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Biomedical subjects

Mitchell C Posner

Publications and source records attributed to Mitchell C Posner.

At least 19 recordsLinked to original sources
PubMed2006

Establishment of a syngeneic model of hepatic colorectal oligometastases.

BACKGROUND: Regional and systemic therapies aimed at improving the outcome for patients with colorectal hepatic metastases have met with modest yet tangible success. Currently, liver resection remains the only curative treatment, but only a minority of patients are candidates for surgery. Animal models are an ideal way to study new treatments for patients with metastatic colorectal cancer. We propose a syngeneic animal model of hepatic colorectal metastases that simulates oligometastases, which is a clinical state considered amenable to regional therapeutic strategies. MATERIALS AND METHODS: BDIX (BD-9) rats underwent intrasplenic injection of DHD/K12/TRb (Prob/K12) cells to create hepatic metastases via the portal system. After injection of 5 x 10(6) cells, rats underwent laparotomy to determine metastatic burden. Histological analysis confirmed the presence of metastases from resected tumors. RESULTS: Fifty-three animals were prospectively treated and observed for the development of oligometastases defined as between 1 and 10 hepatic lesions. Thirty-six (68%) of the animals developed detectable metastases while 32 (60%) developed oligometastases (average = 4.40 +/- 2.67). Four animals had overwhelming metastatic liver and peritoneal disease. All animals underwent peritoneal examination and thoracotomy to ensure localized disease. Histological analysis of five hepatectomy specimens confirmed the presence of metastatic cancer. Animals with oligometastases were healthy as evidenced by normal feeding and grooming behavior. CONCLUSIONS: An animal model of oligometastatic colorectal cancer to the liver can reproducibly mimic the stage IV state in humans conducive to regional therapy and can be used reliably to test novel treatments and mechanisms of metastatic colorectal cancer.

Animals↗
PubMed2006

Activated MEK suppresses activation of PKR and enables efficient replication and in vivo oncolysis by Deltagamma(1)34.5 mutants of herpes simplex virus 1.

Herpes simplex virus mutants lacking the gamma(1)34.5 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 Deltagamma(1)34.5 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 Deltagamma(1)34.5 mutant viruses to replicate in and destroy tumor cells.

Animals↗
PubMed2005

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.

Animals↗
PubMed2005

Determinants of unresectability and outcome of patients with occult colorectal hepatic metastases.

BACKGROUND: Patients chosen for liver resection of colorectal liver metastases are a select group with minimal disease, favorable tumor biology and earlier presentation when compared to unresectable patients. Despite intense preoperative assessments, operative detection of occult unresectable disease is inevitable for a small group of patients. The aim of this study was to evaluate determinants of occult unresectability, and to establish if patients with occult unresectable disease demonstrate survival benefits similar to resected patients, or more similar to patients diagnosed with metastatic disease who were never explored. METHODS: A retrospective medical record review was performed on 171 patients with colorectal hepatic metastases who underwent exploration with the intent of performing a curative liver resection. Patient and tumor characteristics, operative findings and survival were evaluated. Univariate and multivariate analysis were performed to evaluate determinants of unresectability, and survival was determined by Kaplan-Meier analysis. RESULTS: One hundred forty-six patients were completely resected and 25 patients were found to have occult unresectable disease during exploration. Of these 25 patients, 10 had more extensive hepatic disease than expected which precluded resection, while 15 patients had unexpected extrahepatic disease. Of the 15 patients with extrahepatic disease, 7 had otherwise resectable liver metastases. Only bilobar disease was a statistically significant finding associated with occult unresectability on multivariate analysis (P = 0.05). Resected patients had a median survival of 37 months, while unresected patients had a median survival of 17 months (P < 0.005). At 3 and 5 years, the overall survival for resected patients was 52% and 29%. The survival at 3 years for patients with occult unresectable disease was only 5%, with no 5 year survivors. CONCLUSIONS: The majority of patients with occult unresectable colorectal hepatic metastases had bilobar disease or extrahepatic spread. Despite the process of patient selection that leads to an attempt for curative resection, patients with occult unresectable disease identified at exploration suffer from poor survival that approximates the outcome of patients never considered for resection.

