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Biomedical subjects

W Scott Melvin

Publications and source records attributed to W Scott Melvin.

At least 19 recordsLinked to original sources
PubMed2006

Stromal osteonectin overexpression is associated with poor outcome in patients with ampullary cancer.

BACKGROUND: Osteonectin has been suggested to be important in the progression of pancreatic cancer but has not been correlated with survival. We determined the osteonectin expression and its influence on survival in patients with ampullary carcinoma. METHODS: Tissue microarrays were constructed from the tumors of 56 patients with ampullary cancer undergoing pancreaticoduodenectomy. Immunohistochemical staining for osteonectin was undertaken and compared with staining in chronic pancreatitis (n = 13) and normal pancreas (n = 19). Survival curves were created by the Kaplan-Meier method and compared by log rank analysis. Median follow-up for all living patients with ampullary cancer was 69.6 months. RESULTS: Osteonectin was significantly (P < .05, Fisher's exact test) overexpressed in the stroma of ampullary cancers (90%) relative to chronic pancreatitis (62%) and normal pancreas (0%). Tumors expressing osteonectin were more likely to have nodal metastases than those lacking osteonectin expression (48% vs. 0%, P = .06, Fisher's exact test) and showed decreased survival. Node-negative status, pylorus preservation at the time of pancreaticoduodenectomy, and lack of osteonectin expression were predictors of prolonged survival by multivariate analysis. CONCLUSIONS: Although the importance of tumor-stroma interactions in periampullary cancers is not fully understood, our data suggest that osteonectin is an integral stromal element in ampullary cancers, and its overexpression is associated with decreased survival.

Adenocarcinoma↗
PubMed2006

Differential gene expression in patients genetically predisposed to pancreatic cancer.

BACKGROUND: Nearly 10% of all pancreatic cancer (PCA) results from genetic predisposition. Although abnormalities in sporadic PCA have been described, little is known about the genetics of heritable PCA. The purpose of this study was to identify novel genes expressed in patients with a presumed genetic predisposition or "familial" PCA. PATIENTS AND METHODS: We defined "familial" PCA as patients having one or more first-degree relatives with biopsy-proven adenocarcinoma of the pancreas. Using a PCR-based subtractive and enrichment procedure, representational difference analysis (RDA), pancreatic tumor cDNA was reverse-transcribed from pooled poly(A)+ mRNA from six such patients (tester) and compared to pooled cDNA from five normal pancreata (driver). Tumor-specific gene fragments were identified and confirmed to be overexpressed in familial PCA by comparative RT-PCR. Six PCA cell lines, 11 sporadic tumors, 5 neuroendocrine tumors, and 3 chronic pancreatitis tissues were screened to determine the specificity of these genes. RESULTS: Sequence analysis revealed several sequences of unknown significance and six genes previously described in neoplasia/carcinogenesis: Apolipoprotein A4, CEA, Keratin 19, Stratifin (14-3-3 sigma), Trefoil Factor, and Calcium Binding Protein S100 A6. Screening of cell lines and pancreatic tissue types showed varying degrees of specificity for familial and sporadic PCA. The APO-A4 gene was up-regulated in familial PCA. CONCLUSIONS: The pattern of frequency in all screened tissue suggests that these genes are associated with conditions that produce significant desmoplastic responses and are difficult to differentiate from chronic inflammatory processes. Apolipoprotein A4 is preferentially expressed in familial patients, suggesting that the importance of fatty acid synthesis in carcinogenesis be investigated further.

Adenocarcinoma↗
PubMed2006

50-year appraisal of gastrinoma: recommendations for staging and treatment.

