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H Richard Alexander

Publications and source records attributed to H Richard Alexander.

At least 37 records · Page 2Linked to original sources
PubMed2004

Alterations in tumor necrosis factor-induced endothelial cell procoagulant activity by hyperthermia.

TNF is a cytokine with potent antitumor activity in murine models and when administered clinically via regional perfusion. There is substantial evidence that this antitumor activity depends in large part on TNF's procoagulant effect on tumor neovasculature, which is mediated by induction of endothelial cell tissue factor (TF), a component of the extrinsic clotting cascade. In regional perfusion of a cancer-bearing limb or organ, TNF is always administered under hyperthermic temperatures; however, little is known about the effect of hyperthermia on TNF-mediated procoagulant activity in endothelium. We examined the effects of hyperthermia on TNF-mediated procoagulant activity in human umbilical vein endothelial cells (HUVECs). HUVECs were exposed to TNF at normothermic (37 degrees C) and hyperthermic (41 degrees C) temperatures for 90 min, then assayed for clotting activity, TF protein production and mRNA production of TF and tissue factor pathway inhibitor-2 (TFPI-2), an endogenous inducible inhibitor of TF activity in HUVECs. TNF treatment at 41 degrees C significantly reduced clotting activity, TF protein and mRNA as well as TFPI-2 mRNA compared to treatment at 37 degrees C. These data show that hyperthermia significantly reduces the procoagulant effects of TNF on endothelial tissue compared to normothermia, which may have important clinical implications for the use of TNF in regional perfusion.

Blood Coagulation Factors↗
PubMed2004

Modulation of tumor-host interactions, angiogenesis, and tumor growth by tissue inhibitor of metalloproteinase 2 via a novel mechanism.

Solid tumors depend on angiogenesis for sustained growth. Tissue inhibitor of metalloproteinase 2 (TIMP-2) is an angiogenesis inhibitor initially characterized for its ability to block matrix metalloproteinases; however, recent data suggest that the antiangiogenic action of TIMP-2 may rely on matrix metalloproteinase-independent mechanisms. The aim of this study was to identify molecular pathways involved in the effects of TIMP-2 on processes dependent on tumor-host interactions such as angiogenesis. Using in vitro cell culture and a syngeneic murine tumor model, we compared the effects of TIMP-2 overexpression on gene expression profiles in vitro to those observed in vivo. Validating these findings by real-time quantitative PCR and layered protein scanning, we identified up-regulation of mitogen-activated protein kinase phosphatase 1 as an effector of the antiangiogenic function of TIMP-2. Up-regulation of mitogen-activated protein kinase phosphatase 1 in tumors overexpressing TIMP-2 leads to dephosphorylation of p38 mitogen-activated protein kinase and inhibition of tumor growth and angiogenesis. Phosphatase activity appears important in regulating tumor angiogenesis, offering a promising direction for the identification of novel molecular targets and antiangiogenic compounds for the treatment of cancer.

Animals↗
PubMed2004

Using gene expression profiling to differentiate benign versus malignant thyroid tumors.

DNA microarrays allow quick and complete evaluation of a cell's transcriptional activity. Expression genomics is very powerful in that it can generate expression data for a large number of genes simultaneously across multiple samples. In cancer research, an intriguing application of expression arrays includes assessing the molecular components of the neoplastic process and utilizing the data for cancer classification (Miller LD, et al. Cancer Cell 2002;2:353-61). Classification of human cancers into distinct groups based on their molecular profile rather than their histological appearance may prove to be more relevant to specific cancer diagnoses and cancer treatment regimes. Several attempts to formulate a consensus about classification and treatment of thyroid carcinoma based on standard histopathological analysis have resulted in published guidelines for diagnosis and initial disease management (Sherman SI. Lancet 2003;361:501-11). In the past few decades, no improvement has been made in the differential diagnosis of thyroid tumors by fine needle aspiration biopsy, specifically suspicious or indeterminate thyroid lesions, suggesting that a new approach to this should be explored. Therefore, in this study, we developed a gene expression approach to diagnose benign versus malignant thyroid lesions in 73 patients with thyroid tumors. We successfully built a 10 and 6 gene model able to differentiate benign versus malignant thyroid tumors. Our results support the premise that a molecular classification system for thyroid tumors is possible, and this in turn may provide a more accurate diagnostic tool for the clinician managing patients with suspicious thyroid lesions.

