Biomedical subjects

Mark Bloomston

Publications and source records attributed to Mark Bloomston.

32 records · Page 2Linked to original sources

PubMed2004

Differential expression of the Tie-2 receptor and its ligands in human pancreatic tumors.

BACKGROUND: Derangements in the balance of the Tie-2 receptor ligands, angiopoietin-1 and angiopoietin-2 (Ang-1 and Ang-2), have been implicated in the growth and differentiation of several human tumors. To assess the potential role of angiogenesis factors in pancreatic tumorigenesis, we confirmed previously observed oligonucleotide-based microarray data by analyzing their expression in pancreatic tumors using semiquantitative reverse transcription polymerase chain reaction and immunohistochemistry. STUDY DESIGN: RNA harvested from tissue samples obtained from patients with normal pancreata, adenocarcinoma of the pancreas, and neuroendocrine tumors of the pancreas (nine each) was grouped by tissue type, pooled, and hybridized to a cDNA microarray and global gene expression patterns were determined. Semiquantitative reverse transcription polymerase chain reaction was applied to individual pool components to specifically determine expression of Tie-2, Ang-1, and Ang-2. A separate set of tumors and matched normal pancreas were then stained for expression of Ang-2 protein using immunohistochemistry. RESULTS: Microarray data showed that Ang-2 was upregulated in neuroendocrine tumors ( approximately 8 times more than normal) and adenocarcinoma of the pancreas ( approximately 5 times more than normal) although Ang-1 and Tie-2 were not differentially expressed. Reverse transcription polymerase chain reaction confirmed these findings showing strong Ang-2 expression in nine of nine neuroendocrine tumors, eight of nine adenocarcinoma of the pancreas, and weak expression in two of nine normal pancreata. Immunohistochemistry showed tumor-specific staining of Ang-2 in 10 of 15 matched adenocarcinoma of the pancreas (67%) and 6 of 8 neuroendocrine tumors (75%). CONCLUSIONS: Although Tie-2 and Ang-1 are not differentially expressed in pancreatic tumors, Ang-2 gene and gene product are overexpressed, suggesting a significant role for Ang-2 in pancreatic tumorigenesis. Differential expression of Ang-2 in human tumors may be useful as a diagnostic and therapeutic target.

Adenocarcinoma↗

PubMed2004

Identification of molecular markers specific for pancreatic neuroendocrine tumors by genetic profiling of core biopsies.

BACKGROUND: There is a paucity of known molecular markers that distinguish pancreatic neuroendocrine tumors from other pancreatic tumor types. We hypothesized that novel markers for pancreatic neuroendocrine tumors could be identified with molecular fingerprinting of pooled RNA samples from core biopsies. METHODS: Total RNA was harvested from nine core biopsies of normal pancreas, pancreatitis, pancreatic adenocarcinoma, pancreatic adenocarcinoma metastases, and pancreatic neuroendocrine tumors. RNA from each group of samples was pooled and hybridized to an oligonucleotide-based microarray. Four genes (ANG2, NPDC1, ELOVL4, and CALCR) were selected for further investigation by reverse transcriptase polymerase chain reaction from the top 20 highest expressed genes, on the basis of potential as novel markers. RESULTS: Neuroendocrine tumors were most unique from normal pancreas. Pancreatitis, pancreatic adenocarcinoma, and metastases are more closely related to each other and to normal pancreas. ANG2 was overexpressed in 89% of neuroendocrine tumors, compared with 22% of normal pancreas, making it the best potential molecular marker or therapeutic target of the four genes selected for analysis. CONCLUSION: We have identified a specific set of molecular markers for pancreatic neuroendocrine tumors distinct from pancreatitis and pancreatic adenocarcinoma. These novel markers may prove useful as molecular markers or therapeutic targets unique to pancreatic neuroendocrine tumors.

Adenocarcinoma↗

PubMed2004

Reoperative fundoplications are effective treatment for dysphagia and recurrent gastroesophageal reflux.

