0.03. In multivariate analyses, BRAF V600E mutants had worse OS (HR 4.04; P = 0.005), while patients undergoing metastatectomy (HR 0.11; P =0.001) and patients who initially presented as stage IV disease had improved OS (HR 0.27; P = 0.003).Patients with MSI-H metastatic CRC do not appear to have improved outcomes. BRAF V600E mutation is a poor prognostic factor in MSI-H metastatic CRC.

Aurora kinases play important roles in cell division and are frequently overexpressed in human cancer. AMG 900 is a novel pan-Aurora kinase inhibitor currently being tested in Phase I clinical trials. We aimed to evaluate the in vitro activity of AMG 900 in a panel of 44 human breast cancer and immortalized cell lines and identify predictors of response. AMG 900 inhibited proliferation at low nanomolar concentrations in all cell lines tested. Response was further classified based on the induction of lethality. 25 cell lines were classified as highly sensitive (lethality at 10 nM of AMG 900 10 %), 19 cell lines as less sensitive to AMG 900 (lethality at 10 nM of AMG 900 10 %). Traditional molecular subtypes of breast cancer did not predict for this differential response. There was a weak association between AURKA amplification and response to AMG 900 (response ratio = 2.53, p = 0.09). mRNA expression levels of AURKA, AURKB, and AURKC and baseline protein levels of Aurora kinases A and B did not significantly associate with response. Cell lines with TP53 loss of function mutations (RR = 1.86, p = 0.004) and low baseline p21 protein levels (RR = 2.28, p = 0.0004) were far more likely to be classified as highly sensitive to AMG 900. AMG 900 induced p53 and p21 protein expression in cell lines with wt TP53. AMG 900 caused the accumulation of cells with4 N DNA content in a majority of cell lines independently of sensitivity and p53 status. AMG 900 induced more pronounced apoptosis in highly sensitive p53-dysfunctional cell lines. We have found that AMG 900 is highly active in breast cancer cell lines and that TP53 loss of function mutations as well as low baseline expression of p21 protein predict strongly for increased sensitivity to this compound in vitro.

A cirrus study has been undertaken during the second Cirrus Cloud-Radiation Experiment field campaign based in Prestwick, Scotland. We report on a case study describing the radiation and microphysics measurements and cloud modelling work.

The Fennec climate programme aims to improve understanding of the Saharan climate system through a synergy of observations and modelling. We present a description of the Fennec airborne observations during 2011 and 2012 over the remote Sahara (Mauritania and Mali) and the advances in the understanding of mineral dust and boundary layer processes they have provided. Aircraft instrumentation aboard the UK FAAM BAe146 and French SAFIRE (Service des Avions Français Instrumentés pour la Recherche en Environnement) Falcon 20 is described, with specific focus on instrumentation specially developed for and relevant to Saharan meteorology and dust. Flight locations, aims and associated meteorology are described. Examples and applications of aircraft measurements from the Fennec flights are presented, highlighting new scientific results delivered using a synergy of different instruments and aircraft. These include (1) the first airborne measurement of dust particles sizes of up to 300 microns and associated dust fluxes in the Saharan atmospheric boundary layer (SABL), (2) dust uplift from the breakdown of the nocturnal low-level jet before becoming visible in SEVIRI (Spinning Enhanced Visible Infra-Red Imager) satellite imagery, (3) vertical profiles of the unique vertical structure of turbulent fluxes in the SABL, (4) in situ observations of processes in SABL clouds showing dust acting as cloud condensation nuclei (CCN) and ice nuclei (IN) at −15 °C, (5) dual-aircraft observations of the SABL dynamics, thermodynamics and composition in the Saharan heat low region (SHL), (6) airborne observations of a dust storm associated with a cold pool (haboob) issued from deep convection over the Atlas Mountains, (7) the first airborne chemical composition measurements of dust in the SHL region with differing composition, sources (determined using Lagrangian backward trajectory calculations) and absorption properties between 2011 and 2012, (8) coincident ozone and dust surface area measurements suggest coarser particles provide a route for ozone depletion, (9) discrepancies between airborne coarse-mode size distributions and AERONET (AERosol Robotic NETwork) sunphotometer retrievals under light dust loadings. These results provide insights into boundary layer and dust processes in the SHL region – a region of substantial global climatic importance.

