Patient- and system-level factors associated with racial/ethnic disparities in the delivery of guideline-concordant therapy among US patients with gastric cancer.

BACKGROUND: Disparities in gastric cancer (GC) outcomes show a higher disease burden among minorities. We aimed to evaluate the associations between sociodemographic and system-level factors and guideline-concordant treatment among GC patients. METHODS: Cohort study with GC patients in the National Cancer Data Base (2006-2018) treated with upfront resection or neoadjuvant therapy (NAT). We used logistic regression to identify associations between deviations from guideline-concordant therapy and patient- and system-level factors, and Cox regression models to assess risk of death. RESULTS: The cohort included 43 597 GC patients treated with endoscopic resection (8.9%), surgery only (47.1%), surgery and adjuvant therapy (20.6%), or NAT followed by surgery (23.5%). A total of 31 470 patients (72.2%) received guideline-concordant therapy. Relative to Non-Hispanic Whites (NHWs), Non-Hispanic Blacks (NHBs) (odds ratio [OR] 1.19, [95% confidence intervals 1.10-1.28]) and Asian/Pacific Islanders (APIs) (OR 1.12 [1.03-1.23]) had an increased risk of deviations from treatment guidelines. Medicare/Medicaid increased the risk of deviations while treatment at high-volume facilities decreased its risk for all races/ethnicities. Deviations from guidelines were associated with an increased risk of death (hazard ratio 1.56 [1.50-1.63]. CONCLUSIONS: Racial disparities in the delivery of guideline-concordant therapy among GC patients are affected by several sociodemographic factors at the patient- and system-level.

High-Fat Diet Drives an Aggressive Pancreatic Cancer Phenotype.

BACKGROUND: Emerging evidence indicates associations between high-fat diet (HFD), metabolic syndrome (MetS), and increased risk of pancreatic cancer. However, individual components of an HFD that increase cancer risk have not been isolated. In addition, a specific pattern of cytokine elevation by which MetS drives pancreatic tumor progression is not well described. We hypothesized that oleic acid (OA), a major component of HFD, would augment pancreatic neoplastic processes. METHODS: An orthotopic pancreatic cancer model with Panc02 cells was used to compare the effect of low-fat diet to OA-based HFD on cancer progression. Tumors were quantitated, analyzed by immunohistochemistry. In addition, serum cytokine levels were quantitated. Proliferation, migration assays, and expression of epithelial-to-mesenchymal transition factors were evaluated on Panc02 and MiaPaCa-2 pancreatic cancer cells cultured in high concentrations of OA. RESULTS: HFD tumor-bearing mice (n = 8) had an 18% weight increase (P < 0.001) and increased tumor burden (P < 0.05) compared with the low-fat diet tumor-bearing group (n = 6). HFD tumors had significantly increased angiogenesis (P < 0.001) and decreased apoptosis (P < 0.05). Serum of HFD mice demonstrated increased levels of glucagon and glucagon-like peptide-1. Two pancreatic cancer cell lines cultured in OA demonstrated significant increases in proliferation (P < 0.001) and a >2.5-fold increase in cell migration (P < 0.001) when treated with OA. Panc02 treated with OA had increased expression of epithelial-to-mesenchymal transition factors SNAI-1 (Snail) and Zeb-1(P < 0.01). CONCLUSIONS: High-fat conditions in vitro and in vivo resulted in an aggressive pancreatic cancer phenotype. Our data support further investigations elucidating molecular pathways augmented by MetS conditions to identify novel therapeutic strategies for pancreatic cancer.

High Mitotic Rate Predicts Sentinel Lymph Node Involvement in Thin Melanomas.