With wide application of antireflux surgery, reoperations for failed fundoplications are increasingly seen. This study was undertaken to document outcomes after reoperative fundoplications. Sixty-four patients, 26 men and 38 women, of average age 55 years+/-15.6 (SD), underwent reoperative antireflux surgery between 1992 and 2003. Fundoplication prior to reoperation had been undertaken via celiotomy in 27 and laparoscopically in 37. Both before and after reoperative antireflux surgery, patients scored their reflux and dysphagia on a Likert Scale (0 = none, 10 = continuous). Reoperation was undertaken because of dysphagia in 16 per cent, recurrent reflux in 52 per cent (median DeMeester Score 52), or both in 27 per cent. Failure leading to reoperation was due to hiatal failure in 28 per cent, wrap failure in 19 per cent, both in 33 per cent, and slipped Nissen fundoplication in 20 per cent. Laparoscopic reoperations were completed in 49 of 54 patients (91%); 15 had reoperations undertaken via celiotomy. Eighty-eight per cent of reoperations were Nissen fundoplications. With reoperation, Dysphagia Scores improved from 9.5+/-0.7 to 2.6+/-2.8, and Reflux Scores improved from 9.1+/-1.4 to 1.8+/-2.7. Seventy-nine per cent of patients with reflux prior to reoperation, 100 per cent with dysphagia, and 74 per cent with both noted excellent or good outcomes after reoperation. We conclude that failure after fundoplication occurs. Reoperations reduce the severity of dysphagia and reflux, thus salvaging excellent and good outcomes in most. Laparoscopic reoperations are generally possible. Reoperative fundoplications are effective treatment for dysphagia and recurrent gastroesophageal reflux, and their application is encouraged.

Adult↗

PubMed2003

Preoperative intervention does not affect esophageal muscle histology or patient outcomes in patients undergoing laparoscopic Heller myotomy.

Botox injection and pneumatic dilation are common therapies for achalasia. We sought to determine the impact of these preoperative therapies on esophageal muscle histology and outcomes after laparoscopic Heller myotomy. A total of 73 consecutive patients had esophageal muscle biopsies taken from the gastroesophageal junction at the time of myotomy between November 1998 and November 2001. Muscle fibrosis was graded by a senior pathologist who was blinded to preoperative treatments and postoperative outcomes. Patients graded their dysphagia and heartburn symptoms before and after myotomy and graded their outcomes at follow-up. Patients were grouped according to the preoperative endoscopic treatment (dilation, Botox, both, or neither) and the groups were compared. Preoperative therapy did not correlate with esophageal fibrosis or postoperative outcomes, and the degree of esophageal muscle fibrosis was not predictive of outcome. Symptom scores improved significantly for dysphagia (4.5 +/- 0.9 vs. 1.6 +/- 1.6) and heartburn (2.3 +/- 1.8 vs. 1.5 +/- 1.4) irrespective of preoperative therapy or fibrosis. Overall, excellent or good outcomes were obtained in 92% of patients at follow-up of 15.7 months +/- 14.4. Successful outcomes are highly probable after laparoscopic Heller myotomy regardless of preoperative interventions. The amount of fibrosis in the esophageal muscle is not related to preoperative intervention and is not predictive of outcomes.

Adult↗

PubMed2003

Post-shunt resource consumption favors small-diameter prosthetic H-graft portacaval shunt over TIPS for patients with poor hepatic reserve.

OBJECTIVE: To define the role of surgical shunting for patients with poor hepatic reserve (Child's class C) in the era of TIPS. SUMMARY BACKGROUND DATA: Most physicians prefer TIPS to surgical shunting for patients with poor hepatic reserve because of anticipated poor long-term survival. METHODS: Sixty-two patients of Child's class C with bleeding varices not amenable to endoscopic sclerotherapy or banding were prospectively randomized to undergo TIPS or 8-mm prosthetic H-graft portacaval shunt (HGPCS) from 1993 to 1999. Resource consumption and survival after shunting were determined. RESULTS: Twenty-nine patients underwent TIPS and 33 underwent HGPCS. After HGPCS, survival at 3 years was favorable but not statistically superior. TIPS was more often associated with shunt stenoses/occlusions, recurrent hemorrhage, shunt revisions, and shunt failure. Long-term follow-up documented that after HGPCS, patients required fewer hospital and ICU days and fewer units of RBCs transfused. After HGPCS, cost of care was less, as was the median cost of care per day of survival. CONCLUSIONS: For Child's class C patients undergoing HGPCS or TIPS, long-term survival is similar, though favoring HGPCS. Similarly, measures of resource consumption and cost of care following hospital discharge favor HGPCS. HGPCS should be preferentially applied for acceptable patients without access to convenient capable post-shunt care or without definitive plans for imminent transplantation.

Adult↗

PubMed2002

MMP-2 and TIMP-1 are derived from, not in response to, pancreatic cancer.

