Introduction: Only type I MET tyrosine kinase inhibitors (TKIs) are approved for treating MET-altered NSCLCs. Preclinically, type II TKIs, such as cabozantinib, can rescue progression on type I TKIs. This phase 2 trial (NCT01639508) evaluated the activity of cabozantinib in patients with MET-dependent lung cancers, including TKI-pretreated cancers. Methods: This phase 2 trial with a Simon two-stage minimax design treated patients with metastatic, MET-altered lung cancers with cabozantinib (60 mg daily) until progression or intolerable toxicity. The primary end point was objective response rate (ORR). We prespecified that cabozantinib would be considered a useful agent if at least a 20% ORR was observed. Secondary end points included progression-free survival, overall survival, and safety. Results: We enrolled 28 patients, 23 patients (82%) with only a MET exon 14 alteration, two patients (7%) with MET amplification, and three patients (11%) with concurrent MET exon 14 alteration and amplification. There were 24 patients (86%) previously treated with a type I MET TKI. The ORR was 20% (5/25 assessable patients; 95% confidence interval [CI]: 8.9%–39.1%), with five partial responses (duration ranged from 4 to 39 mo). Four of five responders were type I MET TKI pretreated. The median progression-free survival and overall survival were 4.5 (95% CI: 3.3–5.7) months and 7.2 (95% CI: 2.9–11.5) months, respectively. Dose modification and discontinuation occurred in 64% (18/28) and 7% (2/28) of patients, respectively. Conclusion: This trial met its primary end point. Importantly, we demonstrated that cabozantinib, a type II MET TKI, could benefit patients with MET-altered lung cancers previously treated with type I MET TKIs.

Energy and environmental data is collected from 5 tower blocks each containing 90 apartments to create two representative calibrated energy models. Three towers (heated by individual natural gas boilers) characterise medium (137.3 kWh/m(2)/yr.) and two (heated by electrical night storage heaters) characterise low (75.4 kWh/m(2)/yr.) thermal demands when benchmarked against actual UK domestic portfolio. Across 2020-2040 time horizon, an uncertain landscape is represented by 12 fuel carbon intensity and 14 economic scenarios in order to examine building fabric upgrade, without or in conjunction with centralised CHP engines, GSHP and biomass boilers in the case study towers. Out of 18 retrofit options examined, 7 or 8 solutions (under annual fuel price rises of 2% or 5.2% respectively) can provide lifetime CO(2)e mitigation at unit costs that fall below the upper bounds of carbon capture and storage technologies (US$143/tCO(2)e). If carbon taxation were to be used to enable full recovery of retrofit capital expenditure with no government subsidy, the lowest tax level observed belongs to a transition to centralised biomass from decentralised natural gas boilers requiring US$111/tCO(2)e (in 2020), while deep retrofits (i.e. plant and fabric) require much more punishing carbon taxes with 2020 figures ranging from US$233/tCO(2)e to US$1665/tCO(2)e. (C) 2019 Elsevier B.V. All rights reserved.

