Assessment of conditional survival probability in resected esophageal adenocarcinoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4030-4030
Author(s):  
Donna M. Graham ◽  
Finian Bannon ◽  
Megan Lloyd ◽  
Fergus Noble ◽  
Rob Walker ◽  
...  
Keyword(s):  
Esophageal Adenocarcinoma ◽  
Survival Data ◽  
Tumor Regression ◽  
Tumor Regression Grade ◽  
Conditional Survival ◽  
Molecular Stratification ◽  
Risk Of Death ◽  
Circumferential Resection Margin Involvement ◽  
The Uk ◽  
Over Time

4030 Background: Prognostication for cancer patients is based upon factors determined at baseline and becomes less relevant over time. Conditional survival (CS) estimates future prognosis based upon survival to a specific time point after treatment. We analyzed CS for patients in the United Kingdom (UK) undergoing surgery and neoadjuvant chemotherapy (NAC) for gastro-esophageal junction (GEJ) or esophageal adenocarcinoma (EAC). Methods: 1409 patients with GEJ/EAC treated with NAC and surgical resection at 7 centers across the UK from 2002-2014 were identified. Clinicopathological and survival data was collected as part of the Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) consortium. A multivariable Cox survival model was used to analyze the association of factors such as node positivity (N+), lymphovascular invasion (LVI+), tumor differentiation, circumferential resection margin involvement (CRM+) and pathological response by tumor regression grade (TRG ≤2) with risk of relapse (RR) or death from time of surgery. Results: Of 1409 patients, 726 (51.5%) were aged <65 years, and 1195 (84.8%) were male. Hazard ratios (HR) for RR conditional on recurrence-free (RF) years to date are detailed below. N+ was the most robust predictor of relapse and mortality over time. LVI+ and moderate to poor differentiation influenced relapse in the first 2 years whereas CRM+ and TRG≤2 had their greatest effect in the year following surgery. Age, sex, and year of surgery had no association with RR or mortality. Similar patterns were observed for risk of death. Conclusions: CS provides a more dynamic estimate of future RR and survival among patients who have accrued survival time, especially in patients with high-risk features. CRM+ and LVI+ govern early survival events but as time from surgery increases these factors become less relevant. [Table: see text]

scholarly journals Genomic Analysis of Response to Neoadjuvant Chemotherapy in Esophageal Adenocarcinoma

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3394
Author(s):  
Fereshteh Izadi ◽  
Benjamin Sharpe ◽  
Stella Breininger ◽  
Maria Secrier ◽  
Jane Gibson ◽  
...  
Keyword(s):  
Neoadjuvant Chemotherapy ◽  
Esophageal Adenocarcinoma ◽  
Copy Number ◽  
Tumor Regression ◽  
Locally Advanced ◽  
Genomic Analysis ◽  
Tumor Regression Grade ◽  
Comparative Genomic ◽  
Mutation Burden ◽  
Response To Neoadjuvant Chemotherapy

Neoadjuvant therapy followed by surgery is the standard of care for locally advanced esophageal adenocarcinoma (EAC). Unfortunately, response to neoadjuvant chemotherapy (NAC) is poor (20–37%), as is the overall survival benefit at five years (9%). The EAC genome is complex and heterogeneous between patients, and it is not yet understood whether specific mutational patterns may result in chemotherapy sensitivity or resistance. To identify associations between genomic events and response to NAC in EAC, a comparative genomic analysis was performed in 65 patients with extensive clinical and pathological annotation using whole-genome sequencing (WGS). We defined response using Mandard Tumor Regression Grade (TRG), with responders classified as TRG1–2 (n = 27) and non-responders classified as TRG4–5 (n =38). We report a higher non-synonymous mutation burden in responders (median 2.08/Mb vs. 1.70/Mb, p = 0.036) and elevated copy number variation in non-responders (282 vs. 136/patient, p < 0.001). We identified copy number variants unique to each group in our cohort, with cell cycle (CDKN2A, CCND1), c-Myc (MYC), RTK/PIK3 (KRAS, EGFR) and gastrointestinal differentiation (GATA6) pathway genes being specifically altered in non-responders. Of note, NAV3 mutations were exclusively present in the non-responder group with a frequency of 22%. Thus, lower mutation burden, higher chromosomal instability and specific copy number alterations are associated with resistance to NAC.