INTRODUCTION: Genetic therapy aimed at disturbing the balance between matrix metalloproteinases (MMP) and their natural tissue inhibitors (TIMP) in treatment of pancreatic cancer requires an understanding of whether MMP and TIMP are tumor- or host-derived. This study was undertaken to determine whether production of MMP-2 and TIMP-1 is by, or in response to, pancreatic cancer. METHODS: PANC-1 (poorly differentiated human pancreatic cancer) or CD-1 (PANC cells transfected to overproduce TIMP-1) cells were implanted into the pancreata of 20 nude mice. After sacrifice, tumors and peritumoral stroma underwent immunohistochemical staining for human and murine MMP-2 and TIMP-1. Normal murine pancreas served as control. All stains were reviewed in a "blinded" manner by a pathologist and graded relative to normal control pancreata. RESULTS: Control pancreata displayed faint murine MMP-2 and TIMP-1 staining and no human MMP-2 or TIMP-1. MMP-2 was most prominent in peritumoral stroma, while TIMP-1 was most prominent in tumors. CD-1 tumors contained very high levels of TIMP-1 compared to PANC-1 tumors and control pancreata. Tumoral and peritumoral MMP-2 were overwhelmingly human. As well, tumoral TIMP-1 was predominantly human. CONCLUSIONS: In a murine model for human pancreatic cancer, nearly all TIMP-1 and MMP-2 expression is tumor-derived (i.e., human). Pharmacologic and gene therapy aimed at disturbing the MMP/TIMP balance in pancreatic cancer should be targeted toward tumor-specific mechanisms and warrants continued investigation.

Animals↗

PubMed2002

TIMP-1 overexpression in pancreatic cancer attenuates tumor growth, decreases implantation and metastasis, and inhibits angiogenesis.

BACKGROUND: Matrix metalloproteinases (MMPs) are involved in pancreatic cancer progression. This study was undertaken to determine the effects of overexpression of a natural tissue inhibitor of MMP (TIMP-1) on pancreatic cancer cell growth, metastasis, and angiogenesis. METHODS: A poorly differentiated human pancreatic cancer cell line (PANC-1) underwent gene transfection to overexpress TIMP-1 (CD-1 cells). One million PANC-1 or CD-1 cells were injected into 40 nude mice subcutaneously (N = 20) or orthotopically (N = 20). Mice were sacrificed at 120 days. TIMP-1 overexpression by CD-1 cells was confirmed prior to injection and after necropsy. Immunohistochemical staining was undertaken after necropsy to evaluate tumors for TIMP-1, MMP-2, apoptosis (TUNEL), and angiogenesis (CD-31). RESULTS: Tumors of CD-1 cells were less likely to implant (35% vs 70%, P = 0.05) and grew to smaller size (0.5 g +/- 0.03 vs 1.5 g +/- 0.20, P < 0.001) than tumors of PANC-1 cells. As well, subcutaneous CD-1 tumors appeared later than PANC-1 tumors (45 days +/- 2.0 vs 27 days +/- 2.2, P < 0.001). Orthotopic CD-1 tumors metastasized less often than PANC-1 tumors (20% vs 60%, P < 0.05). MMP-2 expression was similar in PANC-1 and CD-1 tumors, while CD-1 tumors showed increased TIMP-1 expression, increased apoptosis, and decreased angiogenesis relative to PANC-1 tumors. CONCLUSIONS: TIMP-1 overexpression reduces pancreatic cancer cell implantation, growth, metastasis, and angiogenesis, while increasing tumor apoptosis, all without altering MMP-2 production. This study demonstrates the potential role of TIMP-1 as a target in gene therapy for pancreatic cancer.

Animals↗

PubMed2002

Matrix metalloproteinases and their role in pancreatic cancer: a review of preclinical studies and clinical trials.

Matrix metalloproteinases (MMPs) have received much attention in recent years for their role in a variety of malignancies. Pancreatic cancer is no exception; MMP-2 and MMP-9 show high levels of expression in clinical and experimental models. Inhibition of MMPs has shown great promise with synthetic inhibitors, such as BB-94, as tumorostatic agents in preclinical models, particularly when these are combined with gemcitabine. These findings have led to several clinical trials using the MMP inhibitors Marimastat and BAY12-9566. Herein, we discuss the roles of MMPs and their inhibition in pancreatic cancer.

Animals↗

PubMed2002

Selective application of fundoplication during laparoscopic heller myotomy ensures favorable outcomes.