Diagnosis, Differential↗
PubMed2004

A novel technique for quantifying changes in vascular density, endothelial cell proliferation and protein expression in response to modulators of angiogenesis using the chick chorioallantoic membrane (CAM) assay.

Reliable quantitative evaluation of molecular pathways is critical for both drug discovery and treatment monitoring. We have modified the CAM assay to quantitatively measure vascular density, endothelial proliferation, and changes in protein expression in response to anti-angiogenic and pro-angiogenic agents. This improved CAM assay can correlate changes in vascular density with changes seen on a molecular level. We expect that these described modifications will result in a single in vivo assay system, which will improve the ability to investigate molecular mechanisms underlying the angiogenic response.

Journal Article↗
PubMed2004

Treatment of patients with unresectable primary hepatic malignancies using hyperthermic isolated hepatic perfusion.

Primary hepatocellular carcinoma is one of the most common malignancies worldwide. Isolated hepatic perfusion (IHP) is a regional treatment technique that isolates the organ to allow delivery of high-dose chemotherapy, biological agents, and hyperthermia directly to unresectable cancers confined to the liver. This study presents our experience using IHP with melphalan with or without tumor necrosis factor (TNF) to treat patients with hepatocellular carcinoma or adenocarcinoma of hepatobiliary origin. Nine patients with unresectable primary hepatic malignancies underwent a 60-minute IHP with 1.5 mg/kg melphalan with or without 1.0 mg TNF. Four patients failed one or more previous treatment regimens, and the mean hepatic replacement by tumor was 41% (range 10% to 75%). Patients were monitored for response, toxicity, time to recurrence, and survival. Six (67%) of nine patients experienced greater than 50% regression of tumor by objective radiographic imaging and an additional patient had a 45% reduction in tumor burden. Mean time to progression was 7.7 months for those who responded to treatment. Patients who had a response to therapy had an average overall survival of 16.3 months. IHP can be performed safely and has significant antitumor activity in patients with unresectable primary hepatic malignancies. Hepatic progression continues to be the dominant factor influencing survival in this group of patients.

Adenocarcinoma↗
PubMed2004

Isolated hepatic perfusion for the treatment of patients with advanced liver metastases from pancreatic and gastrointestinal neuroendocrine neoplasms.

BACKGROUND: We report results of using isolated hepatic perfusion (IHP) in patients with advanced progressive liver metastases (LM) from pancreatic and gastrointestinal neuroendocrine neoplasms (NENs). METHODS: Thirteen patients with LM from NENs (mean percent hepatic replacement, 30; range, 10-60) were treated with a 1-hour hyperthermic IHP via a laparotomy with the use of 1.5 or 2.0 mg/kg melphalan and/or 1 mg tumor necrosis factor. An oxygenated extracorporeal circuit with inflow through the gastroduodenal artery and common hepatic artery, and outflow to a segment of the inferior vena cava was used. Portal flow and inferior vena cava flow were shunted to the axillary vein. Radiographic response, recurrence pattern, and survival were assessed. RESULTS: Mean operative time was 9 hours (8-11 hours), and a median hospital stay was 10 days (6-64 days). Fifty percent of evaluable patients had a radiographic partial response in the liver (mean duration, 15 months; range, 6-26 months; 2 ongoing). Four had a marginal response (25%-49% reduction in the neoplasm). The median, hepatic, progression-free survival was 7 months (range, 3-27 months). The median actuarial survival was 48 months including 1 treatment mortality (median follow-up, 23 months). CONCLUSIONS: For patients with advanced LM from NENs, IHP provides a reasonable response rate and duration with acceptable morbidity; continued clinical evaluation is important.

Adult↗
PubMed2004

Pseudo-Meigs' syndrome secondary to isolated colorectal metastasis to ovary: a case report and review of the literature.