scholarly journals 474 GENOMIC ANALYSIS OF RESPONSE TO NEOADJUVANT CHEMOTHERAPY IN ESOPHAGEAL ADENOCARCINOMA

2020 ◽  
Vol 33 (Supplement_1) ◽  
Author(s):  
F Izadi ◽  
G Devonshire ◽  
R Walker ◽  
M Lloyd ◽  
J Gibson ◽  
...  
Keyword(s):  
Dna Damage ◽  
Neoadjuvant Chemotherapy ◽  
Esophageal Adenocarcinoma ◽  
Tumor Regression ◽  
Locally Advanced ◽  
Chemotherapy Resistance ◽  
Treatment Modalities ◽  
Tumor Regression Grade ◽  
Driver Genes ◽  
The Impact

Abstract   In the UK, neoadjuvant chemotherapy (NAC) for locally advanced esophageal adenocarcinoma (EAC) is the standard of care. Unfortunately, response to NAC, following surgery is often low (&lt;30%) and survival benefit at 2 years is only 5.1%. The EAC genome is complex and heterogeneous between patients, where specific mutagenic processes and mutations may result in chemotherapy resistance. Here we report preliminary results from whole-genome sequencing (WGS) of 48 patients who were subsequently treated with NAC. Methods We defined response as Mandard Tumor Regression Grade (TRG) 1-2 (n = 15) and non-response as TRG4-5 (n = 33). WGS of 50x coverage and calling of genomic events (Strelka2, SCAT/GISTIC) was performed according to Frankell Nat Genet 2019 with modifications, to differentiate driver from passenger mutations (dNdScv, oncodriveCLUST), determine variant allele frequencies (VAF; copy number-adjusted) and mutation signatures (NMF R-package). Following stringent variant QC (Phred score ≥ 30), filtering (VAF &gt;0.02) and annotation (ANNOVAR, cancer census/helper, the 77 known EAC drivers and false positive genes) and visualisation in maftools, we evaluated the data for associations between genomic events and response to NAC. Results COSMIC mutation signatures 2 (TRG1-2; Cosθ = 0.89) and 6 (TRG4-5; Cosθ = 0.82) were enriched, suggesting defective mismatch repair in non-responders. Using 5,193 high-confidence non-silent mutations (TRG1-2,n = 1969; TRG4-5, n = 3224), we identified 39 mutated driver genes (Figure-1) with a median of 2.9(0-5) (TRG1-2) and 2.7(0-9) (TRG4-5) driver events/patient. Shared dysregulated pathways, included DNA-damage (TP53), cell cycle (CDKN2A), TGF-β (SMAD4) and chromatin regulation (ARID1A). There was no difference in the prognostic of SMAD4 and GATA4 genes. Interestingly, NAV3 mutations were only present in non-responders (21%,7/33); and in responders TP53 incidence was higher (93% vs. 58%) with a concomitant reduction in clonal cell fraction (0.25 vs. 0.39;Wilcoxon, p &lt; 0.0001). Conclusion The data suggest that specific genomic events, such as NAV3 mutation and the intra-tumoral heterogeneity of mutated DNA-damage response genes may offer additional predictive value. Ongoing work includes analysis of the impact of non-coding variation on response. While our analysis is limited by sample size and requires validation in additional cohorts, it demonstrates the potential of genomic sequencing to identify NAC response biomarkers and may guide alternative or novel treatment modalities for chemo-resistant tumours.