Background: Glioblastoma (GBM) is an aggressive cancer that often recurs despite multimodal therapy. Median survival is 12-15 months. Genomic profiling studies have shown marked tumor heterogeneity with distinct mutations among treated and untreated samples. The Cancer Genome Atlas (TCGA), revealed that mutations in TP53, CDKN2A, PTEN, EGFR and NF1 are predominant in untreated tumors. Of 19 patients who progressed on therapy, seven samples were hypermutated with mutations in mismatch repair proteins, mainly MSH6. We proposed to use the Cellecta Lentiviral-based tagging library, a novel model system to assess the role of intratumor heterogeneity (ITH) in the presumptive tumor-initiating fraction of primary GBM and in the development of resistance to temozolomide (TMZ). From a pool of 30,000,000 barcodes, the system enables the genetic integration of a unique barcode sequence into each cell. Each barcode can be quantitatively tracked via next-generation sequencing, allowing for dynamic monitoring of the subclonal architecture. Methods: GSC 272 and 627 (sensitive and resistant to TMZ) were derived from core biopsies of GBM patients. Cells were transduced with a lentiviral vector containing luciferase. Cells were expanded and infected with the Cellecta Lentiviral library. Multiplicity of infection was determined. Transduced cells were injected into B6.Cg-Foxn1nu/J mice brains using a guide screw system. Half of the mice were treated with TMZ via gavage at two weeks. Brain tumors were removed and total DNA was extracted. Barcode inserts were amplified and the Illumina Sequencing platform was used for barcode quantification. Additionally, whole exome sequencing was performed to assess mutation status. Results: Confirmation of luciferase signal has been performed using a Luciferase Reporter Assay. Multiplicity of infection was found to be 0.15 and 1 for GSC 6-27 and 272 respectively. Initial methylation studies showed GSC 272 to have methylation of MGMT while GSC 627 did not. There was no difference in OS in the TMZ Resistant (GSC 627) untreated vs. treated cohort (with a median OS of 55 days in both groups (N= 23 vs 25 respectively, P= 0.563). TMZ Sensitive (GSC 272) untreated mice did not survive as long as the treated cohort (N= 24 vs. 25, Median OS 43 vs. 206 days, P= 4.61e-09). Barcode and whole exome sequencing results is currently being analyzed. Conclusions: The Cellecta lentiviral tagging system is an innovative way to track ITH and clonal evolution in glioblastoma orthotopic models. We hope to discover novel insights into TMZ treatment response and resistance. Citation Format: Jennifer Brooke Goldstein, Ravesanker Ezhilarasan, Mona Jaffari, Alessandro Carugo, Giulio Draetta, Roeland Verhaak, Sahil Seth, Erik Sulman, Phillip Andrew Futreal. The clonal evolution of glioblastoma [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 2916. doi:10.1158/1538-7445.AM2017-2916

4116 Background: Family history of BRCA-related tumors may correlate with response to chemotherapy and overall survival in patients with pancreatic cancer (PC). We retrospectively compared family history of such cancers with clinical outcomes and underlying molecular aberrations. Methods: A retrospective chart review was conducted of 350 metastatic PC patients treated with first line FOLFIRINOX and Gem/Abraxane at MDACC from 1/2010 -1/2016. Family history was defined as 1st through 3rdgeneration relatives with breast, ovarian, or pancreas cancer. Germline DNA was collected and sequenced using a familial cancer panel using an Illumina 2500. Average coverage was 200X. Platypus calls were analyzed for germline mutations. We assessed mutations in BRCA1, BRCA2, PALB2, MMR genes, ATM, and PolE. Results: Average age was 61. 60% of patients were male. We sequenced blood and tissue samples where available. We found at lease one mutation in 47 of 129 patients tested. There were 56 mutations identified among the 47 patients. Of patients with 0-1,2, or 3 or more affected family members we found mutations in 44%, 47%, and 29%, respectively. Patients with 3+ family members affected tended to have mutations in BRCA1 or PolE. Among the subset of patients with possible deleterious mutations, there were trends towards improved survival in pts with BRCA or PALB aberrations (307d vs 271d, p = ns) but worse outcomes in those with MMR gene defects (181d vs 387d, p = .126). Table 1 indicates outcomes based on number of family members with cancer and their associated mutations. Conclusions: Approximately one third of all patients tested had at least one germline mutation in previously described familial pancreas cancer genes. Screening for inherited cancer susceptibility genes may have prognostic value. [Table: see text]

e23203Background: The MD Anderson Cancer Center Translational Research Accelerator (TRA) platform is implemented to capture, store and integrate over 230,000 patient records, associated diagnoses, ...