BACKGROUND: Gastrinoma is a rare neuroendocrine tumor associated with ulcerogenic syndrome. The purpose of this study was to provide information on current controversies related to treatment, including staging, patient selection, and outcomes for surgical resection. STUDY DESIGN: A retrospective review of 106 patients with gastrinoma. Patients were classified as sporadic gastrinoma (SG) or MEN. End points of analysis included disease-free and disease-specific survival. Kaplan-Meier survival analysis was performed and significance (p < 0.05) was determined by Mantel-Haenszel log-rank test. RESULTS: Gastrinoma can be staged by TNM criteria into four groups (stage 0, I, II, and III), which had notably different survival curves, dependent on tumor size and distant metastases (p < 0.0001), but independent of lymph node metastases (p = 0.324). Surgical resection was possible in 72 patients (SG, n = 50; MEN, n = 22). Durable cure rate for SG was 26%, compared with 4% for MEN-1. Surgical resection achieving gross removal of all tumor resulted in improved survival in both SG and MEN patients (p < 0.0001). Improved survival was independent of a normal postoperative serum gastrin. Stage III was highly predictive of incomplete resection and the associated failure to improve survival (p = 0.0001). CONCLUSIONS: Staging provides a reliable method for the clinician to select patients for operation and to provide a prognosis, and should permit better comparisons of treatment between institutions. In the management of gastrinoma, it is recommended that SG and MEN patients with clinical stage I and II disease have surgical exploration, patients with stage III disease not have mandatory surgical treatment, and some stage 0 patients might not need routine surgical exploration.

Disease-Free Survival↗
PubMed2006

A structurally optimized celecoxib derivative inhibits human pancreatic cancer cell growth.

Deregulation of the phosphatidylinositol 3-kinase (PI-3K)/PDK-l/Akt signaling cascade is associated with pancreatic cancer tumor invasion, angiogenesis, and tumor progression. As such, it has been postulated that PDK-1/Akt signaling inhibitors may hold promise as novel therapeutic agents for pancreatic cancer. Disadvantages of currently available Akt inhibitors include tumor resistance, poor specificity, potential toxicity, and poor bioavailability. Previous studies have demonstrated that OSU-03012, a celecoxib derivative, specifically inhibits PDK-1 mediated phosphorylation of Akt with IC(50) values in the low muM range. Human pancreatic cancer cell lines AsPC-1, BxPC-3, Mia-PaCa 2, and PANC-1 were cultured in media containing varying concentrations of OSU-03012, 5-fluorouracil (5-FU), and gemcitabine, and changes in Akt phosphorylation and cell viability were evaluated using western blotting and a 3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide (MTT) assay, respectively. Treatment with OSU-03012 resulted in decreased PDK-1-mediated Akt phosphorylation and cell growth inhibition for all cell lines with IC(50) values ranging between 1.0 and 2.5 muM. Resistance to 5-FU and gemcitabine was observed in cell lines AsPC-1 and BxPC-3. Further analyses indicate that OSU-03012 induces both proapoptotic and antiproliferative effects in these cells. Taken together, these data suggest that OSU-03012 has potential value as a novel therapy for pancreatic cancer.

3-Phosphoinositide-Dependent Protein Kinases↗
PubMed2006

Preoperative carbohydrate antigen 19-9 is most predictive of malignancy in older jaundiced patients undergoing pancreatic resection.

OBJECTIVES: Given the increased detection of occult pancreatic neoplasms with modern imaging modalities, it is often difficult to determine the risk of malignancy before curative pancreatectomy. We reviewed patients who underwent pancreatectomy to determine factors predictive of malignancy with particular attention to the serum marker carbohydrate antigen 19-9 (CA19-9). METHODS: One hundred eighteen patients underwent radical pancreatectomy for malignant (n = 59) or benign (n = 59) pancreatic lesions. Demographic data, preoperative CA19-9 levels (normal, <37 U/mL), and follow-up were obtained from patient charts. Logistic regression analysis was used to determine univariate and multivariate predictors of malignancy. RESULTS: Significant multivariate predictors of malignancy were increased CA19-9, age older than 50 years, and preoperative jaundice. The sensitivity and specificity of increased preoperative CA19-9 alone were 71% and 83%, respectively. The combination of age older than 50 years and jaundice was a more accurate predictor than CA19-9 (sensitivity, 76%; specificity, 92%). Increased CA19-9 was highly specific (97%) for malignancy in older jaundiced patients or when the preoperative level was greater than 150 U/mL. CONCLUSIONS: Age and preoperative jaundice are more predictive of malignancy than CA19-9 alone unless levels are greater than 150 U/mL. Preoperative CA19-9 levels should be interpreted within the context of these other clinical factors.