The National Cancer Database: Survival Between Head and Neck Melanoma and Melanoma of Other Regions

2021 ◽  
pp. 019459982110532
Author(s):  
Claudia I. Cabrera ◽  
Shawn Li ◽  
Rosalynn Conic ◽  
Brian R. Gastman
Keyword(s):  
Head And Neck ◽  
Survival Data ◽  
Controlled Trial ◽  
Additional Patient ◽  
National Cancer Database ◽  
Risk Of Death ◽  
Increased Risk ◽  
Head And Neck Melanoma ◽  
Over Time

Objective Primary site is considered an important prognostic factor for cutaneous malignant melanoma (CMM); however, opinions vary regarding its influence on survival. This study compares overall survival between head and neck melanoma (HNM) and melanoma of other regions (MOR), as well as between melanoma of the scalp and neck (MSN) and melanoma of other head regions (MOHR). Study Design Level III retrospective cohort study. Setting Patients from Commission on Cancer–accredited cancer programs affiliated to the National Cancer Database (NCDB). Methods Patients with HNM (MSN and MOHR included) and MOR, stages I to IV (n = 39,754), and their linked survival data using the NCDB were identified. Survival was analyzed using propensity score matching methods. Results After matching using propensity scores, allowing this observational study to mimic a randomized controlled trial, subjects with HNM showed a 22% increased mortality when compared to MOR ( P < .01). Among those with HNM, hazard was not proportional over time. Overall, subjects with MSN in the first 3.5 years of follow-up (75% of subjects) showed a 15% increased mortality when compared to MOHR ( P < .01); however, after 3.5 years, no difference in survival was noted ( P = .5). Conclusion Patients with HNM showed a higher mortality when compared to MOR. The risk of death of primary sites within the head and neck varies over time, showing a higher risk of mortality for scalp and neck during the first 3.5 years of follow-up. This increased risk was not evident after the 3.5-year threshold. Further research is needed to evaluate additional patient factors or differences in treatment approaches.

scholarly journals Linking Circulating Serum Proteins with Clinical Outcomes in Esophageal Adenocarcinoma—An Emerging Role for Chemokines

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3356
Author(s):  
Noel E. Donlon ◽  
Andrew Sheppard ◽  
Maria Davern ◽  
Fiona O’Connell ◽  
James J. Phelan ◽  
...  
Keyword(s):  
Treatment Response ◽  
Clinical Outcomes ◽  
Esophageal Adenocarcinoma ◽  
Immune Cell ◽  
Serum Proteins ◽  
Tumor Regression ◽  
Tumor Biology ◽  
Tumor Regression Grade ◽  
Western World ◽  
Poor Responders

Esophageal adenocarcinoma (EAC) is an aggressive cancer with poor prognosis and incidence is increasing rapidly in the Western world. Multi-modal treatment has improved survival outcomes but only for a minority of patients. Currently no markers have been identified to predict treatment response. This study investigated the association between clinical outcomes and pre-treatment levels of 54 serum proteins in n = 80 patients with EAC. Low tumor regression grade (TRG), corresponding to a favorable treatment response, was linked to prolonged overall survival (OS). CCL4 was higher in patients with a favorable treatment response, while Tie2 and CRP were higher in poor responders. Elevated CCL22 and CCL26 was associated with improved OS, while elevated IL-10 showed a negative association. CCL3, CCL4, IL-1α and IL-12/IL23p40 were highest in individuals with no adverse features of tumor biology, whereas levels of Tie2 and VEGF were lowest in this cohort. CCL4 was also elevated in patients with high tumor lymphocyte infiltration. Comparison of matched pre- and post-treatment serum (n = 28) showed a large reduction in VEGFC, and a concomitant increase in other cytokines, including CCL4. These data link several serum markers with clinical outcomes, highlighting an important role for immune cell trafficking in the EAC antitumor immune response.

scholarly journals Genomic analysis of response to neoadjuvant chemotherapy in esophageal adenocarcinoma

2021 ◽  
Author(s):  
Fereshteh Izadi ◽  
Benjamin P Sharpe ◽  
Stella P Breininger ◽  
Maria Secrier ◽  
Jane Gibson ◽  
...  
Keyword(s):  
Neoadjuvant Chemotherapy ◽  
Esophageal Adenocarcinoma ◽  
Copy Number ◽  
Tumor Regression ◽  
Locally Advanced ◽  
Genomic Analysis ◽  
Tumor Regression Grade ◽  
Comparative Genomic ◽  
Mutation Burden ◽  
Response To Neoadjuvant Chemotherapy