INTRODUCTION: Pseudo-Meigs' syndrome is a syndrome that includes hydrothorax and/or ascites secondary to ovarian neoplasms other than benign primary tumors. Gastrointestinal malignancies, including colorectal or gastric adenocarcinoma, are rare etiologies for this syndrome. CASE REPORT: In this report, we present the case of a 49-year-old woman with metastatic colon cancer who acutely developed a massive pleural effusion and ascites coincident with a rapidly enlarging adnexal mass and a rising CA-125 level. DISCUSSION: Seven cases of pseudo-Meigs' syndrome secondary to gastrointestinal primaries have been reported to date. This case highlights the difficulty in discerning the diagnosis of pseudo-Meigs' syndrome from that of disseminated colorectal cancer or a new primary ovarian neoplasm and the importance in making the distinction to initiate appropriate therapy.

Colorectal Neoplasms↗
PubMed2004

Oncolytic vaccinia virus expressing the human somatostatin receptor SSTR2: molecular imaging after systemic delivery using 111In-pentetreotide.

Oncolytic vaccinia viruses (VV) have demonstrated tumor specificity, high levels of transgene expression, and anti-tumor effects. The ability to visualize vector biodistribution noninvasively will be necessary as gene therapy vectors come to clinical trials, and the creation of a VV that can both treat tumors and permit noninvasive imaging after systemic delivery is therefore an exciting concept. To facilitate imaging, a VV expressing the human somatostatin receptor type 2 (SSTR2) was created. Cells infected with the SSTR2-expressing VV or controls were incubated with the somatostatin analog 111In-pentetreotide with or without an excess of nonradiolabeled pentetreotide. The SSTR2-infected cells bound 111In-pentetreotide sixfold more efficiently than control virus-infected cells and this binding was specifically blocked by nonradiolabeled pentetreotide. Nude mice bearing subcutaneous murine colon CA xenografts were injected intraperitoneally with the SSTR2-expressing VV or control VV. After 6 days, mice were injected with 111In-pentetreotide and imaged. Mice were sacrificed and organs collected and counted in a gamma counter. The uptake of radioactivity in tumors and normal tissues (percentage injected dose per gram) and tumor-to-normal tissue ratios were determined. Tumors infected with the SSTR2-expressing VV accumulated significantly higher concentrations of radioactivity compared to tumors in animals receiving the control virus. SSTR2-infected tumors were visible on imaging 6 days after VV injection and could be visualized for up to 3 weeks post-viral injection using repeat injections of 111In-pentetreotide. This reporter gene imaging strategy could be a very effective method to visualize vector distribution, expression, and persistence over time and enhances the potential of VV as a novel anti-cancer therapeutic.

Animals↗
PubMed2004

Does the use of routine duodenotomy (DUODX) affect rate of cure, development of liver metastases, or survival in patients with Zollinger-Ellison syndrome?

OBJECTIVE: To determine whether routine use of duodenotomy (DUODX) alters cure rate, survival, or development of liver metastases in 143 patients (162 operations) with Zollinger-Ellison syndrome (ZES) without MEN1. SUMMARY BACKGROUND DATA: DUODX has been shown to increase the detection of duodenal gastrinomas, but it is unknown if it alters rate of cure, liver metastases, or survival. Data from our prospective studies of surgery in ZES allow us to address this issue because DUODX was not performed before 1987, whereas it was routinely done after 1987. METHODS: All patients with sporadic ZES (non-MEN1) undergoing surgery for possible cure without a prior DUODX from November 1980 to June 2003 were included. Patients had preoperative computed tomography (CT), magnetic resonance imaging (MRI), or ultrasound; if unclear, angiography and somatostatin receptor scintigraphy since 1994. At surgery, all had the same standard ZES operation and were assessed immediately postoperatively, at 3 to 6 months, and yearly for cure (fasting gastrin, secretin test. and imaging studies). RESULTS: A DUODX was performed in 79 patients (94 operations), and no DUODX was performed in 64 patients (68 operations), with 10 patients having both (no DUODX, then a DUODX later). Gastrinoma was found in 98% with DUODX compared with 76% with no DUODX (P < 0.00001). Duodenal gastrinomas were found more frequently with DUODX (62% vs. 18%; P < 0.00001), whereas pancreatic, lymph node, and other primary gastrinomas occurred similarly. Six of the 10 patients with 2 operations had a duodenal tumor found with DUODX during a second operation that was missed in the first operation without DUODX. Both the immediate postoperative cure rate (65% vs. 44%; P = 0.010) and long-term cure rate at last follow-up (8.8 +/- 0.4 years; range, 0.1 to 21.5) (52% vs. 26%; P = 0.0012) were significantly greater with a DUODX than without. In patients without pancreatic tumors or liver metastases at surgery, both the rate of developing liver metastases (6% vs. 9.5%) and the disease-related death rate (0% vs. 2%) were low and not significantly different in patients with or without a DUODX. CONCLUSIONS: These results demonstrate that routine use of DUODX increases the short-term and long-term cure rate due to the detection of more duodenal gastrinomas. The rate of development of hepatic metastases and/or disease-related mortality in patients without pancreatic tumors is low, and no effect of DUODX on these parameters was seen. Duodenotomy (DUODX) should be routinely performed during all operations for cure of sporadic ZES.