e23202Background: One of the greatest challenges to cancer research is compiling millions of patient records to investigate complex hypotheses. The Translational Research Accelerator (TRA) is a lar...

e23204Background: MD Anderson Cancer Center seeks to leverage its considerable clinical and research enterprise by developing a Translational Research Accelerator (TRA) platform to integrate longit...

e23160Background: The University of Texas MD Anderson Cancer Center (MDACC) is a freestanding, NCI-designated comprehensive cancer center. Since its inception, MDACC has cared for over 900,000 pati...

TPS2617 Background: Cancer cells deficient in BRCA1/2 and other components of the homologous recombination repair pathway are selectively sensitive to the double stranded DNA breaks whose repairs a...

The developing retina is characterized by 'retinal waves', spontaneous depolarizations that propagate through a developing network of interneurons and retinal ganglion cells. Although the circuitry underlying retinal waves is well characterized, the secreted factors that are critical for its normal development are not defined. Dissociated cell culture provides an ideal system for defining these factors; however, it is difficult to recapitulate retinal circuitry in culture. Here we demonstrate that by culturing dissociated retinal neurons in the presence of cells from the superior colliculus (SC), retinal neurons form networks that are similar to those described in the intact retina. Whole-cell voltage clamp recordings reveal the presence of a spontaneously active network of interneurons. In addition, we observed spontaneous, propagating activity reminiscent of that observed in the intact retina. We propose that the presence of factors secreted from the SC results in the development of networks that reproduce critical features of the intact retina. Copyright (C) 2004 S. Karger AG, Basel.

320 Background: Pancreatic cancer is a disease that generally presents in advanced stage and is nearly fatal in all cases. In 2011, we reported our experience with pancreatic cancer patients enrolled on phase 1 clinical trials from 2004-2009. At the time, gemcitabine and erlotinib were the only US FDA approved drugs for pancreatic cancer. Median overall survival from presentation in the phase 1 clinic was 5 months. After an additional 5 years of progress, we queried the impact of novel cancer therapeutics, evolving molecular profiling, and targeted therapy on pancreatic cancer patient outcomes in the phase 1 setting. Methods: A retrospective review of advanced pancreatic adenocarcinoma patients from the Department of Investigational Cancer Therapeutics at MD Anderson Cancer Center, was conducted for patients treated from 1/2009 to 1/2014. Statistical analyses utilized the Kaplan-Meier method. Results: A total of 90 patients were identified in 50 trials reviewed. Median age was 62 years (40-84), 57% were male, and 40% had stage IV disease at presentation. Median documented PS was 1 (range 0-3). The median time from diagnosis to treatment on a phase I protocol was 15 months (0.2-119). Patients were treated with an average of 4 prior regimens prior to Phase 1 referral (0-10) with 8% having undergone >5 treatments. The median overall survival from the first phase I treatment was 5.2 months, 95% CI = (4.4-6.3) and the 1 year overall survival from the first phase 1 treatment was 15% (9%- 25%). The median duration on regimen with best phase I response was 1.9 months (0.2-21.3). Of 88 evaluable, the best responses were PR in 1 patient and SD (> 6 months) in 5 patients. Although 47 patients had biomarker profiling performed and 61 patients were treated with targeted therapy alone or in combination with cytotoxic therapy, only 6 patients (5 PD, 1 SD currently on protocol) were placed on trials based on biomarker testing results. Conclusions: Pancreatic cancer remains a difficult disease to treat with poor outcome. Referral to phase 1 occurs late in the disease course. Biomarker based therapies may be more successful with more stringent patient selection and when referred earlier or used prior to cytotoxic treatment.

