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Biomedical subjects

John T Mullen

Publications and source records attributed to John T Mullen.

14 recordsLinked to original sources
PubMed2006

Results of surgical salvage after failed chemoradiation therapy for epidermoid carcinoma of the anal canal.

BACKGROUND: The standard treatment for epidermoid carcinoma of the anal canal consists of combined radiation and chemotherapy. For patients who present with persistent or locally recurrent disease, salvage abdominoperineal resection is the treatment of choice. The purpose of this study is to review our experience with salvage surgery in this group of patients. METHODS: From 1990-2002, 31 patients underwent radical salvage surgery with curative intent after failure of initial sphincter-conserving therapy, and the medical records of these patients were retrospectively reviewed. Clinicopathologic variables were determined and comparisons performed with the Cox proportional hazards model. Survival was calculated by the Kaplan-Meier method. RESULTS: Eleven patients underwent radical salvage surgery for persistent disease and 20 patients for recurrent disease. The median follow-up time was 29 months. The actuarial 5-year overall survival was 64%. Twelve patients developed recurrent disease after radical salvage surgery. Patients who received an initial radiation dose of less than 55 Gy had a significantly worse survival than those who received at least 55 Gy as part of their initial treatment (5-year overall survival 37.5% vs. 75%; age-adjusted hazard ratio 8.2 [95% CI: 1.1-59.8], P = .037). The presence of positive lymph nodes at presentation also adversely affected survival (P < .05). Factors that were not found to have an impact on survival included the presence of persistent versus recurrent disease, tumor (T) stage, and margin status of resection. CONCLUSIONS: Long-term survival following salvage surgery for persistent or locally recurrent epidermoid carcinoma of the anal canal can be achieved in the majority of patients. However, patients who initially present with node-positive disease and patients who receive a radiation dose of less than 55 Gy as part of their initial chemoradiation therapy regimen have a worse prognosis after radical salvage surgery.

Adult↗
PubMed2006

Invasive squamous cell carcinoma of the skin: defining a high-risk group.

BACKGROUND: Unlike its more common non-invasive form, invasive squamous cell carcinoma (SCC) of the skin can be biologically aggressive and is prone to recur. The objectives of this study were to identify relevant clinicopathologic prognostic factors associated with the outcomes of patients with invasive SCC in order to define a high-risk group. METHODS: We retrospectively reviewed the records of patients with invasive cutaneous SCC of the trunk or extremities who received surgical treatment at a tertiary care cancer center over the past 10 years. We examined the patterns of presentation, all known clinical and histological risk factors for recurrence, and their association with survival. RESULTS: 136 patients were identified, of whom 102 (74%) were male. Patterns of presentation included primary (n = 91), locally recurrent (n = 16), regional nodal (n = 24), and distant (n = 5) disease. Univariate analysis identified poorly differentiated carcinomas (hazard ratio [HR] = 2.92, P = .016), scar carcinomas (HR = 3.12, P = .008), tumor size > 2 cm (HR = 3.79, P = .006), and regional nodal disease (HR = 5.77, P < .0001) as significant risk factors for recurrence or death. On multivariate analysis, however, only regional nodal disease at presentation (HR = 7.64, P < .0001) was found to be significant. CONCLUSIONS: Patients with invasive SCCs metastatic to regional nodes constitute a group at high risk for recurrence and death. Such patients should be considered for adjuvant therapy trials.

Adult↗
PubMed2006

Comparison between hepatic wedge resection and anatomic resection for colorectal liver metastases.

