James J. Mezhir

Progression of Barrett's Metaplasia to Adenocarcinoma Is Associated with the Suppression of the Transcriptional Programs of Epidermal Differentiation

We did expressional profiling on 24 paired samples of normal esophageal epithelium, Barretts metaplasia, and esophageal adenocarcinomas. Matching tissue samples representing the three different histologic types were obtained from each patient undergoing esophagectomy for adenocarcinoma. Our analysis compared the molecular changes accompanying the transformation of normal squamous epithelium with Barretts esophagus and adenocarcinoma in individual patients rather than in a random cohort. We tested the hypothesis that expressional profiling may reveal gene sets that can be used as molecular markers of progression from normal esophageal epithelium to Barretts esophagus and adenocarcinoma. Expressional profiling was done using U133A GeneChip (Affymetrix), which represent approximately two thirds of the human genome. The final selection of 214 genes permitted the discrimination of differential gene expression of normal esophageal squamous epithelium, Barretts esophagus, and adenocarcinoma using two-dimensional hierarchical clustering of selected genes. These data indicate that transformation of Barretts esophagus to adenocarcinoma is associated with suppression of the genes involved in epidermal differentiation, including genes in 1q21 loci and corresponding to the epidermal differentiation complex. Correlation analysis of genes concordantly expressed in Barretts esophagus and adenocarcinoma revealed 21 genes that represent potential genetic markers of disease progression and pharmacologic targets for treatment intervention. PCR analysis of genes selected based on DNA array experiments revealed that estimation of the ratios of GATA6 to SPRR3 allows discrimination among normal esophageal epithelium, Barretts dysplasia, and adenocarcinoma.

Sarcopenia is an independent predictor of complications following pancreatectomy for adenocarcinoma

Sarcopenia, which is subclinical loss of skeletal muscle mass, is commonly observed in patients with malignancy. The objective of this study is to determine the correlation between sarcopenia and operative complications following pancreatectomy for cancer.

Activated MEK Suppresses Activation of PKR and Enables Efficient Replication and In Vivo Oncolysis by Δγ134.5 Mutants of Herpes Simplex Virus 1

ABSTRACT Herpes simplex virus mutants lacking the γ134.5 gene are not destructive to normal tissues but are potent cytolytic agents in human tumor cells in which the activation of double-stranded RNA-dependent protein kinase (PKR) is suppressed. Thus, replication of a Δγ134.5 mutant (R3616) in 12 genetically defined cancer cell lines correlates with suppression of PKR but not with the genotype of RAS. Extensive analyses of two cell lines transduced with either dominant negative MEK (dnMEK) or constitutively active MEK (caMEK) indicated that in R3616 mutant-infected cells dnMEK enabled PKR activation and decreased virus yields, whereas caMEK suppressed PKR and enabled better viral replication and cell destruction in transduced cells in vitro or in mouse xenografts. The results indicate that activated MEK mediates the suppression of PKR and that the status of MEK predicts the ability of Δγ134.5 mutant viruses to replicate in and destroy tumor cells.

A prognostic nomogram for prediction of recurrence in desmoid fibromatosis.

Objective: To construct a postoperative nomogram to estimate the risk of local recurrence for patients with desmoid tumors. Background: The standard management of desmoid tumors is resection, but many recur locally. Other options include observation or novel chemotherapeutics, but little guidance exists on selecting treatment. Methods: Patients undergoing resection during 1982–2011 for primary or locally recurrent desmoids were identified from a single-institution prospective database. Cox regression analysis was used to assess risk factors and to create a recurrence nomogram, which was validated using an international, multi-institutional data set. Results: Desmoids were treated surgically in 495 patients (median follow-up of 60 months). Of 439 patients undergoing complete gross resection, 100 (23%) had recurrence. Five-year local recurrence–free survival was 69%. Eight patients died of disease, all after R2 resection. Adjuvant radiation was not associated with improved local recurrence–free survival. In multivariate analysis, factors associated with recurrence were extremity location, young age, and large tumor size, but not margin. Abdominal wall tumors had the best outcome (5-year local recurrence–free survival rate of 91%). Age, site, and size were used to construct a nomogram with concordance index of 0.703 in internal validation and 0.659 in external validation. Integration of additional variables (R1 margin, sex, depth, and primary vs recurrent presentation) did not importantly improve concordance (internal concordance index of 0.707). Conclusions: A postoperative nomogram including only size, site, and age predicts local recurrence and can aid in counseling patients. Systemic therapies may be appropriate for young patients with large, extremity desmoids, but surgery alone is curative for most abdominal wall lesions.

The impact of sarcopenia on survival and complications in surgical oncology: A review of the current literature

Sarcopenia is the subclinical loss of skeletal muscle and strength and has been extensively studied in both the cancer and surgical literature. Specifically, sarcopenia has gained significant recognition as an important prognostic factor for both complications and survival in cancer patients. Herein, we review the current literature to date highlighting the specific impact of sarcopenia in patients undergoing oncologic procedures. J. Surg. Oncol. 2015; 112:503–509.