Neoadjuvant therapy followed by surgery is the standard of care for locally advanced esophageal adenocarcinoma (EAC). Unfortunately, response to neoadjuvant chemotherapy (NAC) is poor (<20%), as is the overall survival benefit at 5 years (5%). The EAC genome is complex and heterogeneous between patients, and it is not yet understood whether specific mutational patterns may result in chemotherapy sensitivity or resistance. To identify associations between genomic events and response to NAC in EAC, a comparative genomic analysis was performed in 65 patients with extensive clinical and pathological annotation using whole-genome sequencing (WGS). We defined response using Mandard Tumor Regression Grade (TRG), with responders classified as TRG1-2 (n=27) and non-responders classified as TRG4-5 (n=38). We report a higher non-synonymous mutation burden in responders (median 2.08/Mb vs 1.70/Mb, P=0.036) and elevated copy number variation in non-responders (282 vs 136/patient, P<0.001). We identified copy number variants unique to each group in our cohort, with cell cycle (CDKN2A, CCND1), c-Myc (MYC), RTK/PIK3 (KRAS, EGFR) and gastrointestinal differentiation (GATA6) pathway genes being specifically altered in non-responders. Of note, NAV3 mutations were exclusively present in the non-responder group with a frequency of 22%. Thus, lower mutation burden, higher chromosomal instability and specific copy number alterations are associated with resistance to NAC.

PD-L1 expression and response to neo-adjuvant chemotherapy in esophageal adenocarcinoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4023-4023
Author(s):  
Eileen E. Parkes ◽  
Jaine K. Blayney ◽  
Eamon McCarron ◽  
Rosalie V. Douglas ◽  
Leanne Stevenson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Adjuvant Chemotherapy ◽  
Esophageal Adenocarcinoma ◽  
T Cell Activation ◽  
Cell Activation ◽  
Tumor Regression ◽  
Pathological Response ◽  
Tumor Regression Grade ◽  
Pre Treatment ◽  
Neo Adjuvant Chemotherapy

4023 Background: Programmed Death-1 Receptor (PD-1) and its ligand (PD-L1) downregulate T cell activation and suppress tumor killing. This study investigated the role of PD-L1 and tumor infiltrating lymphocytes (TILs) in response to neo-adjuvant therapy and prognosis in esophageal adenocarcinoma (EAC). Methods: Transcriptional profiling of 273 formalin fixed paraffin embedded pre-treatment endoscopic EAC biopsies was carried out using the Almac Diagnostics Xcel array and the expression levels of PD-L1 probesets corresponding to protein encoding extracted. Response was assessed by tumor regression grade (TRG; score ≤ 2 = response). Immunohistochemistry (IHC) for PD-L1 and CD8 was performed in matched resection specimens from 135 patients. All EAC patients were treated with cisplatin-based neo-adjuvant chemotherapy followed by surgical resection between 2003 and 2014 at four UK centers as part of the OCCAMS consortium. Associations between expression, protein levels and TRG were assessed by Kruskal-Wallis, Mann-Whitney Unpaired, Spearman rank correlation or chi-squared tests. Survival analysis was performed using Cox Proportional Hazards regression. Results: High PD-L1 gene expression in the pre-chemotherapy biopsies was associated with pathological response (TRG ≤ 2; p = 0.02) following neo-adjuvant chemotherapy. PD-L1 ( > 5%) was expressed in the tumor or stromal cells in 4% and 15% of resection specimens respectively. PD-L1 gene and IHC expression ( > 5%) were closely associated between the biopsies and both the tumor (p = 0.032) and stroma (p = 0.019) of the matched resection specimens. Patients with PD-L1 IHC positivity in tumor cells demonstrated improved relapse-free survival (HR 0.314; 95% CI 0.099-0.997; p = 0.049) and positive stromal PD-L1 IHC staining correlated with pathological response (p = 0.05). Biopsy gene expression of PD-L1 and CD8 was closely associated (p = 0.024) and the presence of CD8+ TILs in the microenvironment strongly correlated with tumor (p < 0.001) and stromal (p < 0.001) PD-L1 positivity. Conclusions: High PD-L1 expression in the pre-treatment biopsies in EAC is predictive of response to neo-adjuvant chemotherapy and may aid selection of conventional and immune-targeted agents.