Duodenal Neoplasms↗
PubMed2004

Molecular pathology of the MEN1 gene.

Multiple endocrine neoplasia type 1 (MEN1), among all syndromes, causes tumors in the highest number of tissue types. Most of the tumors are hormone producing (e.g., parathyroid, enteropancreatic endocrine, anterior pituitary) but some are not (e.g., angiofibroma). MEN1 tumors are multiple for organ type, for regions of a discontinuous organ, and for subregions of a continuous organ. Cancer contributes to late mortality; there is no effective prevention or cure for MEN1 cancers. Morbidities are more frequent from benign than malignant tumor, and both are indicators for screening. Onset age is usually earlier in a tumor type of MEN1 than of nonhereditary cases. Broad trends contrast with those in nonneoplastic excess of hormones (e.g., persistent hyperinsulinemic hypoglycemia of infancy). Most germline or somatic mutations in the MEN1 gene predict truncation or absence of encoded menin. Similarly, 11q13 loss of heterozygosity in tumors predicts inactivation of the other MEN1 copy. MEN1 somatic mutation is prevalent in nonhereditary, MEN1-like tumor types. Compiled germline and somatic mutations show almost no genotype/phenotype relation. Normal menin is 67 kDa, widespread, and mainly nuclear. It may partner with junD, NF-kB, PEM, SMAD3, RPA2, FANCD2, NM23beta, nonmuscle myosin heavy chain II-A, GFAP, and/or vimentin. These partners have not clarified menin's pathways in normal or tumor tissues. Animal models have opened approaches to menin pathways. Local overexpression of menin in Drosophila reveals its interaction with the jun-kinase pathway. The Men1+/- mouse has robust MEN1; its most important difference from human MEN1 is marked hyperplasia of pancreatic islets, a tumor precursor stage.

Animals↗
PubMed2004

Regional treatment options for patients with ocular melanoma metastatic to the liver.

Ocular melanoma is the most common primary ocular malignancy and has a significant predilection for metastasis to the liver. More than 40% of patients have hepatic metastases present at initial diagnosis, and the liver becomes involved in up to 95% of individuals who develop metastatic disease. The median survival of patients after diagnosis of liver metastasis ranges from 2 to 7 months. Metastatic disease localized to the liver has proven to be resistant to most available chemotherapy and immunotherapy regimens. Recognition of the grave prognosis associated with liver metastasis from ocular melanoma has led to the evaluation of new regional treatment modalities primarily designed to control tumor progression in the liver, including hepatic arterial chemotherapy, hepatic artery chemoembolization, regional immunotherapy, isolated hepatic perfusion, and percutaneous hepatic perfusion. This article reviews the efficacy, outcomes, and morbidities of the multiple locoregional therapies available today.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2004

The past decade of experience with isolated hepatic perfusion.

Metastatic or primary unresectable cancers confined to the liver are the sole or life-limiting component of disease for many patients with colorectal cancer, ocular melanoma, neuroendocrine tumors, or primary colangio- or hepatocellular carcinomas. Regional treatment strategies including infusional chemotherapy and local ablative therapy are under investigation, but have limitations with respect to the clinical conditions under which they can be employed. Isolated hepatic perfusion (IHP) was first clinically applied over 40 years ago, but because of its technical complexity, the attendant potential morbidity, and the lack of documented efficacy, it has not enjoyed consistent or widespread evaluation. In light of the antitumor activity with isolated limb perfusion with tumor necrosis factor (TNF) and melphalan in patients with unresectable extremity sarcoma or in transit melanoma, this regimen has been administered via IHP at several centers worldwide for patients with unresectable liver cancers. IHP with TNF and melphalan can result in significant regression of advanced refractory cancers from multiple histologies confined to the liver. Patient selection is important to ensure good results with minimal morbidity and mortality. Work to define the appropriate clinical groups is ongoing at many clinical centers.

