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Two comprehension studies were conducted with 46 deaf college students. In the first, 20 deaf college students representing higher and lower reading-ability levels were tested for correctly stating the main idea of a passage, answering content questions, indicating their understanding of the words and phrases, and recognizing a topically incongruent sentence embedded in the passage. The results suggest that deaf students profess a better understanding of what they read than they are able to demonstrate. The students' inability to identify a topically incongruent sentence in the passage further suggests a need for them to more carefully and accurately evaluate their understanding of what they are reading. A second study investigated the effect of strategy review instruction on deaf college students' comprehension of short reading passages. Students reading at a higher level showed improved comprehension on the posttraining passage, but students reading at a lower level did not. Similarly, the control group of deaf students comparable to the higher-level readers did not show improved comprehension. [ABSTRACT FROM AUTHOR]

Background: Preoperative selection of patients with Peritoneal Carcinomatosis (PC) for Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) is challenging due to associated risks. Diagnostic laparoscopy (DL), an emerging alternative to conventional radiological imaging, has uncertain efficacy. This study aims to evaluate DL's diagnostic performance through a systematic review of available literature., Methods: A comprehensive search of MEDLINE and SCOPUS databases from January 1987 to September 2023 identified studies investigating DL's diagnostic accuracy in selecting PC patients for CRS-HIPEC. Methodological bias assessment and analysis of performance metrics such as positive predictive value (PPV), sensitivity, specificity, and diagnostic odds ratio (DOR) were conducted. Subgroup analyses were performed for primary ovarian cancer studies, and false positive sites were identified. The summary receiver operating characteristic curve (sROC) was plotted to assess overall diagnostic efficacy, with meta-regression conducted to identify sources of heterogeneity across studies., Results: This study included 25 studies comprising 3820 patients. Pooled PPV was 93.04 %, with a complication rate of 1.61 %. Pooled sensitivity was 98.26 % and pooled specificity was 83.67 %. The pooled DOR was 139.18, and sROC plot yielded an area under the curve of 0.96. Meta-regression found the ovarian subgroup as a strong source of heterogeneity. Subgroup analysis indicated similar findings in primary ovarian cancer studies, while false positives were commonly observed in the celiac axis, mesentery, ureters and para-aortic lymph nodes., Conclusion: DL demonstrates robust diagnostic accuracy in selecting PC patients for CRS-HIPEC, with potential benefits in patient outcomes and resource optimization. Further multicenter investigations are warranted to validate DL's efficacy across diverse primary cancer types., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Peritoneal metastasis (PM), the regional progression of intra-abdominal malignancies, is a common sequelae of colorectal cancer (CRC). Immunotherapy is slated to be effective in generating long-lasting anti-tumour response as it utilizes the specificity and memory of the immune system. In the tumour microenvironment, tumour associated macrophages (TAMs) are posited to create an anti-inflammatory pro-tumorigenic environment. In this paper, we aimed to identify immunomodulatory factors associated with colorectal PM (CPM). A publicly available colorectal single cell database (GSE183916) was analysed to identify possible immunological markers that are associated with the activation of macrophages in cancers. Immunohistochemical analysis for V-set and immunoglobin containing domain 4 (VSIG4) expression was performed on tumour microarrays (TMAs) of tumours of colorectal origin (n = 211). Expression of VSIG4 in cell-free ascites obtained from CPM patients (n = 39) was determined using enzyme-linked immunosorbent assay (ELISA). CD163-positive TAMs cluster expression was extracted from a publicly available single cell database and evaluated for the top 100 genes. From these macrophage-expressed genes, VSIG4, a membrane protein produced by the M2 macrophages, mediates the up-regulation of anti-inflammatory and down-regulation of pro-inflammatory macrophages, contributing to an overall anti-inflammatory state. CRC TMA IHC staining showed that low expression of VSIG4 in stromal tissues of primary CRC are associated with poor prognosis (p = 0.0226). CPM ascites also contained varying concentrations of VSIG4, which points to a possible role of VSIG4 in the ascites. The contribution of VSIG4 to CPM development can be further evaluated for its potential as an immunotherapeutic agent., (© 2024. The Author(s).)

Introduction: Field cancerization is suggested to arise from imbalanced differentiation in individual basal progenitor cells leading to clonal expansion of mutant cells that eventually replace the epithelium, although without evidence., Methods: We performed deep sequencing analyses to characterize the genomic and transcriptomic landscapes of field change in two patients with synchronous aerodigestive tract tumors., Results: Our data support the emergence of numerous genetic alterations in cancer-associated genes but refutes the hypothesis that founder mutation(s) underpin this phenomenon. Mutational signature analysis identified defective homologous recombination as a common underlying mutational process unique to synchronous tumors., Discussion: Our analyses suggest a common etiologic factor defined by mutational signatures and/or transcriptomic convergence, which could provide a therapeutic opportunity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Tan, Shannon, Lim, Teo, Yap, Lek, Tan, Tan, Hendrikson, Liu, Ng, Chong, Guo, Koh, Ng, Rajasegaran, Wong, Seo, Ong, Lim, Teh, Kon, Chia, Soo, Iyer and Ong.)

Distinguishing low- versus high-risk HPV-associated oropharyngeal squamous cell carcinoma (OPSCC) is pivotal for tailoring treatment. Liquid biopsy, measuring cell-free HPV-DNA in serum and saliva, assesses treatment response and early-recurrence risk. Postoperative lymphatic fluid may better guide future adjuvant therapy decisions due to its proximity to primary lesions and lymph nodes. See related article by Earland et al., p. 1409., (©2024 American Association for Cancer Research.)