Aged↗
PubMed2005

Forphenicinol enhances the antitumor effects of cyclophosphamide in a model of squamous cell carcinoma.

We examined the interaction between forphenicinol (FPL) and cyclophosphamide (CPA) or ionizing radiation (IR) on the growth of murine squamous cell carcinoma tumors SCCVII. Primary tumors were established in C3H mice by injecting SCCVII tumor cells subcutaneously into the right hind limb. FPL (100 mg/kg for 8 days) and/or CPA (25 mg/kg twice) were administered by intraperitoneal injection. Tumors were irradiated to a total dose of 40 Gy (eight 5-Gy fractions). SCCVII tumor growth was inhibited by FPL (P=0.054), IR (P=0.003) and CPA (P<0.001) compared with control. The combination of FPL and CPA inhibited tumor growth additively compared with either treatment alone in both small- and large-volume tumors. FPL did not significantly enhance the antitumor effects of IR, however, when CPA+FPL were combined with IR, significant tumor growth inhibition was observed compared with FPL alone (P<0.001), CPA alone (P=0.002) and IR alone (P=0.002). Due to its low toxicity profile, FPL may be combined with CPA, IR and other cytotoxic therapies to potentially enhance the therapeutic ratio.

Adjuvants, Immunologic↗
PubMed2005

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, Barrett's 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 Barrett's 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 Barrett's 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, Barrett's esophagus, and adenocarcinoma using two-dimensional hierarchical clustering of selected genes. These data indicate that transformation of Barrett's 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 Barrett's 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, Barrett's dysplasia, and adenocarcinoma.

Adenocarcinoma↗
PubMed2005

Presence of distal intramural spread after preoperative combined-modality therapy for adenocarcinoma of the rectum: what is now the appropriate distal resection margin?

BACKGROUND: Preoperative combined-modality therapy (CMT) is considered the treatment approach of choice for rectal cancer. To examine the effect of CMT on distal intramural spread (DIS), we determined the extent of DIS in rectal cancer specimens after CMT. METHODS: Specimens from 20 patients after preoperative CMT and total mesorectal excision for rectal cancer were analyzed for extent of DIS. Specimens were washed, fixed in formalin, and sectioned in 5-mm cuts from the distal border of the residual tumor to the distal resection margin. RESULTS: Eleven patients (55%) had DIS. Two patients had a complete pathologic response (10%). The mean extent of DIS was 0.50 cm (standard deviation, 0.64 cm; range, 0.0 to 2.5 cm). Only 1 patient in the study had DIS beyond 1 cm from the residual tumor. Six of the patients have died at a median of 30.4 months after operation (range, 19.0 to 51.1 months). No correlation was found between the extent of residual DIS and survival. CONCLUSIONS: Our study shows that the vast majority of patients with rectal cancer after neoadjuvant CMT have no tumor cells beyond 1 cm from the residual tumor. Our data suggest that a 2-cm margin of resection when feasible from the macroscopic tumor margin after neoadjuvant CMT is adequate.

Adenocarcinoma↗
PubMed2005

Chemo-inducible gene therapy.

Chemo-inducible cancer gene therapy is a potential new treatment for solid tumors that may in part enhance the anti-tumor effects of chemotherapy while minimizing toxicity. This approach combines viral vectors expressing cytotoxic transgenes that can be transcriptionally activated by DNA-damaging agents. The development of chemo-inducible gene therapy has numerous implications for the treatment of both localized and metastatic disease in patients with solid tumors.

Antineoplastic Agents↗
PubMed2004

Glioblastoma cells block radiation-induced programmed cell death of endothelial cells.