Some investigators have suggested that wedge resection (WR) confers a higher incidence of positive margins and an inferior survival compared with anatomic resection (AR) of colorectal liver metastases (CLM). We sought to investigate the margin status, pattern of recurrence, and overall survival of patients with CLM treated with WR or AR. We identified 253 consecutive patients, in a multi-institutional database from 1991 to 2004, who underwent either WR or AR. WR was defined as a nonanatomic resection of the CLM, and AR was defined as single or multiple resections of one or two contiguous Couinaud segments. Clinicopathologic factors were analyzed with regard to pattern of recurrence and survival. One hundred six WRs were performed in 72 patients and 194 ARs in 181 patients. There was no difference in the rate of positive surgical margin (8.3%), overall recurrence rates, or patterns of recurrence between patients treated with WR vs. AR. Patients who had a positive surgical resection margin were more likely to recur at the surgical margin regardless of whether they underwent WR or AR. The median survival was 76.6 months for WR and 80.8 months for AR, with 5-year actuarial survival rates of 61% and 60%, respectively. AR is not superior to WR in terms of tumor clearance, pattern of recurrence, or survival. WR should remain an integral component of the surgical treatment of CLM.

Adult↗
PubMed2005

Pancreaticoduodenectomy after placement of endobiliary metal stents.

Contemporary treatment programs for patients with potentially resectable pancreatic cancer often involve preoperative therapy. When the duration of preoperative therapy exceeds 2 months, the risk of plastic endobiliary stent occlusion increases. Metal stents have much better patency but may complicate subsequent pancreaticoduodenectomy (PD). We evaluated rates of perioperative morbidity, mortality, and stent complications in 272 consecutive patients who underwent PD at our institution from May 2001 to November 2004. Of these 272 patients, 29 (11%) underwent PD after placement of a metal stent, 141 underwent PD after placement of a plastic stent, 10 had PD after biliary bypass without stenting, and 92 had PD without any form of biliary decompression. No differences were found between the Metal Stent group and all other patients in median operative time, intraoperative blood loss, or length of hospital stay. No perioperative deaths occurred in the Metal Stent group versus 3 (1.2%) deaths in the other 243 patients. The incidence of major perioperative complications was similar between the two groups, including the rates of pancreatic fistula, intra-abdominal abscess, and wound infection. Furthermore, there were no differences in the perioperative morbidity or mortality rates between patients who underwent preoperative biliary decompression with a stent of any kind (metal or plastic) and those patients who underwent no biliary decompression at all. Metal stent-related complications occurred in 2 (7%) of 29 patients during a median preoperative interval of 4.1 months; in contrast, 75 (45%) of the 166 patients who had had plastic stents experienced complications, including 98 stent occlusions, during a median preoperative interval of 3.9 months (P < 0.001). We conclude that the use of expandable metal stents does not increase PD-associated perioperative morbidity or mortality, and as such an expandable metal stent is our preferred method of biliary decompression in patients with symptomatic malignant distal bile duct obstruction in whom surgery is not anticipated, or in whom there is a significant delay in the time to surgery.

Adult↗
PubMed2005

Carcinoid tumors of the duodenum.

BACKGROUND: Carcinoid tumors of the duodenum are rare, and their natural history has not been defined. Consequently, there is no consensus on the optimal extent of surgical treatment. METHODS: The authors reviewed the records of all patients with primary carcinoid tumors of the duodenum treated at their institution from 1969 through 2004. Patients with primary periampullary tumors and gastrinomas were excluded. RESULTS: Twenty-four patients had a pathologic diagnosis of duodenal carcinoid tumor. The majority (89%) of tumors measured less than 2 cm in diameter, and most (85%) were limited to the mucosa or submucosa. Lymph node metastases were identified in the surgical specimen in 7 (54%) of 13 patients in whom lymph nodes were examined, including 2 patients with tumors smaller than 1 cm and limited to the submucosa. At a mean follow-up of 46 months, the disease-specific survival rate was 100%, and only 2 patients have had recurrences in regional lymph nodes. No patient has had distant metastases or the carcinoid syndrome. CONCLUSIONS: Carcinoid tumors of the duodenum are indolent. The presence of regional lymph node metastases cannot be predicted reliably on the basis of tumor size or depth of invasion, and their impact on survival is uncertain.

Adult↗
PubMed2004

Oncolysis by viral replication and inhibition of angiogenesis by a replication-conditional herpes simplex virus that expresses mouse endostatin.