Adult↗
PubMed2005

Dissection of CDK4-binding and transactivation activities of p34(SEI-1) and comparison between functions of p34(SEI-1) and p16(INK4A).

Recent studies showed that p34(SEI-1), also known as TRIP-Br1 or SEI-1, plays a dual role in the regulation of cell-cycle progression. It exhibits the transactivation activity and regulates a number of genes required for G1/S transition, while it also binds and activates cyclin-dependent kinase 4 (CDK4) independent of the inhibitory activity of p16. The goals of this paper are to further dissect the two roles and to compare the functions between SEI-1 and p16. (i) Yeast one-hybrid-based random mutagenesis was first used to identify a number of SEI-1 residues important for LexA-mediated transactivation, including residues L51, K52, L53, H54, L57, and L69 located within the heptad repeat (residues 30-88), a domain required for LexA-mediated transactivation, and two residues M219 and L228 at the C-terminal segment that contributes to transactivation through modulating the heptad repeat. (ii) The functional significance of these residues was further confirmed by site-directed mutagenesis. It was also shown that the heptad repeat-involving transactivation is distinct from the well-known acidic region-involving transactivation. (iii) Yeast two-hybrid-based binding analysis was made possible with the transactivation-negative SEI-1 mutants, and the results showed that some of such mutants retain full ability to bind and activate CDK4. (iv) Site-specific mutants of CDK4 were used to show that there are notable differences among SEI-1, p16, and cyclin D2 in binding to CDK4. (v) The expression levels of SEI-1 and p16 were compared in 32 tumor specimens of human squamous cell carcinomas of the head and neck. The results indicate that SEI-1 was consistently overexpressed, while p16 was consistently underexpressed. These results provide important information on the molecular mechanism of the functions of SEI-1 and on the comparison between SEI-1 and p16 at both molecular and cellular levels.

Amino Acid Sequence↗
PubMed2005

Dermal excisional wound healing in pigs following treatment with topically applied pure oxygen.

Hypoxia, caused by disrupted vasculature and peripheral vasculopathies, is a key factor that limits dermal wound healing. Factors that can increase oxygen delivery to the regional tissue, such as supplemental oxygen, warmth, and sympathetic blockade, can accelerate healing. Clinical experience with adjunctive hyperbaric oxygen therapy (HBOT) in the treatment of chronic wounds have shown that wound hyperoxia may increase granulation tissue formation and accelerate wound contraction and secondary closure. However, HBOT is not applicable to all wound patients and may pose the risk of oxygen toxicity. Thus, the efficacy of topical oxygen treatment in an experimental setting using the pre-clinical model involving excisional dermal wound in pigs was assessed. Exposure of open dermal wounds to topical oxygen treatment increased tissue pO2 of superficial wound tissue. Repeated treatment accelerated wound closure. Histological studies revealed that the wounds benefited from the treatment. The oxygen treated wounds showed signs of improved angiogenesis and tissue oxygenation. Topically applied pure oxygen has the potential of benefiting some wound types. Further studies testing the potential of topical oxygen in pre-clinical and clinical settings are warranted.

Administration, Topical↗
PubMed2005

Computer-enhanced robotic telesurgery minimizes esophageal perforation during Heller myotomy.