Abstract Background: Neratinib (N) is a potent irreversible inhibitor of HER1, HER2, and HER4 and has been shown to have antitumor activity in patients (pts) with human epidermal growth factor receptor 2 (HER2) - positive breast cancer. A previous study of combination of neratinib with capecitabine (X) was associated with > G 3 diarrhea in > 20% of patients. Currently, the NALA study is evaluating this combination of N with X at standard schedule against control. X at 7 day on and 7 day off schedule (7/7) has been shown to be well-tolerated with less ≥G3 toxicities. We are conducting a phase Ib/II study of N with X (7/7) in pts with pretreated HER2+ MBC (NCT03377387). Methods: Eligible pts had HER2+ MBC, normal left ventricular ejection fraction (LVEF ≥ 50%); pts can have any and up to 4 prior chemotherapy-based treatments in phase Ib and II portions, respectively. Primary endpoints are to define maximum tolerated dose and efficacy in phase I and phase II portions, respectively. Secondary endpoints include safety and tolerability; exploratory endpoint is to quantify cell-free DNA to correlate with response for phase II portion. There were 4 cohorts for phase Ib with dose level 1 with starting dose of X at 1500 mg BID at 7/7 schedule with N at 240 mg daily. Results: As of July 1, 2018 8 pts have been enrolled in 2 cohorts. The median age is 63y (range: 57-79), and median ECOG is 0 (range: 0-1). 4 patients were treated at dose level 1 and 2 of 4 patients experienced dose-limiting toxicity with G3 diarrhea during cycle 1. Other significant toxicities included G3 hand foot syndrome (n=1), G3 fatigue (n=1) and G3 nausea (n=1). Three pts have now been treated at dose level -1 (X at 1000 mg twice daily 7/7 and N at 240 mg daily) and no ≥ G3 toxicities has been noted. Once MTD is reached, the phase II portion will occur to assess the efficacy and to further establish the safety and tolerability of capecitabine and neratinib at the MTD. Conclusions: The phase Ib/II study combining neratinib and capecitabine 7/7 is ongoing and updated result will be presented. Citation Format: Wang R, Singh J, Sterlin V, Goldstein M, Lake D, Wong S, Baselga J, Norton L, Dang C. Phase Ib/II study of capecitabine 7/7 schedule with neratinib in patients with HER2-positive metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-18-30.

Host characteristics such as pigmentary traits, childhood UV exposure and sunburn history, common nevi, and family history of melanoma are established risk factors for melanoma. Whether these characteristics may change the risk of atypical nevi (AN) has not previously been well recognized. We aimed to examine the associations between host characteristics and risk of AN, as well as number of AN and severity of AN. In the Health Professionals Follow-up Study (n=23,494 males only), lifetime diagnosis of AN was asked in 2012 and confirmed by a supplementary questionnaire.. Information on hair color, tanning ability, number of childhood sunburns, UV index of residence state, and family history of melanoma was collected using mailed questionnaires. A total of 1382 atypical nevi cases were identified. We found a significantly increased risk of AN associated with number of childhood sunburns (P-trend=0.0006), number of common nevi (P-trendversus no). Among these factors, number of common nevi was positively associated with number of AN (P-heterogeneity=0.03 for the comparisons of trend in risk between 1 AN, 2-4 AN and ≥5 AN compared with 0 AN) but was not differentially associated with AN by the presence of surgical excision (P for heterogeneity=0.83), a surrogate measure for AN severity. However, suggestive heterogeneity in risk of AN by the presence of surgical excision was found in the association with number of childhood sunburns, with higher risk estimates for AN with surgical excision (P-heterogeneity=0.06 for the trend). We provide evidence suggesting that number of common nevi, number of childhood sunburns and family history of melanoma may be associated with risk of lifetime atypical nevi.