BACKGROUND: In preclinical models, infection of tumors by oncolytic strains of herpes simplex virus 1 (HSV-1) resulted in the destruction of tumor cells by viral replication and release of progeny virion that infected and destroyed adjacent tumor cells. However, complete tumor regression was rarely observed. METHODS: To augment the antitumor effect of viral oncolysis, a replication conditional HSV-1 mutant (HSV-Endo) was constructed in which the murine endostatin gene was incorporated into the HSV-1 genome. RESULTS: Replication of HSV-Endo effectively destroyed several colon carcinoma cell lines in vitro. Secretion of endostatin by HSV-Endo-infected HT29 human colon carcinoma cells was confirmed by Western blot analysis. The secreted endostatin was biologically active as assessed in a chick chorioallantoic membrane assay. Importantly, endostatin production at the site of viral replication did not inhibit viral replication. Direct injection of HSV-Endo into flank tumors caused tumor destruction, and some of the HSV-Endo-treated flank tumors completely sloughed. Immunohistochemical staining of the tumors revealed a decreased number of blood vessels in the HSV-Endo-treated group versus the control group. CONCLUSIONS: The oncolytic HSV-1 mutant HSV-Endo provided a two-pronged therapy; namely, inhibition of angiogenesis and direct tumor cell destruction by viral replication.

Allantois↗
PubMed2004

Selectivity of an oncolytic herpes simplex virus for cells expressing the DF3/MUC1 antigen.

Replication-conditional viruses destroy tumors in a process referred to as viral oncolysis. An important prerequisite for this cancer therapy strategy is use of viruses that replicate preferentially in neoplastic cells. In this study the DF3/MUC1 promoter/enhancer sequence is used to regulate expression of gamma(1)34.5 to drive replication of a Herpes simplex virus 1 (HSV-1) mutant (DF3gamma34.5) preferentially in DF3/MUC1-positive cells. HSV-1 gamma(1)34.5 functions to dephosphorylate elongation initiation factor 2alpha, which is an important step for robust HSV-1 replication. After DF3gamma34.5 infection of cells, elongation initiation factor 2alpha phosphatase activity and viral replication were observed preferentially in DF3/MUC1-positive cells but not in DF3/MUC1-negative cells. Regulation of gamma(1)34.5 function results in preferential replication in cancer cells that express DF3/MUC1, restricted biodistribution in vivo, and less toxicity as assessed by LD(50). Preferential replication of DF3gamma34.5 was observed in DF3/MUC1-positive liver tumors after intravascular perfusion of human liver specimens. DF3gamma34.5 was effective against carcinoma xenografts in nude mice. Regulation of gamma(1)34.5 by the DF3/MUC1 promoter is a promising strategy for development of HSV-1 mutants for viral oncolysis.

Animals↗
PubMed2003

Viral oncolysis for malignant liver tumors.

Viral oncolysis represents a unique strategy to exploit the natural process of viral replication to kill tumor cells. Although this concept dates back nearly a century, recent advances in the fields of molecular biology and virology have enabled investigators to genetically engineer viruses with greater potency and tumor specificity. In this article we review the general mechanisms by which oncolytic viruses achieve their antineoplastic efficacy and specificity. We focus on the development of several classes of oncolytic viruses for the treatment of malignant liver tumors, including adenoviruses, vaccinia viruses, and herpes simplex viruses, and discuss the results of clinical trials for these viruses. We also describe results from our laboratory research program, which is focused on developing effective, liver tumor-specific Herpes simplex virus 1 mutants.

Adenoviridae↗
PubMed2002

Prodrug bioactivation and oncolysis of diffuse liver metastases by a herpes simplex virus 1 mutant that expresses the CYP2B1 transgene.