Introduction: Prehabilitation, which involves improving a patient's physical and psychological condition before surgery, has shown potential benefits but has yet to be extensively studied from an economic perspective. To address this gap, a systematic review was conducted to summarize existing economic evaluations of prehabilitation interventions., Methods: The PRISMA Protocols 2015 checklist was followed. Over 16,000 manuscripts were reviewed, and 99 reports on preoperative interventions and screening tests were identified, of which 12 studies were included in this analysis. The costs are expressed in Pounds (GBP, £) and adjusted for inflation to December 2022., Results: The studies were conducted in Western countries, focusing on specific surgical subspecialties. While the interventions and study designs varied, most studies demonstrated cost savings in the intervention group compared to the control group. Additionally, all cost-effectiveness analysis studies favored the intervention group. However, the review also identified several limitations. Many studies had a moderate or high risk of bias, and critical information such as time horizons and discount rates were often missing. Important components like heterogeneity, distributional effects, and uncertainty were frequently lacking as well. The misclassification of economic evaluation types highlighted a lack of knowledge among physicians in prehabilitation research., Conclusion: This review reveals a lack of robust evidence regarding the economics of prehabilitation programs for surgical patients. This suggests a need for further research with rigorous methods and accurate definitions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ke, Ng, Elangovan, Leong, Goh, Graves, Shannon and Abdullah.)

Objective: To examine the association between the performance of mapping biopsies and surgical outcomes postexcision of extramammary Paget's disease (EMPD)., Background: Primary EMPD is a rare entity associated with poorly defined surgical margins and difficult-to-access sites of lesions. Surgical resection with clear margins remains the preferred management method. The use of mapping biopsies might be beneficial, particularly in lowering disease recurrence., Methods: Available literature was reviewed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses methodology before a fixed-effect meta-analysis was performed to identify the presence of a correlation between performing mapping biopsies and positive margins on permanent sections as well as disease-free survival. Additional study results not included in the quantitative assessment were qualitatively assessed and reported., Results: A total of 12 studies were shortlisted for final analysis. 294 patients who underwent mapping biopsies and 48 patients who did not undergo mapping biopsies were included in the assessment. Forest plot analysis revealed a pooled rate ratio of 0.50 (95% CI, 0.32-0.77) in the prevalence of positive margins in patients with mapping biopsies performed as compared to patients without. The pooled rate ratio of the prevalence of disease-free survival in patients with mapping biopsies performed as compared to patients without was 1.38 (95% CI, 1.03-1.84). Qualitative assessment of the remaining selected studies revealed equivocal results., Conclusions: Mapping biopsies are able to improve EMPD surgical excision outcomes but given the rarity of the disease and heterogeneity of mapping biopsy procedures, further confirmation with randomized controlled trials or a larger patient pool is necessary., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: Major abdominal emergency surgery (MAES) patients have a high risk of mortality and complications. The time-sensitive nature of MAES necessitates an easily calculable risk-scoring tool. Shock index (SI) is obtained by dividing heart rate (HR) by systolic blood pressure (SBP) and provides insight into a patient's haemodynamic status. We aimed to evaluate SI's usefulness in predicting postoperative mortality, acute kidney injury (AKI), requirements for intensive care unit (ICU) and high-dependency monitoring, and the ICU length of stay (LOS)., Method: We retrospectively reviewed 212,089 MAES patients from January 2013 to December 2020. The cohort was propensity matched, and 3960 patients were included. The first HR and SBP recorded in the anaesthesia chart were used to calculate SI. Regression models were used to investigate the association between SI and outcomes. The relationship between SI and survival was explored with Kaplan-Meier curves., Results: There were significant associations between SI and mortality at 1 month (odds ratio [OR] 2.40 [1.67-3.39], P<0.001), 3 months (OR 2.13 [1.56-2.88], P<0.001), and at 2 years (OR 1.77 [1.38-2.25], P<0.001). Multivariate analysis revealed significant relationships between SI and mortality at 1 month (OR 3.51 [1.20-10.3], P=0.021) and at 3 months (OR 3.05 [1.07-8.54], P=0.034). Univariate and multivariate analysis also revealed significant relationships between SI and AKI (P<0.001), postoperative ICU admission (P<0.005) and ICU LOS (P<0.001). SI does not significantly affect 2-year mortality., Conclusion: SI is useful in predicting postopera-tive mortality at 1 month, 3 months, AKI, postoperative ICU admission and ICU LOS., Competing Interests: There are no conflicts of interest.

Background: The COVID-19 pandemic has led to a decrease in cancer screening due to the redeployment of health care resources and public avoidance of health care facilities. Breast cancer is the most common cancer diagnosed in female individuals, with improved survival rates from early detection. An avoidance of screening, resulting in late detection, greatly affects survival and increases health care resource burden and costs., Objective: This study aimed to evaluate if a sustained decrease in public interest in screening occurred and to evaluate other search terms, and hence interest, associated with that., Methods: This study used Google Trends to analyze public interest in breast cancer screening and symptoms. We queried search data for 4 keyword terms ("mammogram," "breast pain," "breast lump," and "nipple discharge") from January 1, 2019, to January 1, 2022. The relative search frequency metric was used to assess interest in these terms, and related queries were retrieved for each keyword to evaluate trends in search patterns., Results: Despite an initial drastic drop in interest in mammography from March to April 2020, this quickly recovered by July 2020. After this period, alongside the recovery of interest in screening, there was a rapid increase in interest for arranging for mammography. Relative search frequencies of perceived breast cancer-related symptoms such as breast lump, nipple discharge, and breast pain remained stable. There was increase public interest in natural and alternative therapy of breast lumps despite the recovery of interest in mammography and breast biopsy. There was a significant correlation between search activity and Breast Cancer Awareness Month in October., Conclusions: Online search interest in breast cancer screening experienced a sharp decline at the beginning of the COVID-19 pandemic, with a subsequent return to baseline interest in arranging for mammography followed this short period of decreased interest., (©Si Ying Tan, Matilda Swee Sun Tang, Chin-Ann Johnny Ong, Veronique Kiak Mien Tan, Nicholas Brian Shannon. Originally published in JMIR Cancer (https://cancer.jmir.org), 06.06.2023.)