BACKGROUND: Indications for sentinel lymph node (SLN) biopsy in the population with thin melanoma have frequently changed over time. The objective of our study was to evaluate T1 melanoma pathologic features predictive of SLN positivity with a primary focus on identifying a specific mitotic value that is most predictive of lymph node disease. Further detailed predictive features would help physicians select patients with thin melanoma for SLN biopsy. METHODS: The Surveillance, Epidemiology, and End Results database was queried for all patients diagnosed with trunk or extremity cutaneous melanoma with ≤1 mm depth who underwent SLN biopsy between the years of 2010 and 2013. Patient demographics and tumor characteristics including depth, mitotic rate (MR), ulceration, and tumor location were evaluated. MR was dichotomized at multiple cut points to identify the ideal number of mitosis for MR as a predictor of SLN status. Multivariable logistic regression analyses were performed to identify the factors affecting nodal positivity and the impact of MR threshold. Kaplan-Meir curves were used for overall survival (OS) analysis. RESULTS: Factors significantly associated with SLN positivity in the entire cohort included MR (P < 0.001, OR 1.24, 95% CI 1.18-1.31), tumor location (P = 0.017, OR 1.48, 95% CI 1.07-2.05), and ulceration (P < 0.001, OR 2.01, 95% CI 1.39-2.93,). An MR ≥ 4 was significant for SLN positivity (P = 0.049, OR 1.08, 95% CI 1.01-1.38). Mean OS was 46.7 mo for MR < 4 compared with 43.2 mo for MR ≥ 4 (P < 0.001). CONCLUSIONS: MR ≥ 4 was significant and associated with SLN positivity in thin melanomas and asulceration. Thus, MR ≥ 4 should be considered as an indication for SLN biopsy in thin melanoma.

miR-145 Antagonizes SNAI1-Mediated Stemness and Radiation Resistance in Colorectal Cancer.

Epithelial-to-mesenchymal transition (EMT) has been closely linked with therapy resistance and cancer stem cells (CSCs). However, EMT pathways have proven challenging to therapeutically target. MicroRNA 145 (miR-145) targets multiple stem cell transcription factors and its expression is inversely correlated with EMT. Therefore, we hypothesized that miR-145 represents a therapeutic target to reverse snail family transcriptional repressor 1 (SNAI1)-mediated stemness and radiation resistance (RT). Stable expression of SNAI1 in DLD1 and HCT116 cells (DLD1-SNAI1; HCT116-SNAI1) increased expression of Nanog and decreased miR-145 expression compared to control cells. Using a miR-145 luciferase reporter assay, we determined that ectopic SNAI1 expression significantly repressed the miR-145 promoter. DLD1-SNAI1 and HCT116-SNAI1 cells demonstrated decreased RT sensitivity and, conversely, miR-145 replacement significantly enhanced RT sensitivity. Of the five parental colon cancer cell lines, SW620 cells demonstrated relatively high endogenous SNAI1 and low miR-145 levels. In the SW620 cells, miR-145 replacement decreased CSC-related transcription factor expression, spheroid formation, and radiation resistance. In rectal cancer patient-derived xenografts, CSC identified by EpCAM+/aldehyde dehydrogenase (ALDH)+ demonstrated high expression of SNAI1, c-Myc, and Nanog compared with non-CSCs (EpCAM+/ALDH-). Conversely, patient-derived CSCs demonstrated low miR-145 expression levels relative to non-CSCs. These results suggest that the SNAI1:miR-145 pathway represents a novel therapeutic target in colorectal cancer to overcome RT resistance.

The clinical implications of immunogenomics in colorectal cancer: A path for precision medicine.

Colorectal cancer (CRC) remains the third most common malignancy and the second-leading cause of cancer-related deaths in the United States. Large multi-omic databases, such as The Cancer Genome Atlas and the International Colorectal Cancer Subtyping Consortium, have identified distinct molecular subtypes related to anatomy. The identification of genomic alterations in CRC is now critical because of the recent success and US Food and Drug Administration approval of pembrolizumab and nivolumab for microsatellite-instable tumors. In parallel, landmark studies have established the prognostic significance of the CRC tumor-infiltrating lymphocyte and the clinical impact of the tumor immune microenvironment. As a result, there is a growing appreciation for immunogenomics, the interconnected relation between tumor genomics and the immune microenvironment. The clinical implications of CRC immunogenomics continue to expand, and it will likely serve as a guide for next-generation immunotherapy strategies for improving outcomes for this disease. Cancer 2018;124:1650-9. © 2018 American Cancer Society.