i CHAPTER I: INTRODUCTION 1 CHAPTER II: LITERATURE REVIEW 4 Mentoring 4 Interracial Mentoring 10 Considering the Forms of Contemporary Racism 14 Conclusion 20 CHAPTER III: THE THEORETICAL FRAMEWORK 23 Introduction 23 Contemporary US Racism Theories 23 Intergroup Contact Hypothesis 30 Additional Optimal Conditions in Light of Contemporary US Racism 35 Hypotheses 44 CHAPTER IV: RESEARCH DESIGN 45 Purpose and Significance 45 Site and Participant Selection 47 Sampling Frame 48 Interviews 51 Data Analysis 53 CHAPTER V: FINDINGS 61 Successful Cross-Race Mentoring Experiences 62 Expectations and Perceptions 63 The Mentoring Relationship 67 The Racial Component 75 Medium Success with Interracial Mentoring Relationships 83

The ability of an upflow, denitrifying biofilter using a fermentation generated carbon source to treat the high nitrate concentrations typically seen in recirculating aquaculture systems was studied using a synthetic nitrate wastewater supplied at two nitrate loadings, 1.13 and 2.52 kg NO3-N/m3/day. A supplemental carbon source was provided primarily through the fermentation of fish food which generated volatile fatty acids (VFA) in the form of acetic, propionic, isobutyric, n-butyric, 2-methylbutyric, 3-methylbutyric, and n-valeric acids. Acetic and propionic acids were the predominant constituents generated, while lower concentrations of the longer carbon chain butyric and valeric acids were produced. The VFAs proved to be a viable carbon source for the denitrification process as indicated by the ability of the biofilm to assimilate all of the constituents generated. Carbon limiting the system resulted in an increase in effluent nitrite and incomplete nitrate removal. During the low nitrate loading condition, influent COD to NO₃-N ratios greater than 5 typically achieved high total nitrogen removals greater than 95%. This influent ratio corresponded with a COD to NOx -N consumption ratio of 4.62 ± 0.28 mg/L as COD per mg/L as N for complete nitrogen removal. Under the high nitrate loading condition, influent COD to NO₃-N ratios achieving high nitrogen removals showed great variability and did not correspond to a distinct value. The COD to NOx -N consumption ratios were often below stoichiometric values, which was attributed to the hydrolysis of influent fermentation solids captured within the column to generate a COD source not measured by filtered samples. The column biofilm kinetics were modeled using a half-order reaction rate and denitrification coefficients (k) of 0.70 ± 0.02 (mg NOx-N/L)1/2 / min and 1.18 ± 0.12 (NOx-N /L)1/2 / min were determined for the low and high nitrate loading phases, respectively. Master of Science

A coordinated atmosphere-ocean research project, centered on a rare wintertime field campaign to the Iceland and Greenland Seas, seeks to determine the location and causes of dense water formation by cold-air outbreaks. The Iceland Greenland Seas Project (IGP) is a coordinated atmosphere-ocean research program investigating climate processes in the source region of the densest waters of the Atlantic Meridional Overturning Circulation. During February and March 2018, a field campaign was executed over the Iceland and southern Greenland Seas that utilized a range of observing platforms to investigate critical processes in the region – including a research vessel, a research aircraft, moorings, sea gliders, floats and a meteorological buoy. A remarkable feature of the field campaign was the highly-coordinated deployment of the observing platforms, whereby the research vessel and aircraft tracks were planned in concert to allow simultaneous sampling of the atmosphere, the ocean and their interactions. This joint planning was supported by tailor-made convection-permitting weather forecasts and novel diagnostics from an ensemble prediction system. The scientific aims of the IGP are to characterize the atmospheric forcing and the ocean response of coupled processes; in particular, cold-air outbreaks in the vicinity of the marginal-ice zone and their triggering of oceanic heat loss, and the role of freshwater in the generation of dense water masses. The campaign observed the lifecycle of a long-lasting cold-air outbreak over the Iceland Sea and the development of a cold-air outbreak over the Greenland Sea. Repeated profiling revealed the immediate impact on the ocean, while a comprehensive hydrographic survey provided a rare picture of these subpolar seas in winter. A joint atmosphere-ocean approach is also being used in the analysis phase, with coupled observational analysis and coordinated numerical modelling activities underway.