Ionizing Radiation Activates Late Herpes Simplex Virus 1 Promoters via the p38 Pathway in Tumors Treated with Oncolytic Viruses

Ionizing radiation potentiates the oncolytic activity of attenuated herpes simplex viruses in tumors exposed to irradiation at specific time intervals by inducing higher virus yields. Cell culture studies have shown that an attenuated virus lacking the viral gamma(1)34.5 genes underproduces late proteins whose synthesis depends on sustained synthesis of viral DNA. Here we report that ionizing radiation enhances gene expression from late viral promoters in transduced cells in the absence of other viral gene products. Consistent with this result, we show that in tumors infected with the attenuated virus, ionizing radiation increases 13.6-fold above baseline the gene expression from a late viral promoter as early as 2 hours after virus infection, an interval too short to account for viral DNA synthesis. The radiation-dependent up-regulation of late viral genes is mediated by the p38 pathway, inasmuch as the enhancement is abolished by p38 inhibitors or a p38 dominant-negative construct. The p38 pathway is not essential for wild-type virus gene expression. The results suggest that ionizing radiation up-regulates late promoters active in the course of viral DNA synthesis and provide a rationale for use of radiation to up-regulate cytotoxic genes introduced into tumor cells by viral vectors for cytoreductive therapy.

Ionizing radiation: a genetic switch for cancer therapy

Gene therapy of cancer represents a promising but challenging area of therapeutic research. The discovery of radiation-inducible genes led to the concept and development of radiation-targeted gene therapy. In this approach, promoters of radiation-inducible genes are used to drive transcription of transgenes in the response to radiation. Constructs in which the radiation-inducible promoter elements activate a transgene encoding a cytotoxic protein are delivered to tumors by adenoviral vectors. The tumoricidal effects are then localized temporally and spatially by X-rays. We review the conceptual development of TNFerade™, an adenoviral vector containing radiation-inducible elements of the early growth response-1 promoter upstream of a cDNA encoding human tumor necrosis factor-α. We also summarize the preclinical work and clinical trials utilizing this vector as a treatment for diverse solid tumors.

Pharmacological Ascorbate Radiosensitizes Pancreatic Cancer

The toxicity of pharmacologic ascorbate is mediated by the generation of H2O2 via the oxidation of ascorbate. Because pancreatic cancer cells are sensitive to H2O2 generated by ascorbate, they would also be expected to become sensitized to agents that increase oxidative damage such as ionizing radiation. The current study demonstrates that pharmacologic ascorbate enhances the cytotoxic effects of ionizing radiation as seen by decreased cell viability and clonogenic survival in all pancreatic cancer cell lines examined, but not in nontumorigenic pancreatic ductal epithelial cells. Ascorbate radiosensitization was associated with an increase in oxidative stress-induced DNA damage, which was reversed by catalase. In mice with established heterotopic and orthotopic pancreatic tumor xenografts, pharmacologic ascorbate combined with ionizing radiation decreased tumor growth and increased survival, without damaging the gastrointestinal tract or increasing systemic changes in parameters indicative of oxidative stress. Our results demonstrate the potential clinical utility of pharmacologic ascorbate as a radiosensitizer in the treatment of pancreatic cancer.

The critical role of peritoneal cytology in the staging of gastric cancer: An evidence-based review

Positive peritoneal cytology (Cyt+) is an important staging tool for patients with locally advanced gastric cancer. The objective of this review is to evaluate the current literature regarding cytology evaluation in patients with gastric cancer and to provide recommendations on the inclusion of this powerful prognosticator in patients with this disease. A literature search was performed for recent and pertinent studies evaluating peritoneal cytology in patients with gastric adenocarcinoma. Peritoneal cytology as the only evidence for M1 disease is present in up to 10% of patients with locally advanced gastric cancer; survival in the setting of Cyt+ is dismal when gastrectomy is the first line of therapy. Improved survival is associated with response to chemotherapy indicated by conversion to negative cytology, good performance status, and antral tumors. Highly select patients with Cyt+ treated with gastrectomy show improved survival in only some of the available studies. There are high quality studies that support the routine practice of peritoneal cytology evaluation in patients with locally advanced gastric cancer. The role of gastrectomy remains unclear in patients with Cyt+ and clinical trials are needed to define the best treatment option for this select group of patients. J. Surg. Oncol. 2014 110:291–297.

Loss of SOD3 (EcSOD) Expression Promotes an Aggressive Phenotype in Human Pancreatic Ductal Adenocarcinoma

Purpose: Pancreatic ductal adenocarcinoma (PDA) cells are known to produce excessive amounts of reactive oxygen species (ROS), particularly superoxide, which may contribute to the aggressive and refractory nature of this disease. Extracellular superoxide dismutase (EcSOD) is an antioxidant enzyme that catalyzes the dismutation of superoxide in the extracellular environment. This study tests the hypothesis that EcSOD modulates PDA growth and invasion by modifying the redox balance in PDA. Experimental Design: We evaluated the prognostic significance of EcSOD in a human tissue microarray (TMA) of patients with PDA. EcSOD overexpression was performed in PDA cell lines and animal models of disease. The impact of EcSOD on PDA cell lines was evaluated with Matrigel invasion in combination with a superoxide-specific SOD mimic and a nitric oxide synthase (NOS) inhibitor to determine the mechanism of action of EcSOD in PDA. Results: Loss of EcSOD expression is a common event in PDA, which correlated with worse disease biology. Overexpression of EcSOD in PDA cell lines resulted in decreased invasiveness that appeared to be related to reactions of superoxide with nitric oxide. Pancreatic cancer xenografts overexpressing EcSOD also demonstrated slower growth and peritoneal metastasis. Overexpression of EcSOD or treatment with a superoxide-specific SOD mimic caused significant decreases in PDA cell invasive capacity. Conclusions: These results support the hypothesis that loss of EcSOD leads to increased reactions of superoxide with nitric oxide, which contributes to the invasive phenotype. These results allow for the speculation that superoxide dismutase mimetics might inhibit PDA progression in human clinical disease. Clin Cancer Res; 21(7); 1741–51. ©2015 AACR.