Evaluation and management of intrahepatic and extrahepatic cholangiocarcinoma.

Cholangiocarcinomas are rare biliary tract tumors that are often challenging to diagnose and treat. Cholangiocarcinomas are generally categorized as intrahepatic or extrahepatic depending on their anatomic location. The majority of patients with cholangiocarcinoma do not have any of the known or suspected risk factors and present with advanced disease. The optimal evaluation and management of patients with cholangiocarcinoma requires thoughtful integration of clinical information, imaging studies, cytology and/or histology, as well as prompt multidisciplinary evaluation. The current review focuses on recent advances in the diagnosis and treatment of patients with cholangiocarcinoma and, in particular, on the role of endoscopy, surgery, transplantation, radiotherapy, systemic therapy, and liver-directed therapies in the curative or palliative treatment of these individuals. Cancer 2016;122:1349-1369. © 2016 American Cancer Society.

Application of an Advanced Image-Based Virtual Monoenergetic Reconstruction of Dual Source Dual-Energy CT Data at Low keV Increases Image Quality for Routine Pancreas Imaging.

PURPOSE: To compare image quality on contrast-enhanced dual-energy computed tomography (DECT) during the pancreatic parenchymal phase of pancreatic masses between linearly-blended simulated 120 kVp images (routine) and advanced image-based virtual monoenergetic reconstructions at 55 keV. METHODS: This was a retrospective evaluation of 24 nonconsecutive adults found to have a focal pancreatic mass on a multiphasic abdominal dual-source DECT (12 adenocarcinoma, 5 neuroendocrine, 7 cystic tumors). For pancreatic-parenchymal phase images, subjects had routine and 55 keV images reconstructed at the time of clinical evaluation. Quantitative evaluation by contrast-to-noise ratio and qualitative evaluations of image quality by (1) direct comparison of image pairs (preference) and (2) blinded assessment of image quality measures based on Likert scores were performed. RESULTS: Mean patient weight was 205.8 ± 26.6 lbs. Mean pancreatic lesion contrast-to-noise ratio was significantly higher at 55 keV (6.8 ± 4.1) compared to the routine image series (5.8 ± 3.8; P = 0.0002). All 3 readers preferred the 55-keV images over routine blended images in 70.1% to 95.8% of cases. No significant differences were observed for subjective sharpness of the mass, visualization of internal mass structures, or image noise. CONCLUSIONS: Use of a single advanced image-based virtual monoenergetic reconstruction at 55 keV in pancreatic DECT showed improved objective image quality and reader preference compared to routine images. As this image reconstruction can be incorporated into the scan protocol, this technique should be considered for routine clinical use.

Slug expression inhibits calcitriol-mediated sensitivity to radiation in colorectal cancer.

Recently, a reciprocal relationship between calcitriol and epithelial-to-mesenchymal transition has been described. Therefore, we hypothesized that calcitriol (1α,25-dihydroxyvitamin D3) would enhance radiation sensitivity in colorectal cancer regulated by epithelial mesenchymal transition. Vitamin-D receptor, E-cadherin and vimentin protein as well as E-cadherin, Snail and Slug mRNA levels were assessed in a panel of human colorectal cancer cell lines at baseline and in response calcitriol. We defined cell lines as calcitriol sensitive based on demonstrating an enhanced epithelial phenotype with increased E-cadherin, reduced vimentin and decreased expression of Snail and Slug as well as decreased cellular migration in response to calcitriol. In calcitriol sensitive cells, including DLD-1 and HCT116, 24 h calcitriol pre-treatment enhanced the radiation sensitivity by 2.3- and 2.6-fold, respectively, at 4 Gy (P < 0.05). In contrast, SW620 cells with high baseline mesenchymal features including high Slug and vimentin expression with low E-cadherin expression demonstrated no significant radiation sensitizing response to calcitriol treatment. Similarly, transfection of Slug in the calcitriol sensitive colon cancer cell lines, DLD-1 and HCT 116, completely inhibited the radiation sensitizing effect of calcitriol. Collectively, we demonstrate that calcitriol can enhance the therapeutic effects of radiation in colon cancer cells and Slug expression mitigates this observed effect potentially representing an effective biomarker for calcitriol therapy.