BACKGROUND: Herpes simplex virus 1 (HSV-1) infection of cancer cells results in viral replication with cell destruction and liberation of progeny virion that infect adjacent tumor cells. rRp450 is a novel replication-conditional HSV-1 mutant that expresses both the endogenous herpes viral thymidine kinase gene and the rat p450 CYP2B1 transgene; p450 bioactivates such cancer prodrugs as cyclophosphamide. METHODS: Viral cytotoxicity and replication assays were performed in colon carcinoma cells as well as primary human hepatocytes. For in vivo studies, diffuse liver metastases were generated by inoculating MC26 cells into the portal system of BALB/c mice. Mice were treated with control media, rRp450, or rRp450 plus cyclophosphamide. RESULTS: Cytopathic effects induced by rRp450 replication in colon carcinoma cells were equivalent to those induced by wild type HSV-1 in vitro. Assays developed to separate cytotoxicity mediated by viral replication from cytotoxicity mediated by chemotherapy confirmed that HSV-1 thymidine kinase bioactivates ganciclovir and CYP2B1 bioactivates cyclophosphamide in rRp450-infected cells. rRp450 mediated cytotoxicity in the presence of cyclophosphamide was increased by 21% to 30% above that achieved by viral replication alone. Cyclophosphamide bioactivation produced bystander killing of colon carcinoma cells but not hepatocytes. In contrast to these effects of cyclophosphamide, rRp450 mediated cytotoxicity was reduced in the presence of ganciclovir. These findings are explained by further experiments showing that bioactivation of cyclophosphamide only minimally affected HSV-1 replication in colon carcinoma cells, whereas bioactivation of ganciclovir markedly attenuated HSV-1 replication. In vivo studies revealed a substantial decrease in hepatic tumor burden in all rRp450-treated animals compared to controls. The addition of cyclophosphamide augmented rRp450's in vivo anti-neoplastic effect. CONCLUSIONS: The rRp450 mutant HSV-1 is highly oncolytic against colon carcinoma cells both in vitro and in vivo. rRp450 displays preferential replication in colon carcinoma cells compared to normal hepatocytes. Activation of cyclophosphamide by the p450 transgene augmented the anti-neoplastic effects of rRp450 without simultaneously decreasing viral replication. Oncolysis induced by HSV-1 replication combined with cyclophosphamide prodrug activation warrants further investigation as a potential therapy for colon carcinoma liver metastases.

Antineoplastic Agents, Alkylating↗
PubMed2002

Viral oncolysis.

Although the concept of using viruses as antineoplastic agents dates back nearly a century, recent advances in the fields of molecular biology, genetics, and virology have enabled investigators to engineer viruses with greater potency and tumor specificity. Further enhancements involve arming these viruses with therapeutic transgenes, and combining the traditional modalities of chemotherapy and radiation therapy with oncolytic viral therapy in hopes of reducing the chance of developing resistant tumor cell clones. Another means of augmenting the antineoplastic effect of these viruses involves modulating the immune response to minimize antiviral immunity, while at the same time maximizing antitumor immunity. A better understanding of mechanisms that viruses use to overcome cellular defenses to achieve robust replication within the cell will lead to development of oncolytic viruses with better tumor specificity and reduced toxicity. Initial clinical studies have shown that oncolytic viral therapy for metastatic disease is safe and well tolerated. In addition, using similar genetic modification strategies, these viruses have demonstrated antineoplastic effects in humans similar to those seen in preclinical animal models.

Adenoviridae↗
PubMed2002

Regulation of herpes simplex virus 1 replication using tumor-associated promoters.

