Jula Veerapong

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.

Resveratrol is an effective inducer of CArG-driven TNF-alpha gene therapy.

We report the anticarcinogenic, anti-aging polyphenol resveratrol activates the radio- and chemo-inducible cancer gene therapy vector Ad.Egr.TNF, a replication-deficient adenovirus that expresses human tumor necrosis factor α (TNF-α) under control of the Egr-1 promoter. Like ionizing radiation or chemotherapeutic agents previously shown to activate Ad.Egr.TNF, resveratrol also induces Egr-1 expression from its chromosomal locus with a possible role for Egr-1 promoter CC(A+T)richGG sequences in the expression of TNF-α. Resveratrol induction of TNF-α in Ad.Egr.TNF-infected tumor xenografts demonstrated antitumor response in human and rat tumor models comparable to that of radio- or chemotherapy-induced TNF-α. Although sirtuins are known targets of resveratrol, in vitro inhibition of SIRT1 activity did not abrogate resveratrol induction of Egr-1 expression. This suggests that SIRT1 is not essential to mediate resveratrol induction of Egr-1. Nevertheless, control of transgene expression via resveratrol activation of Egr-1 may extend use of Ad.Egr.TNF to patients intolerant of radiation or cytotoxic therapy and offer a novel tool for development of other inducible gene therapies.

Systemic Delivery of γ134.5-Deleted Herpes Simplex Virus-1 Selectively Targets and Treats Distant Human Xenograft Tumors That Express High MEK Activity

Deltagamma(1)34.5 mutant herpes simplex type 1 viruses are under active clinical investigation as oncolytic therapy for cancer. Mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) activity has been shown to suppress protein kinase R and thereby confer oncolytic susceptibility to some human tumors by R3616, a virus deleted for both copies of gamma(1)34.5. We report that systemic delivery of R3616 can selectively target and destroy human xenograft tumors that overexpress MEK activity compared with tumors that express lower MEK activity. These results suggest systemic delivery of R3616 may be effective in the treatment of some human tumors.

Adenovirally Delivered Tumor Necrosis Factor-A Improves the Antiglioma Efficacy of Concomitant Radiation and Temozolomide Therapy

Purpose: Treatment of malignant glioma involves concomitant temozolomide and ionizing radiation (IR). Nevertheless, overall patient survival remains poor. This study was designed to evaluate if addition of Ad.Egr–tumor necrosis factor (TNF), a replication defective adenovector encoding a cDNA for TNF-α, to temozolomide and IR can improve overall antiglioma effect. Experimental Design: The efficacy of combination treatment with Ad.Egr-TNF, IR, and temozolomide was assessed in two glioma xenograft models. Animal toxicity and brain histopathology after treatment were also examined. In addition, in an attempt to explain the antitumor interaction between these treatments, the activation status of the transcription factor nuclear factor-κB was examined. Results: Triple therapy (Ad.Egr-TNF, IR, and temozolomide) leads to significantly increased survival in mice bearing glioma xenografts compared with dual treatment. Fifty percent of animals treated with the triple regimen survive for >130 days. Pathologic examination shows that triple therapy leads to a complete response with formation of a collagenous scar. No significant change in myelination pattern is noted after triple therapy, compared with any double treatment. Treatment of intracranial glioma bearing mice with Ad.Egr-TNF and IR leads to cachexia and poor feeding that does not improve, whereas triple therapy results in less toxicity, which improves over 21 days. Both Ad.Egr-TNF and IR activate nuclear factor-κB, and temozolomide inhibits this activity in an inhibitor of κBα (IκBα)–independent manner. Conclusion: This work shows that the addition of adenoviral TNF-α gene delivery to temozolomide and IR significantly improves antiglioma efficacy and illustrates a potential new treatment regimen for use in patients with malignant glioma.

Metaplastic breast cancer: histologic characteristics, prognostic factors and systemic treatment strategies.

Metaplastic breast cancer (MBC) is a rare subtype of invasive breast cancer that tends to have an aggressive clinical presentation as well as a variety of distinct histologic designations. Few systemic treatment options are available for MBC, as it has consistently shown a suboptimal response to standard chemotherapy regimens. These characteristics result in a worse overall prognosis for patients with MBC compared to those with standard invasive breast cancer. Due to its rarity, data focusing on MBC is limited. This review will discuss the clinical presentation, breast imaging findings, histologic and molecular characteristics of MBC as well as potential future research directions.

A Review of Resistance Patterns and Phenotypic Changes in Gastrointestinal Stromal Tumors Following Imatinib Mesylate Therapy

Gastrointestinal stromal tumors are neoplastic lesions that arise from the interstitial cells of Cajal and are associated with somatic mutations in the tyrosine kinase receptor, KIT. The only known curative therapy is complete surgical resection. Unfortunately, postsurgical recurrence rates exceed 50% and most tumors are resistant to standard chemotherapy and radiation. Imatinib mesylate, a novel tyrosine kinase inhibitor, holds promise as a potential adjuvant therapy to prevent recurrence and improve long-term survival. However, as resistance data emerge, it appears that a potential “escape pathway” may originate from secondary mutations in the KIT receptor. This paper reviews the historical clinical experience with imatinib mesylate and discusses resistance patterns following targeted therapy. We highlight this review with an interesting case report that illustrates unique phenotypic tumoral changes associated with imatinib mesylate resistance.