Antineoplastic Agents, Alkylating↗
PubMed2003

Analysis of factors associated with outcome in patients with malignant peritoneal mesothelioma undergoing surgical debulking and intraperitoneal chemotherapy.

PURPOSE: Malignant mesothelioma (MM) arising in the peritoneal cavity is a rare neoplasm characterized by peritoneal progression and for which there are limited therapeutic options. We evaluated the peritoneal progression-free and overall survival (PFS and OS, respectively) for patients with peritoneal MM after surgical resection and regional chemotherapy. PATIENTS AND METHODS: Forty-nine patients (28 males, 21 females; median age, 47 years; range, 16 to 76 years) with MM underwent laparotomy, tumor resection, continuous hyperthermic peritoneal perfusion with cisplatin (median dose 250 mg/m2), and a single postoperative intraperitoneal dwell of fluorouracil and paclitaxel (n = 35) on protocols approved by the Institutional Review Board. Standard techniques for actuarial analyses of potential prognostic variables (Kaplan-Meier method with two-tailed log-rank test and Cox proportional hazards model) were performed. RESULTS: At a median potential follow-up of 28.3 months, median actuarial PFS is 17 months and actuarial OS is 92 months. Factors associated with improved PFS and OS by the Cox proportional hazards model were a history of previous debulking surgery, absence of deep tissue invasion, minimal residual disease after surgical resection (OS only), and age younger than 60 years (OS only). CONCLUSION: Surgical resection and regional chemotherapy for MM results in durable PFS and OS. Favorable outcome is associated with age, tumor biology (selection of patients with a history of previous debulking), lack of invasive tumor growth, and minimal residual disease after tumor resection.

Adolescent↗
PubMed2003

Hyperthermic isolated hepatic perfusion using melphalan for patients with ocular melanoma metastatic to liver.

PURPOSE: Liver metastases are the sole or life-limiting component of disease in the majority of patients with ocular melanoma who recur. Because median survival after diagnosis of liver metastases is short and no satisfactory treatment options exist, we have conducted clinical trials evaluating isolated hepatic perfusion (IHP) for patients afflicted with this condition. EXPERIMENTAL DESIGN: Twenty-nine patients (male: 14, female: 15; mean age, 49 years) with unresectable liver metastases from ocular melanoma were treated with a 60-min hyperthermic IHP using 1.5 mg/kg of melphalan (mean total dose 105 mg). Via laparotomy, perfusion inflow was established with a cannula in the gastroduodenal artery and outflow via a cannula positioned in an isolated segment of the retrohepatic inferior vena cava. Portal and infra-renal inferior vena cava blood flow was shunted externally to the axillary vein using a veno-veno bypass circuit. Patients were assessed for toxicity, radiographic response, and survival. RESULTS: There was no treatment related mortality and transient grade 3/4 hepatic toxicity was observed in 19 patients (65%). Mean length of operation and hospital stay was 8.3 h and 10 days, respectively. There were 3 (10%) complete responses (duration: 12, 14+, 15 months) and 15 partial responses (52%; mean duration: 10 months). The initial site of disease progression included liver in 17 of 25 patients (68%) who recurred. At a median follow-up of 30.7 months the median actuarial progression-free and overall survivals were 8 and 12.1 months, respectively. CONCLUSIONS: IHP with melphalan alone results in significant regression of established liver metastases for patients with ocular melanoma. However, after IHP, disease progression is most commonly observed in the liver, and survival after disease progression is short. On the basis of a pattern of tumor progression predominantly in liver, continued clinical evaluation of hepatic directed therapy in this patient population is justified.

Adult↗
PubMed2003

Parathyroid gland-specific deletion of the mouse Men1 gene results in parathyroid neoplasia and hypercalcemic hyperparathyroidism.