Translational and oncologic significance of tertiary lymphoid structures in pancreatic adenocarcinoma.

Pancreatic adenocarcinoma (PDAC) is an aggressive tumor with poor survival and limited treatment options. PDAC resistance to immunotherapeutic strategies is multifactorial, but partially owed to an immunosuppressive tumor immune microenvironment (TiME). However, the PDAC TiME is heterogeneous and harbors favorable tumor-infiltrating lymphocyte (TIL) populations. Tertiary lymphoid structures (TLS) are organized aggregates of immune cells that develop within non-lymphoid tissue under chronic inflammation in multiple contexts, including cancers. Our current understanding of their role within the PDAC TiME remains limited; TLS are complex structures with multiple anatomic features such as location, density, and maturity that may impact clinical outcomes such as survival and therapy response in PDAC. Similarly, our understanding of methods to manipulate TLS is an actively developing field of research. TLS may function as anti-tumoral immune niches that can be leveraged as a therapeutic strategy to potentiate both existing chemotherapeutic regimens and potentiate future immune-based therapeutic strategies to improve patient outcomes. This review seeks to cover anatomy, relevant features, immune effects, translational significance, and future directions of understanding TLS within the context of PDAC.

Targeting SNAI1-Mediated Colorectal Cancer Chemoresistance and Stemness by Sphingosine Kinase 2 Inhibition.

Background: Epithelial-to-mesenchymal transition (EMT), cancer stem cells (CSCs), and colorectal cancer (CRC) therapy resistance are closely associated. Prior reports have demonstrated that sphingosine-1-phosphate (S1P) supports stem cells and maintains the CSC phenotype. We hypothesized that the EMT inducer SNAI1 drives S1P signaling to amplify CSC self-renewal capacity and chemoresistance. Methods: CRC cell lines with or without ectopic expression of SNAI1 were used to study the role of S1P signaling as mediators of cancer stemness and 5-fluorouracil (5FU) chemoresistance. The therapeutic ability of sphingosine kinase 2 (SPHK2) was assessed using siRNA and ABC294640, a SPHK2 inhibitor. CSCs were isolated from patient-derived xenografts (PDXs) and assessed for SPHK2 and SNAI1 expression. Results: Ectopic SNAI1 expressing cell lines demonstrated elevated SPHK2 expression and increased SPHK2 promoter activity. SPHK2 inhibition with siRNA or ABC294640 ablated in vitro self-renewal and sensitized cells to 5FU. CSCs isolated from CRC PDXs express increased SPHK2 relative to the non-CSC population. Combination ABC294640/5FU therapy significantly inhibited tumor growth in mice and enhanced 5FU response in therapy-resistant CRC patient-derived tumor organoids (PDTOs). Conclusions: SNAI1/SPHK2 signaling mediates cancer stemness and 5FU resistance, implicating S1P as a therapeutic target for CRC. The S1P inhibitor ABC294640 holds potential as a therapeutic agent to target CSCs in therapy refractory CRC.

MicroRNA-510 promotes cell and tumor growth by targeting peroxiredoxin1 in breast cancer.