UK Fiscal Squeezes over a Century

2017 ◽  
Author(s):  
Christopher Hood ◽  
Rozana Himaz
Keyword(s):  
Data Sources ◽  
Fiscal Consolidation ◽  
Financial Outcomes ◽  
Financial Conditions ◽  
Deficit Reduction ◽  
Before And After ◽  
The Uk ◽  
Changes Over Time ◽  
Spending Cuts ◽  
Over Time

This chapter draws on historical statistics reporting financial outcomes for spending, taxation, debt, and deficit for the UK over a century to (a) identify quantitatively and compare the main fiscal squeeze episodes (i.e. major revenue increases, spending cuts, or both) in terms of type (soft squeezes and hard squeezes, spending squeezes, and revenue squeezes), depth, and length; (b) compare these periods of austerity against measures of fiscal consolidation in terms of deficit reduction; and (c) identify economic and financial conditions before and after the various squeezes. It explores the extent to which the identification of squeeze episodes and their classification is sensitive to which thresholds are set and what data sources are used. The chapter identifies major changes over time that emerge from this analysis over the changing depth and types of squeeze.

scholarly journals Maternal mortality in six low and lower-middle income countries from 2010 to 2018: risk factors and trends

2020 ◽  
Vol 17 (S3) ◽  
Author(s):  
Melissa Bauserman ◽  
Vanessa R. Thorsten ◽  
Tracy L. Nolen ◽  
Jackie Patterson ◽  
Adrien Lokangaka ◽  
...  
Keyword(s):  
Risk Factors ◽  
Maternal Mortality ◽  
Maternal Deaths ◽  
Middle Income ◽  
Maternal Risk ◽  
Live Births ◽  
Middle Income Countries ◽  
Risk Of Death ◽  
Increased Risk ◽  
Over Time

Abstract Background Maternal mortality is a public health problem that disproportionately affects low and lower-middle income countries (LMICs). Appropriate data sources are lacking to effectively track maternal mortality and monitor changes in this health indicator over time. Methods We analyzed data from women enrolled in the NICHD Global Network for Women’s and Children’s Health Research Maternal Newborn Health Registry (MNHR) from 2010 through 2018. Women delivering within research sites in the Democratic Republic of Congo, Guatemala, India (Nagpur and Belagavi), Kenya, Pakistan, and Zambia are included. We evaluated maternal and delivery characteristics using log-binomial models and multivariable models to obtain relative risk estimates for mortality. We used running averages to track maternal mortality ratio (MMR, maternal deaths per 100,000 live births) over time. Results We evaluated 571,321 pregnancies and 842 maternal deaths. We observed an MMR of 157 / 100,000 live births (95% CI 147, 167) across all sites, with a range of MMRs from 97 (76, 118) in the Guatemala site to 327 (293, 361) in the Pakistan site. When adjusted for maternal risk factors, risks of maternal mortality were higher with maternal age > 35 (RR 1.43 (1.06, 1.92)), no maternal education (RR 3.40 (2.08, 5.55)), lower education (RR 2.46 (1.54, 3.94)), nulliparity (RR 1.24 (1.01, 1.52)) and parity > 2 (RR 1.48 (1.15, 1.89)). Increased risk of maternal mortality was also associated with occurrence of obstructed labor (RR 1.58 (1.14, 2.19)), severe antepartum hemorrhage (RR 2.59 (1.83, 3.66)) and hypertensive disorders (RR 6.87 (5.05, 9.34)). Before and after adjusting for other characteristics, physician attendance at delivery, delivery in hospital and Caesarean delivery were associated with increased risk. We observed variable changes over time in the MMR within sites. Conclusions The MNHR is a useful tool for tracking MMRs in these LMICs. We identified maternal and delivery characteristics associated with increased risk of death, some might be confounded by indication. Despite declines in MMR in some sites, all sites had an MMR higher than the Sustainable Development Goals target of below 70 per 100,000 live births by 2030. Trial registration The MNHR is registered at NCT01073475.