Background: Multidisciplinary tumor board (MDT) discussion is standard practice in the management of Upper Gastrointestinal (UGI) cancers. However, poor adherence to MDT recommendations may account for the lack of improved oncological outcomes with MDTs. We aim to quantify adherence rates and compare outcomes between adherent and non-adherent patients., Methods: We included all patients with potentially curable primary UGI carcinomas who were discussed at UGI MDT from 2017 to 2018. MDT recommendations were compared to actual treatment received. Oncological and survival outcomes were compared between both groups., Results: Amongst 153 patients, 64 (41.8%) were non-adherent to MDT recommendations. Reasons for non-adherence were patient refusal (50.0%), treatment-related complications (31.3%), disease factors (17.2%) and clinician decision (1.56%). Univariate analysis showed that non-adherent patients were older (71.6 vs 65.2 years, p < 0.001), with higher clinical stage at point of diagnosis (p = 0.028), pathological stage after resection (p < 0.001) and were more likely to be recommended for multimodal therapy. No significant factors were associated with non-adherence at multivariate analysis. Non-adherent patients had worse median overall survival (19.5 months) compared to adherent patients (not reached at follow-up) with both unmatched and propensity-score matched analysis. Patients who received only part of the intended adjuvant chemotherapy course had worse median overall survival and disease-free survival compared to patients who completed or did not initiate adjuvant chemotherapy., Conclusions: Non-adherence to MDT recommendations was associated with advanced age and tumor stage, and potentially contributes to the worse oncological outcomes in a group of patients already predisposed to poor outcomes., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Following ultralow anterior resection for distal rectal cancers, a coloanal anastomosis is usually created along with a defunctioning ileostomy (DI). Recent evidence suggests that abdominoperineal pull-through with delayed coloanal anastomosis (DCAA) is a viable alternative to immediate coloanal anastomosis (ICAA), minimizing the risk of anastomotic leakage and avoiding the need for stoma creation with the risk of stoma-associated morbidity. However, DCAA requires a longer initial hospitalization. We aimed to perform a cost-effectiveness analysis to compare DCAA versus ICAA for elective rectal cancer surgery., Methods: A decision tree model was used to compare the cost-effectiveness of the two strategies. Cost data were obtained from the 2019 to 2020 United Kingdom National Health Service reference costs. Model probabilities were derived from published studies. Univariate and probabilistic sensitivity analyses were used to evaluate the robustness of the results., Results: DCAA was the overall cheaper strategy at £13 541 compared with £14 856 for ICAA in the base case analysis. This was explained by the decreased overall costs of hospitalization/surgery, reduction in costs associated with anastomotic or stoma-related complications, specifically dehydration-induced hospital readmissions and avoidance of stoma maintenance costs. Sensitivity analysis demonstrated that DCAA remained consistently more inexpensive except when the duration of total parenteral nutrition exceeded 14 days., Conclusion: Despite a longer index hospitalization with higher initial costs, this economic analysis demonstrates that DCAA without stoma is overall more cost-effective compared with ICAA with DI following ultralow anterior resection. Cost savings should be considered an additional benefit when selecting the DCAA approach for rectal cancer surgery., (© 2022 Royal Australasian College of Surgeons.)

Background: The current Lee's Revised cardiac risk index (RCRI) was created in 1999. Validation studies have found RCRI to be only moderately discriminant. The "Diabetes Mellitus on insulin" component of the score does not accurately reflect the severity of the disease. A previously studied HbA1C:Hemoglobin ratio shows an improved association with outcomes than individual components alone., Study Design: A retrospective cohort study was performed in diabetic patients undergoing non-cardiac surgery. Ethics approval was obtained. The study compares the predictive value of RCRI and substitution of the "DM on insulin" component with HH ratio for 30- and 90-day mortality, and postoperative acute myocardial injury (AMI) and acute kidney injury (AKI)., Results: A total of 20,099 adult patients were included in the final analysis. The incidence of 30- and 90-day mortality was at 4.2 and 6.5%, respectively. Substitution of HH ratio in RCRI resulted in 687 more patients being in the moderate to high-risk category. The substituted HH-RCRI score had better prediction for 30-day (AUC 0.66 vs. 0.69, p < 0.001) and 90-day mortality (AUC 0.67 vs. 0.70, p < 0.001), and postoperative AMI (AUC 0.69 vs. 0.71, p < 0.001) and AKI (AUC 0.57 vs. 0.62, p < 0.001)., Conclusion: Although currently not an universal practice, substitution of "DM on insulin" with HbA1C:Hemoglobin ratio in RCRI score improves the accuracy of the RCRI risk prediction model in diabetic patients going for non-cardiac surgery., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ke, Shannon and Abdullah.)

Background: There have been few reports on the feasibility and safety of robotic multivisceral surgeries. The da Vinci Xi boasts significant upgrades that improve its applicability in combined resections. We report our early experience of multivisceral, multi-quadrant resections with the Xi system., Methods: Between May 2015 and August 2019, 13 multivisceral resections were performed. Patient demographics, procedural data, and perioperative outcomes were evaluated., Results: The procedures were completed at a median operative time of 290 (range, 210-535) minutes. The median postoperative length of hospital stay was 3.5 (range, 2-7) days. There was one case of readmission for anastomotic leak, but no positioning injuries, external robot arm collisions or issues arising from trocar position. There were no cases of perioperative mortality., Conclusion: Multivisceral resections can be safely accomplished using the Xi. Further studies are necessary to ascertain whether there are benefits of the robotic approach over conventional laparoscopy in these complex cases., (© 2022 Royal Australasian College of Surgeons.)

Background: Oral squamous cell carcinoma (OSCC) is a common head and neck cancer with high morbidity and mortality. Currently, treatment decisions are guided by TNM staging, which omits important negative prognosticators such as lymphovascular invasion, perineural invasion (PNI), and histologic differentiation. We proposed nomogram models based on adverse pathological features to identify candidates suitable for treatment escalation within each risk group according to the National Comprehensive Cancer Network (NCCN) guidelines., Methods: Anonymized clinicopathologic data of OSCC patients from 5 tertiary healthcare institutions in Asia were divided into 3 risk groups according to the NCCN guidelines. Within each risk group, nomograms were built to predict overall survival based on histologic differentiation, histologic margin involvement, depth of invasion (DOI), extranodal extension, PNI, lymphovascular, and bone invasion. Nomograms were internally validated with precision-recall analysis and the Kaplan-Meier survival analysis., Results: Low-risk patients with positive pathological nodal involvement and/or positive PNI should be considered for adjuvant radiotherapy. Intermediate-risk patients with gross bone invasion may benefit from concurrent chemotherapy. High-risk patients with positive margins, high DOI, and a high composite score of histologic differentiation, PNI, and the American Joint Committee on Cancer (AJCC) 8th edition T staging should be considered for treatment escalation to experimental therapies in clinical trials., Conclusion: Nomograms built based on prognostic adverse pathological features can be used within each NCCN risk group to fine-tune treatment decisions for OSCC patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tu, Shannon, Thankappan, Balasubramanian, Pillai, Shetty, Rangappa, Chandrasekhar, Kekatpure, Kuriakose, Krishnamurthy, Mitra, Pattatheyil, Jain, Iyer, Subramaniam and Iyer.)