INTRODUCTION: MicroRNAs are small non-coding RNAs that are involved in the post-transcriptional negative regulation of mRNAs. MicroRNA 510 (miR-510) was initially shown to have a potential oncogenic role in breast cancer by the observation of its elevated levels in human breast tumor samples when compared to matched non-tumor samples. Few targets have been identified for miR-510. However, as microRNAs function through the negative regulation of their direct targets, the identification of those targets is critical for the understanding of their functional role in breast cancer. METHODS: Breast cancer cell lines were transfected with pre-miR-510 or antisense miR-510 and western blotting and quantitative real time PCR were performed. Functional assays performed included cell growth, migration, invasion, colony formation, cytotoxicity and in vivo tumor growth. We performed a PCR assay to identify novel direct targets of miR-510. The study focused on peroxiredoxin 1 (PRDX1) as it was identified through our screen and was bioinformatically predicted to contain a miR-510 seed site in its 3' untranslated region (3'UTR). Luciferase reporter assays and site-directed mutagenesis were performed to confirm PRDX1 as a direct target. The Student's two-sided, paired t-test was used and a P-value less than 0.05 was considered significant. RESULTS: We show that miR-510 overexpression in non-transformed and breast cancer cells can increase their cell growth, migration, invasion and colony formation in vitro. We also observed increased tumor growth when miR-510 was overexpressed in vivo. We identified PRDX1 through a novel PCR screen and confirmed it as a direct target using luciferase reporter assays. The reintroduction of PRDX1 into breast cancer cell lines without its regulatory 3'UTR confirmed that miR-510 was mediating its migratory phenotype at least in part through the negative regulation of PRDX1. Furthermore, the PI3K/Akt pathway was identified as a positive regulator of miR-510 both in vitro and in vivo. CONCLUSIONS: In this study, we provide evidence to support a role for miR-510 as a novel oncomir. We show that miR-510 directly binds to the 3'UTR of PRDX1 and blocks its protein expression, thereby suppressing migration of human breast cancer cells. Taken together, these data support a pivotal role for miR-510 in breast cancer progression and suggest it as a potential therapeutic target in breast cancer patients.

Pre-treatment inflamed tumor immune microenvironment is associated with FOLFIRINOX response in pancreatic cancer.

Introduction: Pancreatic adenocarcinoma (PDAC) is an aggressive tumor with limited response to both chemotherapy and immunotherapy. Pre-treatment tumor features within the tumor immune microenvironment (TiME) may influence treatment response. We hypothesized that the pre-treatment TiME composition differs between metastatic and primary lesions and would be associated with response to modified FOLFIRINOX (mFFX) or gemcitabine-based (Gem-based) therapy. Methods: Using RNAseq data from a cohort of treatment-naïve, advanced PDAC patients in the COMPASS trial, differential gene expression analysis of key immunomodulatory genes in were analyzed based on multiple parameters including tumor site, response to mFFX, and response to Gem-based treatment. The relative proportions of immune cell infiltration were defined using CIBERSORTx and Dirichlet regression. Results: 145 samples were included in the analysis; 83 received mFFX, 62 received Gem-based therapy. Metastatic liver samples had both increased macrophage (1.2 times more, p < 0.05) and increased eosinophil infiltration (1.4 times more, p < 0.05) compared to primary lesion samples. Further analysis of the specific macrophage phenotypes revealed an increased M2 macrophage fraction in the liver samples. The pre-treatment CD8 T-cell, dendritic cell, and neutrophil infiltration of metastatic samples were associated with therapy response to mFFX (p < 0.05), while mast cell infiltration was associated with response to Gem-based therapy (p < 0.05). Multiple immunoinhibitory genes such as ADORA2A, CSF1R, KDR/VEGFR2, LAG3, PDCD1LG2, and TGFB1 and immunostimulatory genes including C10orf54, CXCL12, and TNFSF14/LIGHT were significantly associated with worse survival in patients who received mFFX (p = 0.01). There were no immunomodulatory genes associated with survival in the Gem-based cohort. Discussion: Our evidence implies that essential differences in the PDAC TiME exist between primary and metastatic tumors and an inflamed pretreatment TiME is associated with mFFX response. Defining components of the PDAC TiME that influence therapy response will provide opportunities for targeted therapeutic strategies that may need to be accounted for in designing personalized therapy to improve outcomes.

Pretreatment Health-Related Quality-of-Life Status and Survival in Pancreatobiliary Surgical Patients.