BACKGROUND: Laparoscopic Heller myotomy has emerged as the treatment of choice for achalasia. However, intraoperative esophageal perforation remains a significant complication. Computer-enhanced operative techniques have the potential to improve outcomes for certain operative procedures. Robotic, computer-enhanced laparoscopic telemanipulators using 3-dimensional magnified imaging and motion scaling are designed uniquely to facilitate certain operations requiring fine-tissue manipulation. We hypothesized that computer-enhanced robotic Heller myotomy would reduce intraoperative complications compared with laparoscopic techniques. METHODS: All patients undergoing an operation for achalasia at 3 institutions with a robotic surgery system (DaVinci; Intuitive Surgical Corporation, Sunnyvale, Calif) were followed-up prospectively. Demographics, perioperative course, complications, and hospital stay were recorded. Follow-up evaluation was obtained via a standardized symptom survey, office visits, and medical records. Data were compared with preoperative symptoms using a Mann-Whitney U test, and operating times were compared using the ANOVA test. RESULTS: Between August 2000 and August 2004 there were 104 patients who underwent a robotic Heller myotomy with partial fundoplicaton. There were 53 women and 51 men. All patients were symptomatic. The operative time was 140.55 minutes overall, but improved from 162.63 minutes to 113.50 minutes from 2000-2002 to 2003-2004 (P = .0001). There were no esophageal perforations. There were 8 minor complications and 1 patient required conversion to an open operation. Sixty-six (62.3%) patients were discharged on the first postoperative day and the average hospital stay was 1.5 days. A symptom survey was completed in 79 of 104 patients (76%) at follow-up evaluation. Symptoms improved in all patients with an average follow-up symptom score of 0.48 compared with 5.0 before the operation (P = .0001). Forty-three of the 79 patients from whom follow-up data were collected had a minimum follow-up period of 1 year. The follow-up period averaged 16 months. No patients required reoperation. CONCLUSIONS: Computer-enhanced robotic laparoscopic techniques provide a clear advantage over standard laparoscopy for the operative treatment of achalasia. We have shown in this large series that Heller myotomy can be completed using this technology without esophageal perforation. The application of computer-enhanced operative techniques appears to provide superior outcomes in selected procedures.

Adult↗
PubMed2005

Eye motion parameters correlate with level of experience in video-assisted surgery: objective testing of three tasks.

BACKGROUND: Laparoscopic skills vary with experience and training; however, objective measures to ascertain the level of training have not yet been established. New technology allows noninterfering measurement of eye motion parameters that correlate with attention and distraction during visually oriented tasks. Our objective was to apply this new technology in the setting of video-assisted surgery to evaluate eye motion parameters among surgeons of varying experience. MATERIALS AND METHODS: Subjects with various levels of laparoscopic experience (novice, intermediate, and expert) were fitted with a noninvasive, Food and Drug Administration approved, eye motion monitoring device. The device was used to measure and record parameters of eye motion, including saccadic rate (SR), standardized peak velocity (PV), standardized saccadic amplitude (SA), and the duration of gaze fixation (FD), during the performance of 3 basic laparoscopic tasks on a laparoscopic training station. RESULTS: A total of 24 subjects (3 groups of 8 each) participated in this study. Experience level was found to have a main significant effect on SR (P = 0.047) and PV (P = 0.028). Two-way ANOVA demonstrated that experience level approached significance for SA (P = 0.058) and FD (P = 0.055). CONCLUSION: The advancement of laparoscopic techniques and instrumentation relies, in part, on expanding the current understanding of operator/instrument interactions. This places an increasing demand on objective methods of monitoring such interactions during laparoscopy. Our study demonstrates a significant difference in eye motion parameters in surgeons with differing levels of experience. Further testing is needed in actual clinical settings to determine the importance of eye motion during surgery.

Analysis of Variance↗
PubMed2004

The nuclear protein p34SEI-1 regulates the kinase activity of cyclin-dependent kinase 4 in a concentration-dependent manner.

Previous studies have shown that p34(SEI-1), also known as TRIP-Br1, is involved in cell cycle regulations by interacting with a number of important proteins including CDK4. However, the detailed mechanism and structural basis of the interaction remains to be determined. We report the use of in vitro studies to address these problems. First, it was shown that p34(SEI-1) binds to CDK4 directly, and the binding does not compete directly with p16. In the presence of p16, a quaternary complex is formed between p34(SEI-1), CDK4, cyclin D2, and p16. Second, it was found that p34(SEI-1) activates the kinase activity of CDK4 at lower concentrations (reaching the maximum at 500 nM) but inhibits the same activity at higher concentrations, implying that p34(SEI-1)-mediated CDK4 activation is dose-dependent. Again, the effects of p34(SEI-1) and p16 are independent of each other. Third, it was shown that p34(SEI-1) possesses a LexA-mediated transactivation activity. Finally, a set of truncation mutants were used to dissect the structural elements responsible for the different functions of p34(SEI-1). The results indicate that the fragment 30-160 can bind, activate, and inhibit CDK4; the fragment 30-132 can bind and activate but does not inhibit CDK4, while the fragment 30-88 cannot bind, activate, or inhibit but retains the LexA-mediated transactivation activity.