CPAP used during radiation treatment reduces tumor motion and expands lung volume. CPAP's effect on the size, position, and motion of the heart has not been reported previously. We hypothesized that the physiologic effects seen with use of CPAP—expansion of the thoracic cavity caused by reduction of motion and flattening of the diaphragm as well as decreased venous return to the heart— affects cardiac parameters important for radiation treatment. We measured the effects of CPAP on the heart in a cohort of patients receiving radiation therapy for lung tumors. IRB approval was given in December 2013. Patients with primary or secondary lung tumors underwent 4-dimensional computed tomography (4DCT) simulation twice using identical positioning with free breathing and with CPAP. The heart was contoured according to RTOG guidelines on all 3D and 4D CT imaging studies. The Boolean operator function on the treatment planning system (TPS) was used to combine contours from all 10 respiratory phases of the 4D scans to create a maximal heart volume (MHV). The TPS was used to coregister all scans using the vertebral bodies for fusion and to measure and compare changes in the size, center of mass, and excursion of the heart and lung. A Wilcoxon signed-rank test was used to assess differences between variables. Spearman rho coefficient was used to assess correlations between changes in lung volume and measured heart parameters. Studies were reviewed from 9 patients. CPAP use decreased mean heart size on 3D and 4D scans by 6% (95% CI: 2%-8.5%, P<.008) and 13% (95% CI: 9%-16%, P<.008), respectively. CPAP decreased change in MHV by 46% (95% CI: 26%-65%, P<.01). CPAP shifted the mean center of mass caudally on 3D and 4D images by 1 cm (95% CI: 0.7 cm-1.4 cm, P<.01) and 1.1 cm (95% CI: 0.8 cm-1.5 cm, P<.01), respectively. Positional shifts in other directions were NS. CPAP reduced the mean excursion vector on 3D and 4D images by 4% (95% CI: 3%-6%, P<0.01) and 6% (95% CI: 5%-7%, P<0.01), respectively. Use of CPAP decreased the change in mean excursion by 36% (95%CI: 4%-67%, P= 0.01). CPAP increased lung volume by 30% (95% CI: 21%-39%, P< 0.01). Spearman correlation coefficient for increase in lung volume and caudal change in heart position and reduced heart excursion were 0.83 (P< 0.005) and 0.87 (P<0.003), respectively. Correlation with change in heart size was NS. The use of CPAP decreased heart size, shifted heart position caudally, reduced heart motion, and increased total lung volume. The increase in total lung volume was correlated with the changes observed in positon and motion of the heart. CPAP should be evaluated further as a novel cardiac motion management strategy to reduce heart exposure when offering radiation therapy.

A method is proposed to support management policy design and verification in complex cyber-physical & human systems (CPHS). A hierarchy of interconnected formal models is built to provide the multi-faceted view of the conflict situation lying in the core of a certain management problem. Game-theoretical analysis reveals the problem and mechanism design suggests the alternative management policy. Its efficiency is verified by multi-agent simulations and gaming experiments with experts. The approach is illustrated using the examples of two market manipulation issues arising on the Russian wholesale electricity market.

The spectral and angular distributions from parametric X-radiation (PXR) from non-relativistic electrons penetrating a multilayer nanostructure are calculated while accounting for contributions of ordinary and diffracted transition radiation. The PXR emission mechanism is shown to be the dominant emission mechanism. The calculation also demonstrates the possibility of a tunable quasi-monochromatic extreme ultraviolet (EUV) source using only non-relativistic electrons whose efficiency can be large enough for practical applications.

BACKGROUND The pathologic features of Down syndrome are assumed to be the result of over-expression of genes located on chromosome 21 and/or a more global transcriptional misregulation that crosses chromosomal borders. METHODS To address this issue, four RNA samples from trisomy 21 placentas and four samples from normal first trimester pregnancies were analyzed using Affymetrix U95v2 microarray. Statistical and bioinformatic analyses were employed to compare global gene expression, functional classes, and pathways to differentiate between placentas taken from trisomy 21 and from normal pregnancies. RESULTS About 750 genes were significantly over-expressed in trisomy 21. This list contains an approximately 4.5-fold over-abundance of genes that map to chromosome 21, compared to that which could be expected for this chromosome, on the microarray. Among the classes of genes that best discriminated the trisomy 21 and normal karyotype, we found genes that are also implicated in Alzheimer disease and genes that are associated with ubiquitination and proteosomal degradation. Finally, using the top 10 most discriminating genes, eight samples taken from a different database were correctly classified as either trisomy 21 or normal. CONCLUSIONS Our results demonstrate that gene expression in trisomy 21 affected placentas significantly differs from that of chromosomally normal placentas, and this difference is only partially explained by over-expression of genes from chromosome 21. Our findings suggest that specific highly discriminatory genes may be potential targets for further research and development of novel prenatal diagnosis techniques.