Peritoneal carcinomatosis (PC) present a ubiquitous clinical conundrum in all intra-abdominal malignancies. Via functional and transcriptomic experiments of ascites-treated PC cells, we identify STAT3 as a key signaling pathway. Integrative analysis of publicly available databases and correlation with clinical cohorts (n = 7,359) reveal putative clinically significant activating ligands of STAT3 signaling. We further validate a 3-biomarker prognostic panel in ascites independent of clinical covariates in a prospective study (n = 149). Via single-cell sequencing experiments, we uncover that PAI-1, a key component of the prognostic biomarker panel, is largely secreted by fibroblasts and mesothelial cells. Molecular stratification of ascites using PAI-1 levels and STAT3 activation in ascites-treated cells highlight a therapeutic opportunity based on a phenomenon of paracrine addiction. These results are recapitulated in patient-derived ascites-dependent xenografts. Here, we demonstrate therapeutic proof of concept of direct ligand inhibition of a prognostic target within an enclosed biological space., Competing Interests: C.-A.J.O., J.H., Y.L., W.H.N., J.W.S.T., Q.X.T., G.H.C.T., C.S.C., and M.C.C.T. report a Patent Cooperation Treaty (PCT) filed by Singapore Health Services for PAI-1 as a biomarker with therapeutic implications for peritoneal carcinomatosis (PCT/SG2020/050177). All of the other authors declare no competing interests., (© 2022 The Author(s).)

HbA1C's predictive value for postoperative complications in cardiac surgery has been mixed. Studies did not account for HbA1C being over-read in anemic patients. This study proposes a novel way of using a ratio of HbA1C over hemoglobin (HH ratio). Retrospective recruitment of patients undergoing cardiac surgery was done with ethics approval. The primary objective of our study is to look for the correlation of HH ratio with 90-day (short-term) and 1-year (long-term) mortality. The secondary objective is to investigate its association with other adverse events. Statistical analysis was done using multivariable regressions and Cox proportional hazard models. Of the 974 patients recruited, 618 had a HH Ratio<0.5, 284 between 0.5-0.7 and 72 had the ratio >0.7. HH ratio of 0.5-0.7 and >0.7 was associated with 90-day mortality (HR 5.12, P = 0.033 and HR 7.25, P= 0.048 respectively) and 1-year mortality (HR 4.53, P = 0.028 and HR 9.20, P = 0.022 respectively). The higher HH ratio groups were also associated with increased length of stay (hours) in the intensive care unit (P < 0.001) and renal complications (P < 0.001). Our study showed a positive association of HH ratio with 90-day and 1-year mortality and postoperative adverse outcomes in patients undergoing cardiac surgery. The HH ratio has the potential to be a new perioperative target., Competing Interests: Declaration of Competing Interest All authors declare no conflict of interest in relation to this research. There are non-financial associations that may be relevant or seen as related to this research., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Ovarian cancer is associated with poor prognosis. Platinum resistance contributes significantly to the high rate of tumour recurrence. We aimed to identify a set of molecular markers for predicting platinum sensitivity. A signature predicting cisplatin sensitivity was generated using the Genomics of Drug Sensitivity in Cancer and The Cancer Genome Atlas databases. Four potential biomarkers (CYTH3, GALNT3, S100A14, and ERI1) were identified and optimized for immunohistochemistry (IHC). Validation was performed on a cohort of patients (n = 50) treated with surgical resection followed by adjuvant carboplatin. Predictive models were established to predict chemosensitivity. The four biomarkers were also assessed for their ability to prognosticate overall survival in three ovarian cancer microarray expression datasets from The Gene Expression Omnibus. The extreme gradient boosting (XGBoost) algorithm was selected for the final model to validate the accuracy in an independent validation dataset (n = 10). CYTH3 and S100A14, followed by nodal stage, were the features with the greatest importance. The four gene signature had comparable prognostication as clinical information for two-year survival. Assessment of tumour biology by means of gene expression can serve as an adjunct for prediction of chemosensitivity and prognostication. Potentially, the assessment of molecular markers alongside clinical information offers a chance to further optimise therapeutic decision making., (© 2021. The Author(s).)

Up to 10% of well-differentiated liposarcoma (WDLS) progress to dedifferentiated liposarcoma (DDLS). We aimed to identify gene expression changes associated with dedifferentiation and whether these were informative of tumour biology of DDLS. We analysed datasets from the Gene Expression Omnibus (GEO, ID = GSE30929) database to identify differentially expressed genes between WDLS ( n = 52) and DDLS ( n = 39). We validated the signature on whole and laser-capture microdissected samples from patients with tumours consisting of mixed WDLS and DDLS components. A subset of this signature was applied to an independent dataset from The Cancer Genome Atlas (TCGA, n = 58 DDLS) database to segregate samples based on gene expression and compared for recurrence and overall survival (OS). A 15-gene signature consisting of genes with increased expression in DDLS compared to WDLS was generated. This signature segregated WDLS and DDLS samples from patients with mixed component tumours and across multiple recurrences. A further subset of this signature, consisting of five genes (AQP7, ACACB, FZD4, GPD1, LEP), segregated DDLS in a TCGA cohort with a significant difference in OS ( p = 0.019) and recurrence-free survival (RFS) ( p = 0.061). The five-gene model stratified DDLS into prognostic groups and outperformed clinical factors in existing models in retroperitoneal DDLS.