Amino Acid Motifs↗
PubMed2004

Reactive oxygen species and EGR-1 gene expression in surgical postoperative peritoneal adhesions.

Postoperative peritoneal adhesions are common and serious complications of general abdominal and gynecological surgery that can lead to chronic abdominal pain, small-bowel obstruction and infertility. The specific pathophysiology of peritoneal adhesions remains elusive and current treatment is relegated to prevention through meticulous surgical technique and protective physical barriers, gels and solutions. We have reported that reactive oxygen species (ROS), generated by phagocytic cells at the site of tissue injury, serve as major signaling molecules regulating the expression of vascular endothelial growth factor (VEGF) and subsequent wound repair. We hypothesized that peritoneal adhesions are a product of over-healing surgical wounds and that, like in wound healing, ROS are implicated in their pathogenesis. We examined the presence of footprints of ROS and the ROS-inducible angiogenic factor VEGF in human adhesion tissue. An experimental model of peritoneal adhesion was established in rodents to study of the dynamics of ROS-induced gene expression during de novo adhesion tissue formation. Immunohistochemical analysis demonstrated presence of ROS/oxidant and macrophages in human peritoneal tissue. The presence of ROS and ROS-sensitive transcription factor EGR-1 was also evident in an experimental rodent peritoneal adhesion model. Along with ROS, VEGF, and a large number of mature and immature CD31/vWF positive blood vessels were present in the adhesion tissue. These observations are not consistent with the contention that adhesions are non-functional scar tissue. The newly developed rodent model of adhesion may present a useful approach to reproducibly and objectively study molecular mechanisms underlying the dynamic process of de novo adhesion tissue formation.

Animals↗
PubMed2004

Delivery of radiofrequency energy to the lower esophageal sphincter improves symptoms of gastroesophageal reflux.

BACKGROUND: The Stretta procedure has been proposed as a novel therapeutic alternative to antireflux surgery for gastroesophageal reflux disease (GERD). Early reports indicated improvement in GERD symptoms overall, but improvement in patients who have poor outcome after surgery remains unclear. METHODS: Patients with reflux who did not have a hiatal hernia were offered the procedure. All were administered a GERD Health Related Quality of Life survey at preprocedure and at greater than 3 months postprocedure. Differences in pre- and postprocedure responses were deemed significant with the use of the Wilcoxon rank sum test with P <.05. RESULTS: Fifty patients underwent the Stretta procedure. There were no complications. All were evaluated postprocedure, with 74% completing a postprocedure survey. Overall heartburn score improved from 3.19 (scale, 0-5) preprocedure to 1.74 postprocedure (P=.0012). Overall symptoms satisfaction score improved from 3.92 to 1.63 (P=.0001). Symptoms satisfaction score of patients who failed antireflux surgery improved from 3.5 to 1.75 (P=.0166), and, in those with a body mass index >30, it improved from 4.11 to 1.56 (P=.0024). Four patients went on to have antireflux surgery after having the Stretta procedure. CONCLUSIONS: Stretta improves heartburn symptoms both overall and in patients with poor outcome after antireflux surgery, with a low procedural risk. It may have a role in the treatment of patients with primary reflux and in those who have failed antireflux surgery or who are a high risk for surgery.

Adult↗
PubMed2004

Robot-assisted general surgery.