We propose that selective fundoplication during laparoscopic Heller myotomy achieves optimal outcomes. Fundoplication was applied selectively in 21 of 100 patients undergoing laparoscopic Heller myotomy with hiatus hernia, patulous esophageal hiatus, or intraoperative perforation. Dysphagia and heartburn incidence and severity in patients undergoing myotomy with or without fundoplication were compared before and after myotomy. Median follow-up was 19 months and was similar for both groups. Preoperative symptoms were similar for both groups of patients and showed significant improvement following myotomy with or without fundoplication. As well, there were no significant differences in postoperative dysphagia (26% vs. 14%), dysphagia score (1.1 +/- 1.4 vs. 0.8 +/- 1.3), heartburn (21% vs. 27%), or heartburn score (0.9 +/- 1.5 vs. 1.4 +/- 1.6). Overall improvement was seen in 86% of patients undergoing myotomy with fundoplication and in 97% without fundoplication (P = 0.06). Selective application of fundoplication during laparoscopic Heller myotomy promotes optimal outcomes.

Adolescent↗

PubMed2002

Transcatheter arterial chemoembolization with or without radiofrequency ablation in the management of patients with advanced hepatic malignancy.

Transcatheter arterial chemoembolization (TACE) is efficacious against hepatic malignancies by rendering tumors ischemic while delivering high-dose chemotherapy. The added benefit of radiofrequency ablation (RFA) has not been determined. We sought to review our experience with TACE with or without RFA in the treatment of hepatocellular carcinoma and colorectal liver metastases in patients not amenable to resection. TACE and RFA were undertaken in 13 patients with hepatocellular carcinoma (n = 7) or colorectal liver metastases (n = 6). Concurrently 24 patients underwent TACE alone for hepatocellular carcinoma (n = 15) or colorectal liver metastases (n = 9). Patients undergoing TACE with or without RFA were similar in age, gender, and diagnosis. Overall follow-up was 9.1 months +/- 7.1. One-year survival was greater in patients undergoing TACE with RFA than with TACE alone (100% vs 67%, P = 0.04). Mean survival was longer after TACE with RFA compared with TACE alone (25.3 months +/- 15.9 vs 11.4 months +/- 7.3, P < 0.05). No patients suffered significant complications. The addition of RFA to TACE improves survival in patients with unresectable primary or metastatic hepatic malignancies. RFA with TACE should be in the armamentarium of surgeons caring for patients with malignant liver lesions.

Carcinoma, Hepatocellular↗

PubMed2002

Preshunt and postshunt portal vein pressures and portal vein-to-inferior vena cava pressure gradients do not predict outcome following partial portal decompression.

This study was undertaken to determine whether preshunt, postshunt, or changes in portal vein (PV) pressures or portal vein-to-inferior vena cava (PV-IVC) pressure gradients determine outcome following partial portal decompression attained through small-diameter prosthetic H-graft portacaval shunt (HGPCS). Seventy-seven adults underwent HGPCS (Child's class A 10%, B 56%, and C 34%) and were prospectively evaluated per protocol. PV pressures and PV-IVC pressure gradients decreased significantly in all patients with shunting (P < 0.001). Eight (10%) patients died within 30 days of shunting (Child's class B 50% and C 50%); seven of these deaths were due to liver failure. Preshunt, postshunt, and changes in PV pressures or PV-IVC pressure gradients with shunting were not different among eight perioperative deaths and survivors. At a mean follow-up of 3 years 24 (35%) additional patients died. Of late deaths 62 per cent were due to liver failure (Child's class B 40% and C 60%). Again preshunt, postshunt, or changes in PV pressures and PV-IVC pressure gradients with shunting did not predict who would die of late liver failure. We conclude that the small-diameter HGPCS effectively provides partial portal decompression. Preshunt or postshunt PV pressures or PV-IVC pressure gradients or changes in pressures with shunting do not determine outcome following HGPCS. Long-tern outcome is influenced by the severity of cirrhosis before shunting and by the self-destructive behaviors typical of patients with alcoholic cirrhosis.

Adult↗

PubMedDate not supplied

The "learning curve" in videoscopic Heller myotomy.