DNA Mismatch Repair Deficiency in Rectal Cancer: Benchmarking Its Impact on Prognosis, Neoadjuvant Response Prediction, and Clinical Cancer Genetics

PURPOSE DNA mismatch repair deficiency (dMMR) hallmarks consensus molecular subtype 1 of colorectal cancer. It is being routinely tested, but little is known about dMMR rectal cancers. The efficacy of novel treatment strategies cannot be established without benchmarking the outcomes of dMMR rectal cancer with current therapy. We aimed to delineate the impact of dMMR on prognosis, the predicted response to fluoropyrimidine-based neoadjuvant therapy, and implications of germline alterations in the MMR genes in rectal cancer. METHODS Between 1992 and 2012, 62 patients with dMMR rectal cancers underwent multimodality therapy. Oncologic treatment and outcomes as well as clinical genetics work-up were examined. Overall and rectal cancer-specific survival were calculated by the Kaplan-Meier method. RESULTS The median age at diagnosis was 41 years. MMR deficiency was most commonly due to alterations in MSH2 (53%) or MSH6 (23%). After a median follow-up of 6.8 years, the 5-year rectal cancer-specific survival was 100% for stage I and II, 85.1% for stage III, and 60.0% for stage IV disease. Fluoropyrimidine-based neoadjuvant chemoradiation was associated with a complete pathologic response rate of 27.6%. The extent of surgical resection was influenced by synchronous colonic disease at presentation, tumor height, clinical stage, and pelvic radiation. An informed decision for a limited resection focusing on proctectomy did not compromise overall survival. Five of the 11 (45.5%) deaths during follow-up were due to extracolorectal malignancies. CONCLUSION dMMR rectal cancer had excellent prognosis and pathologic response with current multimodality therapy including an individualized surgical treatment plan. Identification of a dMMR rectal cancer should trigger germline testing, followed by lifelong surveillance for both colorectal and extracolorectal malignancies. We herein provide genotype-specific outcome benchmarks for comparison with novel interventions.

Successful Percutaneous Retrieval of an Inferior Vena Cava Filter Migrating to the Right Ventricle in a Bariatric Patient

The use of an inferior vena cava filter has an important role in the management of patients who are at high risk for development of pulmonary embolism. Migration is a rare but known complication of inferior vena cava filter placement. We herein describe a case of a prophylactic retrievable vena cava filter migrating to the right ventricle in a bariatric patient. The filter was retrieved percutaneously by transjugular approach and the patient did well postoperatively. A review of the current literature is given.

Resection of tumor from the supragastric lesser sac with peritonectomy

This 48 yr old lady underwent laparotomy for primary appendiceal carcinoma metastatic within the peritoneal cavity including the lesser omentum (LO) and supragastric lesser sac (Fig. 1). The left triangular ligament was divided allowing retraction of the left lobe of the liver. The stomachwasmanually pulled to stretch out the LO and facilitate resection. The left gastric, common hepatic and left hepatic arteries and the vagal nerves of Latarjet running along the lesser curve of the stomachwere avoided. Tumorwasmobilized frombetween the left liver and anterior caudate lobe and from behind the pont hepatique. Care was taken to avoid damage to a branch of the left hepatic artery running in the roof of the lesser sac. The stomach was elevated and the caudate lobe carefully retracted to expose the posterior surface of the supragastric lesser sac formed by a single layer of peritoneum. This was stripped off and then detached from the caudate lobe. Tumor was then stripped or wiped off the anterior surface of the caudate lobe. Residual visible tumor was ablated. At the end of the procedure there was no visible disease. The patientwas then treatedwith hyperthermic intraperitoneal chemotherapy with mitomycin for 90min. The postoperative course was uncomplicated apart from short-term ileus and urinary retention.

Primary Angiosarcoma of the Pancreas

The pancreas is a glandular organ located in the retroperitoneum composed of an exocrine component, which includes acini and ducts and an endocrine component, the islets of Langerhans. Stroma is scant in a normal pancreas [1]. Pancreatic cancer continues to be one of the deadliest cancers, with only a 6 % 5-year survival rate [2]. The most common primary neoplasms of the pancreas are ductal adenocarcinomas, which comprise 85 % of all pancreatic tumors [1]. Mesenchymal tumors are neoplasms of mesoderm-derived connective tissue (stroma) and can be benign or malignant. Primary mesenchymal tumors of the pancreas are rare with only 221 cases reported in the English literature to date [3]. Of these, only 76 are primary malignant mesenchymal tumors (sarcomas) [3–5]. The most frequently reported sarcomas of the pancreas are leiomyosarcomas and Ewing sarcoma/ primitive neuroectodermal tumor (PNET) [6]. Angiosarcomas (AS) are highly malignant neoplasms with endothelial cell differentiation that arise from blood or lymphatic vessels. AS represent 1% of all soft tissue sarcomas [7], which in turn represent 1 % of all adult solid malignancies [8]. AS can arise from any site on the body, most commonly from the cutaneous tissue of the breast and scalp [9]. So far, only three cases of primary angiosarcoma of the pancreas have been reported in the literature [4, 10, 11]. Herein, we report the fourth case of primary angiosarcoma of the pancreas.