Objectives: We have previously identified and validated a panel of molecular prognostic markers (ATP13A3, SSR3, and ANO1) for Head and Neck Squamous Cell Carcinoma (HNSCC). The aim of this study was to investigate the consequence of ATP13A3 dysregulation on signaling pathways, to aid in formulating a therapeutic strategy targeting ATP13A3-overexpressing HNSCC., Materials and Methods: Gene Set Enrichment Analysis (GSEA) was performed on HNSCC microarray expression data (Internal local dataset [n = 92], TCGA [n = 232], EMBL [n = 81]) to identify pathways associated with high expression of ATP13A3. Validation was performed using immunohistochemistry (IHC) on tissue microarrays (TMAs) of head and neck cancers (n = 333), staining for ATP13A3 and phosphorylated Aurora kinase A (phospho-T288). Short interfering RNA was used to knockdown ATP13A3 expression in patient derived HNSCC cell lines. Protein expression of ATP13A3 and Aurora kinase A was then assessed by immunoblotting., Results: GSEA identified Aurora kinase pathway to be associated with high expression of ATP13A3 (p = 0.026). The Aurora kinase pathway was also associated with a trend towards poor prognosis and tumor aggressiveness (p = 0.086, 0.094, respectively). Furthermore, the immunohistochemical staining results revealed a significant association between Aurora kinase activity and high ATP13A3 expression (p < 0.001). Knockdown of ATP13A3 in human head and neck cell lines showed decrease in Aurora kinase A levels., Conclusion: Tumors with high ATP13A3 are associated with high Aurora kinase activity. This suggests a potential therapeutic role of Aurora kinase inhibitors in a subset of poor prognosis HNSCC patients with overexpression of ATP13A3., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

A 79-year-old Chinese gentleman presented with unilateral acute lower limb ischaemia and received intra-arterial catheter-directed thrombolysis, initially with good result and reversal of the ischaemia. However, he developed an extensive spontaneous spinal epidural haematoma within hours of the procedure and was left with permanent paraplegia after being deemed unsuitable for decompressive spinal surgery. This report serves as a reminder of the risk of severe complications of catheter-directed thrombolysis by describing this rare but devastating side-effect that occurred even despite early detection from onset of symptoms., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article., (© The Author(s) 2020.)

Generation of large amounts of genomic data is now feasible and cost-effective with improvements in next generation sequencing (NGS) technology. Ribonucleic acid sequencing (RNA-Seq) is becoming the preferred method for comprehensively characterising global transcriptome activity. Unique to cytoreductive surgery (CRS), multiple spatially discrete tumour specimens could be systematically harvested for genomic analysis. To facilitate such downstream analyses, laser capture microdissection (LCM) could be utilized to obtain pure cell populations. The aim of this protocol study was to develop a methodology to obtain high-quality expression data from matched primary tumours and metastases by utilizing LCM to isolate pure cellular populations. We demonstrate an optimized LCM protocol which reproducibly delivered intact RNA used for RNA sequencing and quantitative polymerase chain reaction (qPCR). After pathologic annotation of normal epithelial, tumour and stromal components, LCM coupled with cDNA library generation provided for successful RNA sequencing. To illustrate our framework's potential to identify targets that would otherwise be missed with conventional bulk tumour sequencing, we performed qPCR and immunohistochemical technical validation to show that the genes identified were truly expressed only in certain sub-components. This study suggests that the combination of matched tissue specimens with tissue microdissection and NGS provides a viable platform to unmask hidden biomarkers and provides insight into tumour biology at a higher resolution.

Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is associated with significant perioperative morbidity and mortality. We aim to generate and validate a biomarker set predicting sensitivity to Mitomycin-C to refine selection of patients with colorectal peritoneal metastasis (CPM) for this treatment. A signature predicting Mitomycin-C sensitivity was generated using data from Genomics of Drug Sensitivity in Cancer and The Cancer Genome Atlas. Validation was performed on CPM patients who underwent CRS-HIPEC (n = 62) using immunohistochemistry (IHC). We determined predictive significance of our set using overall survival as a surrogate endpoint via a logistic regression model. Three potential biomarkers were identified and optimized for IHC. Patients exhibiting lower expression of PAXIP1 and SSBP2 had poorer survival than those with higher expression (p = 0.045 and 0.140, respectively). No difference was observed in patients with differing DTYMK expression (p = 0.715). Combining PAXIP1 and SSBP2 in a set, patients with two dysregulated protein markers had significantly poorer survival than one or no dysregulated marker (p = 0.016). This set independently predicted survival in a Cox regression model (HR 5.097; 95% CI 1.731-15.007; p = 0.003). We generated and validated an IHC prognostic set which could potentially identify patients who are likely to benefit from HIPEC using Mitomycin-C.

Background: Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) is routinely used for selected patients with peritoneal metastasis, but can be associated with high complication rates, prolonged hospital stay, and mortality. Our objective was to determine the learning curve of CRS/HIPEC in our institution, representing the largest Asian cohort to date., Methods: A total of 200 consecutive patients with peritoneal metastasis treated with CRS/HIPEC between 2001 and 2016 were grouped into four cohorts of 50 patients and studied. Primary outcomes were severe morbidity (Clavien-Dindo III-V), procedure-related mortality, and duration of ICU and hospital stays. Secondary outcome was duration of surgery., Results: Median age was 53 years (10-75). There was no significant age, sex, or histology difference across cohorts. Rates of severe morbidity (23 %), and 60 day inpatient mortality (0.5 %) were comparable to previously reported data. Decreases in rates of serious morbidity, (34 %, 30 %, 12 %, 14 %, p<0.01) and duration of total hospital stay (14, 16, 13, 12 days, p=0.041) were seen across consecutive cohorts. Operation time decreased significantly after the first cohort (10, 7.8, 7.8, 7.2 h, p<0.01), despite increase in average PCI score after the first cohort (8, 14, 12, 13, p=0.063)., Conclusions: Whilst 50 cases were adequate for procedural familiarity and decreased average operation time, significant improvement in rate of serious morbidity was observed after 100 operations. We demonstrate a novel biphasic nature to the learning curve, reflecting initial training in which technical competence is achieved, followed by a subsequent period characterized by increasingly complex cases (higher PCI score) and finally refinement of patient selection., Competing Interests: Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