14103 Background: Advanced pancreatic adenocarcinoma (PCa) portends a poor prognosis. Both capecitabine (CAP) and oxaliplatin (OX) have demonstrated activity in pancreas cancer, may be synergistic, and are well tolerated. We report the outcomes and toxicities of patients (pts) with PCa treated with CAP and OX in combination. Methods: Entry criteria: ECOG PS ≥ 2, adequate renal, hepatic and bone marrow function and at least one measurable lesion. Pts were allowed to have received one prior chemotherapy for advanced disease, or adjuvant therapy if completed more than 12 months prior. Pts received CAP 2000 mg/m2 po taken in two divided doses for 14 days starting on day one and OX 130 mg/m2 IV on day 1 of each 21 day cycle. Response was recorded per RECIST criteria. Results: Sixteen pts have been enrolled, 14 have been treated (2 pts suffered rapid decline prior to start) thus far. The average number of cycles was 2.7, and 3 pts received 4 or more cycles. Of 10 evaluable pts, 6 had stable disease, 1 had a partial response and 3 had progressive disease. Of the 5 pts who had received prior chemotherapy with progression, 3 had stable disease, and one had a partial response, and 1 had progressive disease. Of the 5 pts who had not recieved prior chemotherapy, 3 had stable disease and 2 had progressive disease. Median time to progression was 7 weeks. Four pts are still undergoing treatment. Toxicity was acceptable in the12 pts evaluated. Three grade 4 events occurred and were unrelated to therapy (venous thromboembolism, stroke, hyperbilirubinemia). Grade 3 toxicity was noted in 5 pts (fatigue, nausea, vomiting and diarrhea). Grade 1/2 toxicity was minimal, predominated by neurosensory deficits in 7 pts, hand foot syndrome (HFS) in four pts, and nausea in 4 pts. Two pts stopped therapy due to toxicity, one for HFS (grade 2) after 1 cycle, and one for diarrhea (grade 3) after two cycles. Four pts required dose reduction. Conclusion: The combination of CAP and OX is reasonable and tolerable treatment of pancreas cancer with activity even in pts receiving second line chemotherapy. Accrual is ongoing. No significant financial relationships to disclose.

To identify genes that are differentially-expressed in trisomy 21-affected placentas compared to placentas of chromosomally normal fetuses. The study included CVS samples from 4 trisomy 21-affected pregnancies and 4 normal controls. Total RNA was extracted from cultured trophoblast and hybridized to Affymetrix® Human Genome U95Av2 Microarray containing ∼12,000 transcripts. For each transcript, a signal value and a detection call were generated using MAS5 and analyzed using GeneSpring® software. Validation of selected genes was performed by quantitative RT- PCR. 5334 genes present in at least 4 out of 8 samples were chosen for non-supervised hierarchical clustering. This set of genes successfully discriminated between all trisomic and normal samples. ANOVA, using False Discovery Rate (FDR) for multiple comparisons correction, identified 65 genes that demonstrated a significant differential-expression between trisomic and normal samples. Two genes significantly over-expressed in trisomy 21 (MEST and LOX), and one under-expressed gene (MAT2A) were further studied by quantitative RT-PCR. This analysis confirmed over-expression of MEST (13.6-fold, p=0.036) and LOX (3.7-fold. p=0.025) (shown below), but did not validate under-expression of MAT2A. These data demonstrate that gene expression in trisomy 21-affected placentas significantly differs from chromosomally normal placentas. Further study is needed to assess the role of MEST and LOX in the pathophysiology of Down syndrome. This approach may facilitate the discovery of additional maternal serum markers of trisomy 21.

The prenatal detection of de novo extra structurally abnormal chromosomes (ESACs) presents a challenge because the associated risk for congenital anomaly ranges from 100% to practically none, depending on the chromosomal origin. Despite the use of standard cytogenetic techniques and even fluorescence in situ hybridization (FISH), the origin of some ESACs often remains elusive. Spectral karyotyping (SKY™) is a molecular cytogenetic technique based on the simultaneous analysis of all chromosomes using a unique probe mix that allows the rapid identification of all chromosomes in 24 colors. The purpose of this study was to evaluate the use of SKY in the characterization of prenatally diagnosed de novo ESACs.