With the initiation of laparoscopic techniques in general surgery, we have seen a significant expansion of minimally invasive techniques in the last 16 years. More recently, robotic-assisted laparoscopy has moved into the general surgeon's armamentarium to address some of the shortcomings of laparoscopic surgery. AESOP (Computer Motion, Goleta, CA) addressed the issue of visualization as a robotic camera holder. With the introduction of the ZEUS robotic surgical system (Computer Motion), the ability to remotely operate laparoscopic instruments became a reality. US Food and Drug Administration approval in July 2000 of the da Vinci robotic surgical system (Intuitive Surgical, Sunnyvale, CA) further defined the ability of a robotic-assist device to address limitations in laparoscopy. This includes a significant improvement in instrument dexterity, dampening of natural hand tremors, three-dimensional visualization, ergonomics, and camera stability. As experience with robotic technology increased and its applications to advanced laparoscopic procedures have become more understood, more procedures have been performed with robotic assistance. Numerous studies have shown equivalent or improved patient outcomes when robotic-assist devices are used. Initially, robotic-assisted laparoscopic cholecystectomy was deemed safe, and now robotics has been shown to be safe in foregut procedures, including Nissen fundoplication, Heller myotomy, gastric banding procedures, and Roux-en-Y gastric bypass. These techniques have been extrapolated to solid-organ procedures (splenectomy, adrenalectomy, and pancreatic surgery) as well as robotic-assisted laparoscopic colectomy. In this chapter, we review the evolution of robotic technology and its applications in general surgical procedures.

Humans↗
PubMed2003

Frequent p16INK4A/CDKN2A alterations in chemically induced Syrian golden hamster pancreatic tumors.

The p16INK4A/CDKN2A (p16) tumor suppressor gene is known to be inactivated in up to 98% of human pancreatic cancer specimens. Chemically induced pancreatic tumors in Syrian golden hamsters have been demonstrated to share many morphological and biological similarities with human pancreatic tumors and represent a potentially suitable model for the evaluation of therapies targeting p16. The purpose of this study was to evaluate primary hamster pancreatic tumor specimens for potentially inactivating p16 alterations. Tumors were induced with N-nitroso-bis-(2-oxopropyl) amine, followed by two cycles of augmentation pressure, and were harvested on day 100. Foci of tumor cells were identified by light microscopy after staining with hematoxylin and eosin, and corresponding tumor tissues were excised for DNA extraction. The techniques of multiplex real-time PCR, direct sequencing and methylation-specific PCR were used to evaluate 30 tumor specimens for homozygous deletions, mutations and aberrant methylation of 5' CpG islands, respectively. Homozygous deletions were identified in 11 of 30 (36.7%) specimens, mutations were identified in four of 30 (13.3%) specimens, and aberrant methylation of 5' CpG islands was found in 14 of 30 (46.7%) specimens. The overall frequency of p16 alterations was 93.3% (28 of 30 specimens) and the majority of changes (83.3%) were noted to be secondary to methylation or homozygous deletion. The four mutations significantly impaired cyclin-dependent kinase 4 inhibitory activity, and two resulted in perturbation of the global structure of P16 protein. These findings indicate that p16 inactivation is a common event in chemically induced hamster tumors, and that this animal model is appropriate for comparative studies evaluating pancreatic cancer therapeutic strategies targeting p16.

Animals↗
PubMed2003

Expression and characterization of Syrian golden hamster p16, a homologue of human tumor suppressor p16 INK4A.

The p16(INK4A)/CDKN2A tumor suppressor gene is known to be inactivated in up to 98% of human pancreatic cancer specimens and represents a potential target for novel therapeutic intervention. Chemically induced pancreatic tumors in Syrian golden hamsters have been demonstrated to share many morphologic and biological similarities with human pancreatic tumors and this model may be appropriate for studying therapies targeting p16(INK4A)/CDKN2A. The purpose of this study was to investigate the fundamental biochemistry of hamster P16 protein. Using both in vivo and in vitro approaches, the CDK4 binding affinity, kinase inhibitory activity, and thermodynamic stability of hamster and human P16 proteins were evaluated. Furthermore, a structural model of hamster P16 protein was generated. These studies demonstrate that hamster P16 protein is biochemically indistinguishable from human P16 protein. From a biochemical perspective, these data strongly support the study of p16-related pancreatic oncogenesis and cancer therapies in the hamster model.

Amino Acid Sequence↗
PubMed2003

Minimally invasive pancreatic surgery.

Robotic surgery remains in its infancy, and little experience has been reported, as surgeons carefully explore the application of this type of technology to diseases of the pancreas. While challenging and controversial, Dr. Zollinger would most likely support the ongoing research in the techniques of pancreatic surgery that can lead only to an improvement in the outcomes of our patients.

Endoscopy, Digestive System↗