Introduction: Currently, factors such as size, mitotic rate, and degree of necrosis have been shown to influence survival in patients with solitary fibrous tumors (SFTs); however, there remains no consensus regarding the associations between tumor characteristics and the malignant nature of these tumors. The aim of this article was to identify factors that would help in prognosticating SFTs and to validate the MD Anderson Cancer Center (MDACC) SFT nomogram in the largest known series of SFTs treated in an Asian population., Methods: A retrospective review of all patients with a diagnosis of SFT treated surgically in our institution between 2005 and 2015 was carried out. Basic demographics, clinicopathological, and surgical factors were analyzed for association with clinical outcomes. Factors that predicted for distant recurrence (DR) and poor survival were identified as high-risk features. The MDACC nomogram was validated by assessing the extent of discrimination, quantified using Harrell's concordance index (C-index)., Results: Fifty-nine patients were included in analysis. Significant univariate associations for DR were found for mitotic rate ( P = .05) and presence of necrosis ( P = .04). Significant univariate associations for overall survival were found for presence of recurrence ( P = .035), presence of necrosis ( P = .072), and mitotic rate ( P = .033). The C-index associated with the nomogram was 0.75., Conclusion: There is a negative association for DR and overall survival, with the mitotic rate and presence of necrosis. We propose that SFTs with these features should be regarded as high risk. The MDACC nomogram generally predicts well for patients in an Asian population.

Aim: Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) is routinely used to treat selected patients with peritoneal carcinomatosis, but can be associated with prolonged hospital stay, significant morbidity and mortality. Our objective was to assess whether patients undergoing gastrectomy as part of CRS/HIPEC were at increased risk of delayed feeding time and prolonged hospital stay., Methods: Two hundred and fourteen consecutive patients with peritoneal carcinomatosis treated with CRS/HIPEC between 2001 and 2016 were stratified by whether CRS included gastrectomy (n = 19, 9%) and compared. Primary outcomes were time to full feeds and rate of serious morbidity (Clavien-Dindo grades III-V). Secondary outcomes were durations of ICU and hospital stays., Results: Of 214 patients undergoing CRS/HIPEC, those undergoing gastrectomy (19, 8.9%) had increased time to full feeds (8 vs. 5 days, p < 0.01), and duration of ICU (2 vs. 1 days, p < 0.01) and total hospital stays (16 vs. 14 days, p = 0.013). There was no significant increase in serious complications, although increased risk of pneumonia was noted (21% vs. 4.1%, p = 0.011). Undergoing gastrectomy was not independently prognostic in multivariable analysis including high peritoneal tumour load (PCI >12), multiple CRS procedures (number >2) and operation duration (>480 min) in which operative duration remained independently prognostic (p < 0.01)., Conclusions: After surgery, early oral refeeding may be beneficial in the majority of patients undergoing CRS/HIPEC. However, patients found to have high peritoneal tumour load with extended surgery and those who underwent gastrectomy should be considered for early post-operative TPN due to the significant risk of delayed time to full feeds.

Introduction: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have been found to prolong survival in patients with peritoneal disease but is associated with significant morbidity. We evaluate the perioperative complications and the association with the chemotherapy agent used for HIPEC., Methods: Retrospective analysis of a prospectively collected database of CRS-HIPEC cases between April 2001 and February 2016 was performed. Patients were stratified by the chemotherapy used, and perioperative complications were compared., Results: Out of 214 CRS-HIPEC cases, 113 procedures used Mitomycin-C(MMC), 92 used cisplatin, 8 used oxaliplatin and the HIPEC regimen for one procedure was not recorded and excluded. 94 patients (44%) suffered low-grade complications (grade I-II), and 49 patients (23%) suffered high-grade complications (grade III-V). The frequency of low-grade complications for the cisplain, oxaliplatin and MMC groups were 49%, 50% and 40%, respectively, whereas that of high-grade complications were 24%, 50% and 20%, respectively. HIPEC with platinum agents was associated with a higher rate of acute renal impairment (ARI) compared to MMC (32% and 62% for cisplatin and oxaliplatin vs. 5.6% for MMC), whereas grade IV ARI requiring dialysis occurred only in the cisplatin group (5.6%). HIPEC with oxaliplatin was associated with higher rates of post-operative bleeding (25% vs. 1.1% and 0.88%). Rates of other complications did not differ significantly between the groups receiving different HIPEC regimens., Conclusions: The overall complication rates do not significantly differ after HIPEC with MMC and platinum based agents. Renal impairment tends to be more common and of greater severity when a platinum agent is used, whereas oxaliplatin is associated with significant post-operative bleeding.

Objective: This study seeks to evaluate pre and post-operative CA-125 in patients undergoing complete cytoreduction surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), and understand the time frame before values normalise allowing use as a surveillance tool to resume., Methods: A retrospective review was carried out of 94 patients undergoing CRS-HIPEC to compare pre-operative CA-125 values, measured within one week prior to surgery to post-operative readings within the first 30 d. Raised CA-125 was defined using as a value >35 U/ml., Results: Of 63 (67%) patients with normal pre-operative CA-125, 22 (35%) had raised post-operative CA-125, and consisted of patients with colorectal (n = 8), appendiceal (n = 6), ovarian (n = 4) or other (n = 4) cancers. The average peak CA-125 was 80 U/ml occurring on median 10th post-operative day (POD) (range 7-30). The median day of normalisation for patients with normal pre-operative and raised post-operative CA-125 was 57 (range 28-115). The median day of normalisation for patients with raised pre-operative CA-125 was POD 41 (range 1-114). Notably 10 patients had initial normalisation (median POD 1, range 1-6), followed by subsequent raised value (median POD 10, range 5-40) and re-normalisation (median POD 47, range 19-104)., Discussion: For patients with raised pre-operative CA-125 an immediate post-operative CA-125 within 3 d may be useful to assess normalisation following surgery. Aside from immediate measurement CA-125 is misleading and should not be measured post-operatively within the first 3 months after surgery following which its use as a surveillance marker can resume.