BACKGROUND: Pancreatobiliary (PB) disorders, especially cancer, negatively affect patients' health-related quality of life (HRQoL). However, the influence of baseline, preintervention HRQoL on perioperative and oncologic outcomes has not been well defined. We hypothesized that low baseline HRQoL is associated with worse perioperative and long-term survival outcomes for PB surgical patients. STUDY DESIGN: Pretreatment Functional Assessment of Cancer Therapy - Hepatobiliary Survey results and clinical data from PB patients (2008 to 2016) from a single center's prospective database were analyzed. Survey responses were aggregated into composite scores and divided into quintiles. Patients in the highest quintile of HRQoL were compared to patients in the bottom four quintiles combined. Overall survival (OS) and disease-free survival (DFS) were analyzed using the Kaplan-Meier method. Logistic and Cox regressions were used to determine associations between quintiles of HRQoL scores and 30-day complications and long-term survival, respectively. RESULTS: Of 162 patients evaluated, 99 had malignancy, and 63 had benign disease. Median follow-up was 31 months. Baseline HRQoL scores were similar for benign and malignant disease (p = 0.42) and were not associated with the development of any (p = 0.08) or major complications (p = 0.64). Patients with highest quintile HRQoL scores had improved 3-year OS (84.6 vs 61.7%, p = 0.03) compared to patients in the lowest four quintiles of HRQoL. Among cancer patients only, those with the highest quintile scores had improved 3-year OS (81.6 vs 47.4%, p = 0.02). On multivariable analysis, highest quintile HRQoL scores were associated with longer OS and DFS for patients with malignancy. CONCLUSIONS: Pretreatment HRQoL was associated with both OS and DFS among PB patients and might have prognostic utility. Future studies are necessary to determine whether patients with poorer HRQoL may benefit from targeted psychosocial interventions.

Novel immunocompetent murine models representing advanced local and metastatic pancreatic cancer.

BACKGROUND: The development of novel therapeutics for pancreatic cancer has been hindered by a lack of relevant preclinical models. The purpose of this study was to evaluate the clinical relevancy of two pancreatic cancer models using standard-of-care therapeutic agent gemcitabine. MATERIALS AND METHODS: Murine Panc02 cells were injected directly into the spleen or pancreas of C57BL/6 mice to respectively create models of metastatic and locally advanced pancreatic cancer. Beginning 7 d post-Panc02 injection, treated mice received 20 mg/kg gemcitabine i.p. every 3 d. Animals were sacrificed when the untreated mice became moribund and tumor/liver weight used to assess tumor burden. RESULTS: Untreated mice became moribund 22 d after pancreatic Panc02 injection. Gross analysis revealed localized pancreatic tumors weighing 1.063 g. Intrasplenic Panc02 injection produced extensive liver metastasis by d 15 when the untreated mice first became moribund. Liver weights at this time averaged 3.6 g compared with the average non-tumor-bearing weight of 1.23 g. Gemcitabine therapy resulted in a 54% decrease in localized pancreatic tumor weight and 62.5% decrease in metastatic liver weight. Additionally, gemcitabine therapy extended animal survival to 20.5 d compared with 18.0 d average for the untreated mice. CONCLUSIONS: We describe two models depicting both locally advanced and metastatic pancreatic cancer in immunocompetent mice. In efforts to establish baseline therapeutic efficacy, we determined that gemcitabine reduces tumor burden in both models and enhances survival in the metastatic model. These clinically relevant models provide valuable tools to evaluate novel therapeutics in pancreatic cancer.

Sociodemographic and Facility-Related Disparities in the Delivery of Guideline-Concordant Therapy Among Patients With Esophageal Adenocarcinoma.