We demonstrate that human umbilical vein endothelial cells (HUVEC) grown in co-culture (CC) with U87 glioblastoma cells transfected with green fluorescent protein (GFP-U87) exhibit resistance to radiation-mediated apoptosis. cDNA macroarray analysis reveals increases in the accumulation of RNAs for HUVEC genes encoding cell adhesion molecules, growth factor-related proteins, and cell cycle regulatory/DNA repair proteins. An increase in protein expression of integrin alphav, integrin beta1, MAPK(p42), Rad51, DNA-PK(CS), and ataxia telangiectasia gene (ATM) was detected in HUVEC grown in CC with GFP-U87 cells compared with HUVEC grown in mono-culture. Treatment with anti-VEGF antibody decreases the expression of integrin alphav, integrin beta1, DNA-PK(CS) and ATM with a corresponding increase in ionizing radiation (IR)-induced apoptosis. These data support the concept that endothelial cells growing in the tumor microenvironment may develop resistance to cytotoxic therapies due to the up-regulation by tumor cells of endothelial cells genes associated with survival.

Apoptosis↗
PubMed2004

Control of gene therapy by MDR1 and EGR1 promoter sequences in transcriptional targeting by chemotherapy (Review).

The promising benefits of cancer gene therapy have been limited by the inability to deliver therapeutic genes homogeneously throughout the tumor mass and to control gene expression within the tumor cells. Transcriptional targeting, the use of DNA regulatory promoter sequences to localize transgene expression, has been employed as a solution to circumvent these limitations. TNF-alpha is a cytokine that exhibits potent anticancer properties, but its utility following systemic administration is limited by toxicity. We review a strategy whereby ligating TNF-alpha to segments of the chemo-inducible EGR1 or MDR1 promoters activates expression of TNF-alpha cDNA and enhances effectiveness of gene therapy and chemotherapy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

Chemoinducible gene therapy: a strategy to enhance doxorubicin antitumor activity.

A replication-defective adenoviral vector, Ad.Egr-TNF.11D, was engineered by ligating the CArG (CC(A/T)6GG) elements of the Egr-1 gene promoter upstream to a cDNA encoding human tumor necrosis factor-alpha. We report here that Ad.Egr-TNF.11D is activated by the clinically important anticancer agents cisplatin, cyclophosphamide, doxorubicin, 5-fluorouracil, gemcitabine, and paclitaxel. N-acetylcysteine, a free radical scavenger, blocked induction of tumor necrosis factor-alpha by anticancer agents, supporting a role for reactive oxygen intermediates in activation of the CArG sequences. Importantly, resistance of PC-3 human prostate carcinoma and PROb rat colon carcinoma tumors to doxorubicin in vivo was reversed by combining doxorubicin with Ad.Egr-TNF and resulted in significant antitumor effects. Treatment with Ad.Egr-TNF.11D has been associated with inhibition of tumor angiogenesis. In this context, a significant decrease in tumor microvessel density was observed following combined treatment with doxorubicin and Ad.Egr-TNF.11D as compared with either agent alone. These data show that Ad.Egr-TNF.11D is activated by diverse anticancer drugs.

Acetylcysteine↗
PubMed2003

Management of the clinically inapparent adrenal mass ("incidentaloma").

The National Institutes of Health Consensus Development Program convened surgeons, endocrinologists, pathologists, biostatisticians, radiologists, oncologists, and other health care professionals, as well as members of the general public, to address the causes, prevalence, and natural history of clinically inapparent adrenal masses, or "incidentalomas"; the appropriate evaluation and treatment of such masses; and directions for future research. Improvements in abdominal imaging techniques have increased detection of adrenal incidentalomas, and because the prevalence of these masses increases with age, appropriate management of adrenal tumors will be a growing challenge in our aging society. To address six predetermined questions, the 12-member nonfederal, nonadvocate state-of-the-science panel heard presentations from 21 experts in adrenal incidentalomas and consulted a systematic review of medical literature on the topic provided by the Agency for Healthcare Research and Quality and an extensive bibliography developed by the National Library of Medicine. The panel recommended a 1-mg dexamethasone suppression test and measurement of plasma-free metanephrines for all patients with an adrenal incidentaloma; additional measurement of serum potassium and plasma aldosterone concentration-plasma renin activity ratio for patients with hypertension; and surgery for patients with biochemical evidence of pheochromocytoma, patients with tumors greater than 6 cm, and patients with tumors greater than 4 cm who also meet other criteria. The panel also advocated a multidisciplinary approach to managing adrenal incidentalomas. The statement is an independent report of the panel and is not a policy statement of the National Institutes of Health or the federal government.