Objective: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are increasingly being used to treat peritoneal malignancies. Urological resections and reconstruction (URR) are occasionally performed during the surgery. We aim to evaluate the impact of these procedures on peri-operative outcomes of CRS and HIPEC patients., Methods: A retrospective review of a prospectively maintained database of all patients who underwent CRS-HIPEC from April 2001 to February 2016 was performed. Outcomes between patients who had surgery involving, and not involving URR were compared. Primary outcomes were the rate of major complications and the duration of stay in the intensive care unit (ICU) and hospital. Secondary outcomes were that of overall survival (OS) and prognostic factors that would indicate a need for URR., Results: A total of 214 CRS-HIPEC were performed, 21 of which involved a URR. Baseline clinical characteristics did not vary between the groups (URR vs. No URR). Urological resections comprised of 52% bladder resections, 24% ureteric resections, and 24% involving both bladder and ureteric resections. All bladder defects were closed primarily while ureteric reconstructions consisted of two end-to-end anastomoses, one ureto-uretostomy, five direct implantations into the bladder and three boari flaps. URR were more frequently required in patients with colorectal peritoneal disease ( p  = 0.029), but was not associated with previous pelvic surgery (76% vs. 54%, p  = 0.065). Patients with URR did not suffer more serious complications (14% vs. 24%, p  = 0.42). ICU (2.2 days vs. 1.4 days, p  = 0.51) and hospital stays (18 days vs. 25 days, p  = 0.094) were not significantly affected. Undergoing a URR did not affect OS ( p  = 0.99), but was associated with increased operation time (570 min vs . 490 min, p  = 0.046)., Conclusion: While concomitant URR were associated with an increase in operation time, there were no significant differences in postoperative complications or OS. Patients with colorectal peritoneal metastases are more likely to require a URR compared to other primary tumours, and needs to be considered during pre-operative planning.

Treatment failure in solid tumors occurs due to the survival of specific subpopulations of cells that possess tumor-initiating (TIC) phenotypes. Studies have implicated G protein-coupled-receptors (GPCRs) in cancer progression and the acquisition of TIC phenotypes. Many of the implicated GPCRs signal through the G protein GNA13. In this study, we demonstrate that GNA13 is upregulated in many solid tumors and impacts survival and metastases in patients. GNA13 levels modulate drug resistance and TIC-like phenotypes in patient-derived head and neck squamous cell carcinoma (HNSCC) cells in vitro and in vivo. Blockade of GNA13 expression, or of select downstream pathways, using small-molecule inhibitors abrogates GNA13-induced TIC phenotypes, rendering cells vulnerable to standard-of-care cytotoxic therapies. Taken together, these data indicate that GNA13 expression is a potential prognostic biomarker for tumor progression, and that interfering with GNA13-induced signaling provides a novel strategy to block TICs and drug resistance in HNSCCs.

Growing tumour syndrome (GTS) is a rare event in which germ cell tumours treated with chemotherapy undergo maturation, acquire resistance to chemotherapy and regrow. The optimum treatment strategy is complete surgical excision. We report on a case of GTS with malignant metastases to the liver presenting 22 years after completion of treatment for immature teratoma, successfully managed with surgical resection alone., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Current management of head and neck squamous cell carcinoma (HNSCC) depends on tumor staging. Despite refinements in clinical staging algorithms, outcomes remain unchanged for the last two decades. In this study, we set out to identify a small, clinically applicable molecular panel to aid prognostication of patients with HNSCC., Materials and Methods: Data from The Cancer Genome Atlas (TCGA) was used to derive copy number aberrations and expression changes to identify putative prognostic genes. To account for cross entity relevance of the biomarkers, HNSCC ( n = 276), breast ( n = 808) and lung cancer ( n = 282) datasets were used to identify robust and reproducible markers with prognostic potential. Validation was performed using immunohistochemistry (IHC) on tissue microarrays of an independent cohort of HNSCC ( n = 333)., Findings: Using GISTIC algorithm together with gene expression analysis, we identified six putative prognostic genes in at least two out of three cancers analyzed, of which four were successfully optimized for automated IHC. Of these, three were successfully validated; each molecular target being significantly prognostic on univariate analysis. Patients were differentially segregated into four prognostic groups based on the number of genes dysregulated ( p < 0.001). The IHC panel remained an independent predictor of survival after adjusting for known survival covariates including clinical staging criteria in a multivariate Cox regression model ( p < 0.001). ., Interpretation: We have identified and validated a clinically applicable IHC biomarker panel that is independently associated with overall survival. This panel is readily applicable, serving as a useful adjunct to current staging systems and provides novel targets for future therapeutic strategies., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interests.

Background: Many prognostic biomarkers have been proposed recently. However, there is a lack of therapeutic strategies exploiting novel prognostic biomarkers. We aimed to propose therapeutic options in patients with overexpression of TRIM44, a recently identified prognostic gene., Methods: Genomic and transcriptomic data of epithelial cancers (n = 1932), breast cancers (BCs; n = 1980) and esophago-gastric cancers (EGCs; n = 163) were used to identify genomic aberrations driving TRIM44 overexpression. The driver gene status of TRIM44 was determined using a small interfering RNA (siRNA) screen of the 11p13 amplicon. Integrative analysis was applied across multiple datasets to identify pathway activation and potential therapeutic strategies. Validation of the in silico findings were performed using in vitro assays, xenografts, and patient samples (n = 160)., Results: TRIM44 overexpression results from genomic amplification in 16.1% of epithelial cancers, including 8.1% of EGCs and 6.1% of BCs. This was confirmed using fluorescent in situ hybridization. The siRNA screen confirmed TRIM44 to be a driver of the amplicon. In silico analysis revealed an association between TRIM44 and mTOR signalling, supported by a decrease in mTOR signalling after siRNA knockdown of TRIM44 in cell lines and colocalization of TRIM44 and p-mTOR in patient samples. In vitro inhibition studies using an mTOR inhibitor (everolimus) decreased cell viability in two TRIM44-amplified cells lines by 88% and 70% compared with 35% in the control cell line. These findings were recapitulated in xenograft models., Conclusions: Genomic amplification drives TRIM44 overexpression in EGCs and BCs. Targeting the mTOR pathway provides a potential therapeutic option for TRIM44-amplified tumors., (© The Author 2014. Published by Oxford University Press.)