scholarly journals Topological and Morphological Controls on Morphodynamics of Salt Marsh Interiors

2021 ◽  
Vol 9 (3) ◽  
pp. 311
Author(s):  
Ben R. Evans ◽  
Iris Möller ◽  
Tom Spencer
Keyword(s):  
Salt Marsh ◽  
Salt Marshes ◽  
East Coast ◽  
Marsh Surface ◽  
Coastal Environments ◽  
Coastal System ◽  
Morphological Segmentation ◽  
The Usa ◽  
The Uk ◽  
Over Time

Salt marshes are important coastal environments and provide multiple benefits to society. They are considered to be declining in extent globally, including on the UK east coast. The dynamics and characteristics of interior parts of salt marsh systems are spatially variable and can fundamentally affect biotic distributions and the way in which the landscape delivers ecosystem services. It is therefore important to understand, and be able to predict, how these landscape configurations may evolve over time and where the greatest dynamism will occur. This study estimates morphodynamic changes in salt marsh areas for a regional domain over a multi-decadal timescale. We demonstrate at a landscape scale that relationships exist between the topology and morphology of a salt marsh and changes in its condition over time. We present an inherently scalable satellite-derived measure of change in marsh platform integrity that allows the monitoring of changes in marsh condition. We then demonstrate that easily derived geospatial and morphometric parameters can be used to determine the probability of marsh degradation. We draw comparisons with previous work conducted on the east coast of the USA, finding differences in marsh responses according to their position within the wider coastal system between the two regions, but relatively consistent in relation to the within-marsh situation. We describe the sub-pixel-scale marsh morphometry using a morphological segmentation algorithm applied to 25 cm-resolution maps of vegetated marsh surface. We also find strong relationships between morphometric indices and change in marsh platform integrity which allow for the inference of past dynamism but also suggest that current morphology may be predictive of future change. We thus provide insight into the factors governing marsh degradation that will assist the anticipation of adverse changes to the attributes and functions of these critical coastal environments and inform ongoing ecogeomorphic modelling developments.

scholarly journals Resource and waste quantification scenarios for wind turbine decommissioning in the United Kingdom

2020 ◽  
Author(s):  
Kiran Tota-Maharaj ◽  
Alexander McMahon
Keyword(s):  
United Kingdom ◽  
Waste Management ◽  
Wind Turbine ◽  
End Of Life ◽  
Wind Turbines ◽  
Rapid Rise ◽  
The United Kingdom ◽  
Management Procedures ◽  
The Uk ◽  
Over Time

AbstractWind power produces more electricity than any other form of renewable energy in the United Kingdom (UK) and plays a key role in decarbonisation of the grid. Although wind energy is seen as a sustainable alternative to fossil fuels, there are still several environmental impacts associated with all stages of the lifecycle of a wind farm. This study determined the material composition for wind turbines for various sizes and designs and the prevalence of such turbines over time, to accurately quantify waste generation following wind turbine decommissioning in the UK. The end of life stage is becoming increasingly important as a rapid rise in installation rates suggests an equally rapid rise in decommissioning rates can be expected as wind turbines reach the end of their 20–25-year operational lifetime. Waste data analytics were applied in this study for the UK in 5-year intervals, stemming from 2000 to 2039. Current practices for end of life waste management procedures have been analysed to create baseline scenarios. These scenarios have been used to explore potential waste management mitigation options for various materials and components such as reuse, remanufacture, recycling, and heat recovery from incineration. Six scenarios were then developed based on these waste management options, which have demonstrated the significant environmental benefits of such practices through quantification of waste reduction and greenhouse gas (GHG) emissions savings. For the 2015–2019 time period, over 35 kilotonnes of waste are expected to be generated annually. Overall waste is expected to increase over time to more than 1200 kilotonnes annually by 2039. Concrete is expected to account for the majority of waste associated with wind turbine decommissioning initially due to foundations for onshore turbines accounting for approximately 80% of their total weight. By 2035–2039, steel waste is expected to account for almost 50% of overall waste due to the emergence of offshore turbines, the foundations of which are predominantly made of steel.

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