PURPOSE: Evidence on health disparities among patients treated with multimodality therapy protocols is still limited. We aimed to evaluate the associations between patient-level and system-level factors and the receipt of guideline-concordant therapy among patients with esophageal adenocarcinoma (EA). METHODS: This is a national cohort study of patients with stage I-III EA in the National Cancer Database (2006-2018) treated with either upfront resection or neoadjuvant therapy followed by surgery. Clinical and pathologic staging data were used for defining guideline-concordant therapy. Logistic regression models were built to identify independent associations between deviations from treatment guidelines and clinical, sociodemographic, and hospital-related factors. RESULTS: Among 18,803 patients with EA treated at 1,049 hospitals, 4,511 had an endoscopic resection, 4,866 had upfront resection, and 9,426 had neoadjuvant therapy followed by surgery. A total of 16,002 patients (85.1%) received guideline-concordant therapy. Patients who were age 70 years or older (odds ratio [OR] 1.35; 95% CI, 1.14 to 1.60), had a Charlson-Deyo modified score of ≥ 1, and were treated at hospitals with a safety-net burden of ≥ 10% (OR 1.13; 95% CI, 1.02 to 1.25) had higher risk of deviations from guidelines, whereas treatment at high-volume facilities (OR 0.84; 95% CI, 0.74 to 0.95) and diagnosis after 2011 decreased this risk. Relative to cT0-1N0 patients, those with cT2N0 disease had the highest risk of deviations from guideline-concordant therapy (OR 3.76; 95% CI, 3.30 to 4.29). Among patients treated at high-volume facilities, safety-net burden over 10% increased the risk of deviations (OR 1.26; 95% CI, 1.01 to 1.57). CONCLUSION: The delivery of guideline-concordant therapy among patients with EA varies significantly across clinical stage groups and is associated with several sociodemographic disparities. This knowledge should be a resource for future quality improvement strategies intended to address inequitable care within vulnerable populations.

Factors associated with inability to return to intended oncologic treatment in pancreatic cancer.

BACKGROUND: Return to Intended Oncologic Treatment (RIOT) has been proposed as a quality metric in the care of cancer patients. We sought to define factors associated with inability to RIOT in Pancreatic Ductal Adenocarcinoma (PDAC) patients. METHODS: The NCDB was queried for patients who underwent pancreaticoduodenectomy for pathologic stage IB, IIA, or IIB PDAC from 2010 to 2016. Multivariable binary logistic regression models identified factors associated with failure to RIOT, and Kaplan-Meier survival analysis and Cox multivariable regression models demonstrated the impact of failure to RIOT on survival. RESULTS: Increasing age (p < .001), Hispanic race (p = .002), pathological stage IB (p = .004) and IIA (p = .001) as compared to IIB, increasing hospital stay (p < .001), and open surgical approach (p = .024) were associated with increased risk of inability to RIOT. Male sex (p < .001), Charlson-Deyo scores of 0 (p < .001) and 1 (p = .001) as compared to >2, negative surgical margins (p = .048), receiving care at academic institutions (p = .001), and increasing institutional case volume (p = .001) were associated with improved odds of RIOT. CONCLUSIONS: Patient features can impact RIOT and should be considered when designing multi-modality treatment strategies.

Slug expression enhances tumor formation in a noninvasive rectal cancer model.

BACKGROUND: Epithelial-to-mesenchymal transition (EMT) is a series of molecular changes allowing epithelial cancer cells to acquire properties of mesenchymal cells: increased motility, invasion, and protection from apoptosis. Transcriptional regulators such as Slug mediate EMT, working in part to repress E-cadherin transcription. We report a novel, noninvasive in vivo rectal cancer model to explore the role of Slug in colorectal cancer (CRC) tumor development. METHODS: For the generation of DLD-1 cells overexpressing Slug (Slug DLD-1), a Slug or empty (Empty DLD-1) pCMV-3Tag-1 (kanamycin-resistant) vector was used for transfection. Cells were evaluated for Slug and E-cadherin expression, and cell migration and invasion. For the in vivo study, colon cancer cells (parental DLD-1, Slug DLD-1, empty DLD-1, and HCT-116) were submucosally injected into the posterior rectum of nude mice using endoscopic guidance. After 28 d, tumors were harvested and tissue was analyzed. RESULTS: Slug expression in our panel of colon cancer cell lines was inversely correlated with E-cadherin expression and enhanced migration/invasion. Slug DLD-1 cells demonstrated a 21-fold increased Slug and 19-fold decreased E-cadherin expression compared with empty DLD-1. Similarly, the Slug DLD-1 cells had significantly enhanced cellular migration and invasion. In the orthotopic rectal cancer model, Slug DLD-1 cells formed rectal tumors in 9/10 (90%) of the mice (mean volume = 458 mm(3)) compared with only 1/10 (10%) with empty DLD-1 cells. CONCLUSION: Slug mediates EMT with enhanced in vivo rectal tumor formation. Our noninvasive in vivo model enables researchers to explore the molecular consequences of altered genes in a clinically relevant rectal cancer in an effort to develop novel therapeutic approaches for patients with rectal cancer.