OBJECTIVES: In the early 1990s, minimally invasive videoscopy was applied to numerous operations. After undertaking more than 50 "open" Heller myotomies, our experience with videoscopic Heller myotomy began in 1992. We sought to determine whether the outcome following videoscopic Heller myotomy is influenced by surgeon experience. METHODS: Seventy-eight patients with severe dysphagia secondary to achalasia underwent videoscopic Heller myotomy between 1992 and 1998. Intraoperative endoscopy was utilized to ensure adequate myotomy in all patients. Patients were stratified into 3 groups: the first 25 patients (group I), the second 25 patients (group II), and the last 28 patients (group III). Clinical outcome was based on length of stay, incidence of intraoperative complications, conversion to an 'open' procedure, and postoperative symptoms. RESULTS: Perioperative complications occurred in 20% of patients in group I compared with 8% and 12% in groups II and III, respectively (P = NS). Only 3 patients required conversion to an 'open' procedure, all in group I (P <0 .05). Symptomatic improvement was achieved in 80% of patients in group I, 100% in group II, and 96% in group III (P < 0.05). Significant reductions in conversions to open, length of stay, and postoperative symptoms were seen after 20 myotomies were undertaken. CONCLUSION: Outcome following videoscopic Heller myotomy, like other videoscopic operations, improves as surgeons progress along the videoscopic "learning curve." After approximately 20 videoscopic Heller myotomies, surgeons can expect fewer conversions to open procedures, shorter hospital stays, and better symptomatic relief.

Cardia↗

PubMedDate not supplied

Videoscopic Heller myotomy with intraoperative endoscopy promotes optimal outcomes.

BACKGROUND AND OBJECTIVES: Minimally invasive surgical techniques are applicable to achalasia, but the optimum approach to intraoperative assessment of adequacy of myotomy remains unestablished. We set out to show that videoscopic Heller myotomy with concurrent endoscopy ensures adequacy of myotomy while limiting postoperative clinically apparent reflux. METHODS: Seventy-eight consecutive patients with achalasia underwent videoscopic Heller myotomy with concomitant endoscopy between 1992 and 1998. Fundoplication was not routinely undertaken. RESULTS: Preoperative symptoms consisted of dysphagia (100%), emesis/regurgitation (68%), heartburn (58%), and postprandial chest pain (49%). Following myotomy, significant improvement (P < 0.0001) was seen in dysphagia (43%), postprandial chest pain (13%), and emesis/regurgitation (9%) at a mean follow-up of 33+/-2.2 months. Mean reflux score (scale 0 to 5) improved from 3.7+/-0.3 to 1.5+/-0.2 (P < 0.0001). Improvement in symptoms was reported in 96% of patients. Fundoplication was used in 8 patients as part of hiatus reconstruction (n = 6) or repair of esophageal perforation (n = 2). CONCLUSIONS: Intraoperative endoscopy during videoscopic Heller myotomy guides the extent and adequacy of myotomy. By utilizing a focused dissection with preservation of the natural antireflux mechanisms around the gastroesophageal junction and limiting the extent of myotomy along the cardia, postoperative reflux symptoms are minimized. We advocate concomitant endoscopy during Heller myotomy to guide myotomy and submit that routine fundoplication is clinically unnecessary.

Adolescent↗

PubMedDate not supplied

Symptoms and antireflux medication use following laparoscopic Nissen fundoplication: outcome at 1 and 4 years.

BACKGROUND: We have reported 1-year outcomes and antacid medication use in 100 patients undergoing laparoscropic Nissen fundoplication. As a follow-up study, we queried these same patients to determine whether their outcomes endured 4 years after fundoplication. METHODS: One hundred patients undergoing laparoscopic Nissen fundoplication between 1992 and 1997 were asked, at 1 to 2 years and 4 to 6 years postoperatively, to grade their symptoms on a scale of 1 (mild) to 10 (severe). Patients were also queried as to the number/cost of antacid medications used before and after fundoplication. RESULTS: Significant improvements were noted in symptoms of heartburn, postprandial emesis, gas/bloating, and dysphagia after fundoplication. Significant decreases in antacid medication use (97% vs 19%) and monthly costs (dollar 168 +/- dollar 91 vs dollar 30 +/- 54) were seen following fundoplication. The number of patients on antacid medications and the monthly costs of these medications (37% and dollar 53 +/- dollar 87, respectively) increased significantly from early to late follow-up, but were still significantly lower than those before surgery. Overall, 87% and 900% of patients were pleased with their outcome at early and late follow-up, respectively, and 93% and 92% of patients stated they would consider undergoing fundoplication again if necessary (P = NS). CONCLUSION: Laparoscopic Nissen fundoplication results in a significant reduction in the symptoms of reflux and the use of antacid medications with a high degree of patient satisfaction. Although some patients return to antacid medications at late follow-up, they continue to have few symptoms and are pleased with their outcomes.

Adolescent↗