OBJECTIVE: To investigate use of transcriptional regulatory elements (promoters) for tumor-associated antigens to achieve HSV-1 replication preferentially in cells that overexpress the tumor-associated antigens. SUMMARY BACKGROUND DATA: An important advantage of replicating viruses for cancer therapy is their ability to simultaneously destroy tumor cells by replication and release progeny virion to infect and destroy adjacent cancer cells. This strategy requires regulation of the viral life cycle to obtain robust replication in neoplastic cells and minimize replication in nonneoplastic cells. METHODS: Promoters for the human carcinoembryonic antigen (CEA) and MUC1/DF3 tumor-associated antigens were characterized and cloned into HSV-1 mutants as heterologous promoters regulating expression of two different HSV-1 genes. Viral replication in tumor cells and cytotoxicity was quantified with in vitro assays. Antineoplastic efficacy was characterized in a flank tumor xenograft model. RESULTS: Several CEA promoters were cloned and characterized using luciferase reporter assays. The most specific promoter was used to construct and isolate two different HSV-1 mutants in which critical genes are regulated by this promoter (ICP4 and gamma(1) 34.5). Similarly, the promoter for the DF3/MUC1 tumor-associated antigen was cloned into a third HSV-1 mutant such that it regulates expression of gamma(1) 34.5. Regulation of ICP4 expression by the CEA promoter during HSV-1 infection overly attenuates viral replication. Regulation of gamma(1) 34.5 expression by either the CEA promoter or the MUC1/DF3 promoter during HSV-1 infection modulates viral replication, with preferential replication in cells that overexpress the corresponding tumor-associated antigen. A single intratumoral inoculation of an HSV-1 mutant with the MUC1/DF3 promoter regulating gamma(1) 34.5 expression results in significant antineoplastic activity in MUC1-positive pancreatic carcinoma xenografts as compared to mock inoculation. CONCLUSIONS: Promoters for tumor-associated antigens may be incorporated into the HSV-1 genome to regulate HSV-1 replication. The choices of HSV-1 gene and tumor-associated promoter are important determinants of success of this strategy. Because of its preferential replication in MUC1-positive tumors, an HSV-1 mutant with the MUC1/DF3 promoter regulating gamma(1) 34.5 expression will undergo further examination as a novel cancer therapy agent.

Animals↗
PubMed2002

Regulation of herpes simplex virus gamma(1)34.5 expression and oncolysis of diffuse liver metastases by Myb34.5.

Myb34.5 is a herpes simplex virus 1 (HSV-1) mutant deleted in the gene for ribonucleotide reductase (ICP6). It also carries a version of gamma(1)34.5 (a viral gene product that promotes the dephosphorylation of eIF-2alpha) that is under control of the E2F-responsive cellular B-myb promoter, rather than of its endogenous promoter. Myb34.5 replication in tumor cells results in their destruction (oncolysis). gamma(1)34.5 expression by HSV-1 subverts an important cell defense mechanism against viral replication by preventing shutoff of protein synthesis after viral infection. Infection of colon carcinoma cells with Myb34.5 results in greater eIF-2alpha dephosphorylation and viral replication compared with infection with HSV-1 mutants completely defective in gamma(1)34.5 expression. In contrast, infection of normal hepatocytes with Myb34.5 results in low levels of eIF-2alpha dephosphorylation and viral replication that are similar to those observed with HSV-1 mutants completely defective in gamma(1)34.5 and ICP6. When administered intravascularly into mice with diffuse liver metastases, Myb34.5 has greater antineoplastic activity than HSV-1 mutants with completely defective gamma(1)34.5 expression and more restricted biodistribution compared with HSV-1 mutants with wild-type gamma(1)34.5 expression. Myb34.5 displays reduced virulence and toxicity compared to HSV-1 mutants with wild-type gamma(1)34.5 expression. Portal venous administration of Myb34.5 significantly reduces liver tumor burden in and prolongs the life of mice with diffuse liver metastases. Preexisting Ab's to HSV-1 do not reduce the antitumor efficacy of Myb34.5 in vivo.

Animals↗
PubMed2002

Viral oncolysis.

The concept of using replicating viruses as anticancer agents is not a new one, but the ability to genetically modify these viruses into increasingly potent and tumor-specific vectors is a recent phenomenon. As more is learned about the functions of viral gene products in controlling the mammalian cell cycle and in disabling cellular defense mechanisms, specific viral functions can be augmented or eliminated to enhance antineoplastic efficacy. In this article, general mechanisms by which oncolytic viruses achieve their antitumor efficacy and specificity are reviewed. The paradoxical roles of the immune response are addressed with respect to oncolytic viral therapy, as it, on one hand, impedes the spread of viral infection, and on the other, augments tumor cell destruction through the recruitment of T cells "vaccinated" against tumor antigens. The most commonly used oncolytic viruses are each reviewed in turn, including adenoviruses, herpes simplex viruses, vaccinia viruses, reoviruses, and Newcastle disease viruses. Special attention is focused on the unique biology of each of these viruses as well as the status of several of these mutants in clinical trials.

Animals↗