Objective: The success of personalised therapy depends on identification and inhibition of the oncogene(s) on which that tumour is dependent. We aimed to determine whether a receptor tyrosine kinase (RTK) array could be used to select the most effective therapeutic strategies in molecularly heterogeneous oesophago-gastric adenocarcinomas., Design: Gene expression profiling from oesophago-gastric tumours (n=75) and preinvasive stages (n=57) identified the active signalling pathways, which was confirmed using immunohistochemistry (n=434). RTK arrays on a cell line panel (n=14) determined therapeutic targets for in vitro cytotoxic testing. Feasibility of this personalised approach was tested in tumour samples (n=46)., Results: MAPK was the most frequently activated pathway (32/75 samples (42.7%)) with progressive enrichment in preinvasive disease stages (p<0.05) and ERK phosphorylation in 148/434 (34.3%) independent samples. Cell lines displayed a range of RTK activation profiles. When no RTKs were activated, tyrosine kinase inhibitors (TKIs) and a Mek inhibitor were not useful (MKN1). In lines with a dominant phosphorylated RTK (OE19, MKN45 and KATOIII), selection of this TKI or Mek in nM concentrations induced cytotoxicity and inhibited Erk and Akt phosphorylation. In cells lines with complex activation profiles (HSC39 and OE33), a combination of TKIs or Mek inhibition (in nM concentrations) was necessary for cytotoxicity and inhibition of Erk and Akt phosphorylation. Human tumours demonstrated diverse activation profiles and 65% of cases had two or more active RTKs., Conclusions: The MAPK pathway is commonly activated in oesophago-gastric cancer following activation of a variety of RTKs. Molecular phenotyping can inform a rational choice of targeted therapy.

The International Cancer Genome Consortium (ICGC) aims to catalog genomic abnormalities in tumors from 50 different cancer types. Genome sequencing reveals hundreds to thousands of somatic mutations in each tumor but only a minority of these drive tumor progression. We present the result of discussions within the ICGC on how to address the challenge of identifying mutations that contribute to oncogenesis, tumor maintenance or response to therapy, and recommend computational techniques to annotate somatic variants and predict their impact on cancer phenotype.

Purpose: Endoscopic surveillance of Barrett's esophagus is problematic because dysplasia/early-stage neoplasia is frequently invisible and likely to be missed because of sampling bias. Molecular abnormalities may be more diffuse than dysplasia. The aim was therefore to test whether DNA methylation, especially on imprinted and X-chromosome genes, is able to detect dysplasia/early-stage neoplasia., Experimental Design: 27K methylation arrays were used to find genes best able to differentiate between 22 Barrett's esophagus and 24 esophageal adenocarcinoma (EAC) samples. These were validated using pyrosequencing on a retrospective cohort (60 Barrett's esophagus, 36 dysplastic, and 90 EAC) and then in a prospective multicenter study (98 Barrett's esophagus patients, including 28 dysplastic and 9 early EAC) designed to utilize biomarkers to stratify patients according to their prevalent dysplasia/EAC status., Results: Genes (23%) on the array, including 7% of X-linked and 69% of imprinted genes, have shown statistically significant changes in methylation in EAC versus Barrett's esophagus (Wilcoxon P < 0.05). 6/7 selected candidate genes were successfully internally (Pearson's P < 0.01) and externally validated (ANOVA P < 0.001). Four genes (SLC22A18, PIGR, GJA12, and RIN2) showed the greatest area under curve (0.988) to distinguish between Barrett's esophagus and dysplasia/EAC in the retrospective cohort. This methylation panel was able to stratify patients from the prospective cohort into three risk groups based on the number of genes methylated (low risk: <2 genes, intermediate: 2, and high: >2)., Conclusion: Widespread DNA methylation changes were observed in Barrett's carcinogenesis including ≈70% of known imprinted genes. A four-gene methylation panel stratified patients with Barrett's esophagus into three risk groups with potential clinical utility., Competing Interests: There is no conflict of interest to declare., (©2012 AACR.)

Nitric oxide (NO) has been shown to induce double strand DNA breaks in Barrett's oesophagus (BO) and in other cancers has a role in invasion. The specific aims of this study were to investigate whether NO can induce invasion in cells representative of different stages of Barrett's progression and to determine possible underlying mechanisms. Physiological concentrations of NO that mimic luminal production of NO from dietary sources enhanced invasion in cell lines from high-grade dysplasia (GihTERT) and oesophageal adenocarcinoma (FLO) but not a non-dysplastic Barrett's cell line (QhTERT). Real-time reverse transcription-polymerase chain reaction revealed that NO induced expression of matrix metalloproteinase (MMP)-1, -3, -7, -9 and -10 and tissue inhibitor of metalloproteinase (TIMP)-1, -2 and -3 in these cell lines. Furthermore, ex vivo treatment of Barrett's biopsy samples with NO induced increases in MMP-1 and TIMP-1 expression, suggesting that NO enhances invasion through deregulating MMP and TIMP expression in epithelial cells. In keeping with these findings, microarray analysis and immunohistochemistry performed on biopsy samples showed enhanced expression of MMP-1, -3, -7 and -10 and TIMP-1 in the progression from non-dysplastic BO to adenocarcinoma, although this could not be directly attributed to the effect of NO. Thus, NO may play a role in Barrett's carcinogenesis through deregulating MMP and TIMP expression to enhance invasive potential.

The stromal compartment is increasingly recognized to play a role in cancer. However, its role in the transition from preinvasive to invasive disease is unknown. Most gastrointestinal tumors have clearly defined premalignant stages, and Barrett's esophagus (BE) is an ideal research model. Supervised clustering of gene expression profiles from microdissected stroma identified a gene signature that could distinguish between BE metaplasia, dysplasia, and esophageal adenocarcinoma (EAC). EAC patients overexpressing any of the five genes (TMEPAI, JMY, TSP1, FAPalpha, and BCL6) identified from this stromal signature had a significantly poorer outcome. Gene ontology analysis identified a strong inflammatory component in BE disease progression, and key pathways included cytokine-cytokine receptor interactions and TGF-beta. Increased protein levels of inflammatory-related genes significantly up-regulated in EAC compared with preinvasive stages were confirmed in the stroma of independent samples, and in vitro assays confirmed functional relevance of these genes. Gene set enrichment analysis of external datasets demonstrated that the stromal signature was also relevant in the preinvasive to invasive transition of the stomach, colon, and pancreas. These data implicate inflammatory pathways in the genesis of gastrointestinal tract cancers, which can affect prognosis.