The inactivation of the MEN1 tumor suppressor gene in patients leads to a constellation of changes in endocrine tissues, including parathyroid neoplasia, pituitary adenomas, pancreatic neuroendocrine tumors, and carcinoids. To study the pathophysiological consequences of the deletion of the MEN1 gene, we set out to create a mouse model of hyperparathyroidism resulting from the deletion of the Men1 gene in parathyroid tissue. We introduced a Men1 gene flanked by loxP sites into the mouse germ line and then used a parathyroid cell-specific promoter to drive the expression of Cre recombinase, resulting in the deletion of the Men1 gene. Here, we show that loss of Men1 gene function in the parathyroid glands of mice results in histological changes consistent with parathyroid neoplasia as well as systemic hypercalcemia. This model provides a means for dissecting the molecular basis of this familial cancer syndrome and may allow for the development of new strategies to treat related forms of hypercalcemia.

Animals↗
PubMed2003

Effect of interleukin 1 receptor antagonist gene transduction on human melanoma xenografts in nude mice.

Interleukin (IL)-1 is a pleiotropic inflammatory cytokine that promotes angiogenesis and enhances tumor growth and metastases. We evaluated the effects of IL-1 receptor antagonist (IL-1ra) on tumor growth and metastases in human melanoma xenografts. We selected two human melanoma lines (SMEL and PMEL) with differential (high versus low, respectively) constitutive production of IL-1 by ELISA. The IL-1ra gene was isolated from monocyte RNA by PCR and retrovirally transduced into SMEL and PMEL. In vitro cell proliferation was evaluated using a WST-1 assay. Athymic nude mice received s.c. or i.v. injection with parental, vector-transduced, or IL-1ra-transduced melanoma cells, and tumor growth, lung metastases, and histology were characterized. IL-1 was produced by SMEL in vitro and ex vivo (117 and 67 pg/ml/10(6) cells/24 h, respectively), but not by PMEL (15 and 0 pg/ml/10(6) cells/24 h, respectively). Neither made IL-1ra natively. Gene-transduced cell lines secreted >1000 pg/ml/10(6) cells/24 h of IL-1ra by ELISA. In vitro proliferation of each parental cell line was comparable to the proliferation rate of each transduced cell line. IL-1ra-transduced SMEL (SMEL/IL-1ra) showed significantly slower tumor growth compared with null-transduced and parental cell lines (P < 0.001, ANOVA-Bonferroni/Dunn). There was no difference in growth rates between PMEL and IL-1ra-transduced PMEL (PMEL/IL-1ra). A mixing study of SMEL and SMEL/IL-1ra showed significant inhibition of tumor growth at various ratios (P < 0.001, ANOVA-Bonferroni/Dunn). There were significantly fewer lung metastases with SMEL/IL-1ra versus SMEL (P < 0.002). IL-1ra decreases in vivo growth and metastatic potential of a human melanoma xenograft that constitutively secretes IL-1. This effect may be exploitable using clinically available IL-1ra for the treatment of human cancers.

Animals↗
PubMed2003

Persistent primary hyperparathyroidism caused by adenomas identified in pharyngeal or adjacent structures.

Abnormalities in the normal migration of the parathyroid glands during embryological development of the head and neck may result in considerable variability in the location of parathyroid tissue. Ectopic parathyroid adenomas present diagnostic and technical challenges and are frequently the cause of persistent primary hyperparathyroidism (HPT) after unsuccessful initial parathyroid surgery. We report a series of eight patients with persistent primary HPT who had adenomas in rare and unusual locations associated with various pharyngeal structures. Four were located within the epineurium of the vagus nerve at or above the level of the carotid bifurcation, and four were located within the paranasopharyngeal space or oropharynx. Noninvasive and invasive preoperative imaging studies were crucial in localizing the neoplasms in these patients and permitted the use of a direct surgical approach, resulting in cure in all patients and a low complication rate. The location of parathyroid glands in high pharyngeal and cervical structures is a consequence of anomalous or arrested descent through developing pharyngeal structures and illustrates the remarkable spectrum of ectopic parathyroid adenomas that occur secondary to this phenomenon.

Adenoma↗