Differential immune signatures in the tumor microenvironment are associated with colon cancer racial disparities.

BACKGROUND: Disparities in colon cancer (CC) outcomes may be due to a more aggressive phenotype in African American patients in the setting of a decreased tumor immunity, though the precise mechanism for this result has not been well elucidated. To explore the molecular factors underlying CC disparities, we compared the immunogenomic signatures of CC from African American and European American patients. METHODS: We identified all CC patients from the publicly available Cancer Genome Atlas for whom race and survival data are available. Immunophenotype signatures were established for African American and European American patients. Comparisons were made regarding survival and a multivariable linear regression model was created to determine the association of immune cellular components with race. Differential gene expression was also assessed. RESULTS: Of the 254 patients identified, 58 (23%) were African American and 196 (77%) were European American. African American patients had a decreased progression free survival (p = 0.04). Tumors from African American patients displayed a reduced fraction of macrophages and CD8+ T cells and an increased fraction of B cells compared with tumors from European Americans. Differences persisted when controlling for sex, age, and disease stage. Immunostimulatory and immunoinhibitory gene profiles including major histocompatibility complex expression differed by race. CONCLUSIONS: Differences in the tumor immune microenvironment of African American as compared to European American CC specimens may play a role in the survival differences between the groups. These differences may provide targeted therapeutic opportunities.

Preinvasive Colorectal Lesions of African Americans Display an Immunosuppressive Signature Compared to Caucasian Americans.

BACKGROUND: African Americans (AAs) have higher colorectal cancer (CRC) incidence and mortality rate than Caucasian Americans (CAs). Recent studies suggest that immune responses within CRCs contribute to the disparities. If racially distinct immune signatures are present in the early phases of carcinogenesis, they could be used to develop interventions to prevent or slow disease. METHODS: We selected a convenience sample of 95 patients (48 CAs, 47 AAs) with preinvasive colorectal adenomas from the surgical pathology laboratory at the Medical University of South Carolina. Using immunofluorescent-conjugated antibodies on tissue slides from the lesions, we quantified specific immune cell populations: mast cells (CD117+), Th17 cells (CD4+RORC+), and NK cell ligand (MICA/B) and inflammatory cytokines, including IL-6, IL-17A, and IFN-γ. We compared the mean density counts (MDCs) and density rate ratios (RR) and 95% CI of immune markers between AAs to CAs using negative binomial regression analysis. We adjusted our models for age, sex, clinicopathologic characteristics (histology, location, dysplasia), and batch. RESULTS: We observed no racial differences in age or sex at the baseline endoscopic exam. AAs compared to CAs had a higher prevalence of proximal adenomas (66% vs. 40%) and a lower prevalence of rectal adenomas (11% vs. 23%) (p =0.04) but no other differences in pathologic characteristics. In age, sex, and batch adjusted models, AAs vs. CAs had lower RRs for cells labeled with IFNγ (RR 0.50 (95% CI 0.32-0.81); p=0.004) and NK cell ligand (RR 0.67 (0.43-1.04); p=0.07). In models adjusted for age, sex, and clinicopathologic variables, AAs had reduced RRs relative to CAs for CD4 (p=0.02), NK cell ligands (p=0.01), Th17 (p=0.005), mast cells (p=0.04) and IFN-γ (p< 0.0001). CONCLUSIONS: Overall, the lower RRs in AAs vs. CAs suggests reduced effector response capacity and an immunosuppressive ('cold') tumor environment. Our results also highlight the importance of colonic location of adenoma in influencing these differences; the reduced immune responses in AAs relative to CAs may indicate impaired immune surveillance in early carcinogenesis. Future studies are needed to understand the role of risk factors (such as obesity) in influencing differences in immune responses by race.