Adrenal Gland Neoplasms↗
PubMed2003

Surgical treatment of gastrointestinal stromal tumors in the imatinib (STI-571) era.

BACKGROUND: Gastrointestinal stromal tumors (GIST) are rare mesenchymal tumors that are characterized by constitutive overexpression of the tyrosine kinase receptor KIT (CD117). Imatinib mesylate is a selective inhibitor of tyrosine kinase-mediated activity. This study reports a single-institution experience of surgical resection and the use of imatinib in the treatment of GIST. METHODS: A retrospective review from 1995 to 2002 identified 57 patients (M:F, 29:28; median age, 61 years) with GIST who were treated at the University of Chicago. Twenty-eight patients underwent exploratory surgery with curative intent; 29 patients were referred for treatment of metastatic disease after surgery at outside institutions. Twenty-nine patients were treated with oral imatinib for either metastatic disease (n=26 patients) or in the adjuvant setting after complete resection (n=3 patients). RESULTS: Resections were performed in 53 patients, and metastatic disease was identified in 17 patients at the time of exploratory surgery. Immunohistochemical staining for CD117 was positive in 96% of patients. A size larger than 5 cm, a mitotic rate larger than 1/10 high-power field, and tumor necrosis predicted recurrence in patients after resection. The median follow-up period was 18 months (range, 4-81 months). Twenty-three patients (40%) are alive without disease; 22 patients (39%) are alive with disease; 7 patients died, and 5 patients are lost to follow-up. Among the 26 patients with metastatic disease who were treated with imatinib, 5 deaths have occurred, and disease stabilization or tumor regression was observed initially in 22 patients, with a median duration of response of 19 months. CONCLUSIONS: Complete surgical extirpation remains the only curative treatment of GIST. Imatinib-targeted therapy of metastatic disease yields encouraging clinical responses. The true efficacy of imatinib in this setting, as induction therapy or as an adjuvant treatment in patients with GIST, is unknown pending the completion of ongoing prospective trials.

Antineoplastic Agents↗
PubMed2003

The role of surgery in the management of oesophageal cancer.

In the absence of medical contraindications to surgery, resection is the mainstay of treatment for localised oesophageal cancer. Advancements in preoperative staging and imaging, anaesthesia delivery, surgical technique, and postoperative care, now enable the surgeon to safely operate on patients with oesophageal tumours and to tailor the procedure on the basis of performance status, tumour location, and extent of disease. During the past 10 years, several "minimally invasive" techniques, which aim to limit the extent of resection, have been introduced; these procedures are currently being investigated for use in both staging and treatment of oesophageal malignant diseases. Despite these accomplishments however, overall 5-year survival remains disappointing: less than 25% of patients live for 5 years after oesophagectomy. For patients with locally or regionally advanced disease (stage IIa, IIb, III, and IVa), combining several treatment approaches, either with or without surgery, can result in good objective responses and, in some patients, durable survival. The role of surgery in such combined modality approaches is still evolving and some investigators have challenged its worth. To provide a definitive review of the issues involved, we outline the types of surgery used to treat cancer of the oesophagus and summarise the available data about their effectiveness. Clinical outcomes, the value of preoperative chemoradiotherapy, and the use of surgery are all considered.

Combined Modality Therapy↗