PubMed Health⌕ Search

Biomedical subjects

J A Drebin

Publications and source records attributed to J A Drebin.

At least 19 recordsLinked to original sources
PubMed2005

A phase II study of alternating cycles of split course radiation therapy and gemcitabine chemotherapy for inoperable pancreatic or biliary tract carcinoma.

Because of increased toxicity, full doses of gemcitabine and radiation therapy cannot routinely be given concurrently. The purpose of the present study was to determine the toxicity and response to treatment with full-dose gemcitabine given between cycles of split-course radiation therapy (nonconcurrent treatment) for inoperable periampullary adenocarcinoma. Treatment consisted of 3 6 week courses for a total of 18 weeks: 1000 mg/m gemcitabine intravenous bolus once a week x 2 weeks; 1 week break; 2 weeks of radiation therapy (1.8 Gy per fraction); 1 week break x 3. The total dose of radiation consisted of 45 Gy to the tumor + regional nodes followed by a 5.4-Gy boost. Patients were restaged at week 15 and at the completion of all treatment. Patients underwent resection if there was sufficient response. A total of 42 patients (40 pancreatic, 1 gallbladder, 1 biliary tract) were enrolled between March 1999 and July 2002. All but 2 medically inoperable patients had evidence of major vessel involvement. Median age was 63 years (range, 40-80 years). All patients were evaluable for response. There were 10 objective partial responses (24%). Six responders underwent resection with a mean survival of 18 months. Mean survival for all 42 patients was 10.3 months (range, 2.0-32.5 months; median, 9.5 months). Four patients experienced grade 3 or 4 gastrointestinal toxicity. Alternating cycles of split-course radiotherapy and gemcitabine chemotherapy permits the delivery of full doses of both modalities with acceptable tolerance. Despite the prolongation in radiation treatment time because of split-course treatment, patients with sufficient response were able to undergo resection.

Adult↗
PubMed2001

Suppression of beta-catenin inhibits the neoplastic growth of APC-mutant colon cancer cells.

Mutations involving the adenomatous polyposis coli (APC) tumor suppressorgene/beta-catenin signaling pathway have been identified in the majority of colon carcinomas. However, the role of aberrant beta-catenin signaling in the neoplastic growth of APC-mutant colon cancer cells has not been directly studied. To address this question, antisense oligonucleotides have been used to specifically down-regulate beta-catenin expression in APC-mutant human colon carcinoma cells. Antisense-mediated suppression of beta-catenin inhibits the in vitro proliferation, anchorage-independent growth, and cellular invasiveness of APC-mutant human colon carcinoma cells. The systemic administration of beta-catenin antisense oligonucleotides down-regulates beta-catenin expression in vivo in human colon cancer xenografts in nude mice. Such treatment inhibits the tumorigenic growth of colon cancer xenografts and can completely eradicate tumors in some treated animals. These studies formally demonstrate the critical role of beta-catenin signaling in the neoplastic growth of APC-mutant colon cancer cells and suggest that strategies targeting beta-catenin may be of use in the therapy of colon cancer.

Animals↗
PubMed2001

Beta-catenin antisense treatment decreases beta-catenin expression and tumor growth rate in colon carcinoma xenografts.

BACKGROUND: Loss of the adenomatous polyposis coli (APC) tumor suppressor gene plays a significant role in colorectal carcinogenesis. One function of the APC gene product is to regulate beta-catenin, a protein that plays a role in cell adhesion and also regulates the activity of certain transcription factors. To more precisely delineate the role of beta-catenin signaling in colon cancer growth, we treated mice bearing APC-mutant SW480 colon cancer xenografts with antisense oligonucleotides (ODNs) directed against beta-catenin mRNA and examined effects on beta-catenin expression and tumor growth. METHODS: Balb/C nude mice underwent subcutaneous injection of 1 x 10(6) SW480 cells to establish tumor xenografts. In one experiment, tumors were allowed to grow for 7 days, after which time animals were randomized to undergo daily intraperitoneal injections of either antisense beta-catenin ODN at doses of 5, 10, or 20 mg/kg, scrambled sequence beta-catenin ODN control, or saline control for 7 days. Tumors were excised and homogenized, and tumor lysates subjected to gel electrophoresis and Western blotting for beta-catenin protein quantification. In a second experiment, tumor-bearing animals began receiving daily intraperitoneal injections of either antisense beta-catenin ODN at doses of 5, 10, or 20 mg/kg, scrambled sequence beta-catenin ODN control, or saline control. Tumor growth was quantitated by measuring tumor volumes twice weekly. A third experiment evaluated the antitumor effects of daily bolus dosing versus continuous infusion of beta-catenin antisense ODNs (20 mg/kg). RESULTS: Treatment of APC-mutant colorectal carcinoma xenografts with beta-catenin antisense resulted in a dose-dependent down-regulation in beta-catenin protein expression as shown by Western blotting. Treatment of tumor-bearing mice with antisense directed at beta-catenin also demonstrated a dose-dependent inhibition of tumor growth. There appears to be little difference in the antitumor effects of antisense ODNs administered by continuous infusion or bolus dosing schedules. CONCLUSIONS: beta-Catenin expression plays a critical role in the tumorigenic growth of APC-mutant colon cancer xenografts. Strategies targeting beta-catenin, including the use of antisense ODNs, may be of use in the treatment of human colon cancer.

Animals↗
PubMed2001

Survival of patients evaluated by FDG-PET before hepatic resection for metastatic colorectal carcinoma: a prospective database study.

OBJECTIVE: To present the survival results for patients with colorectal carcinoma metastases who have undergone liver resection after being staged by [(18)F] fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET). SUMMARY BACKGROUND DATA: Hepatic resection is standard therapy for colorectal metastases confined to the liver, but recurrence is common because of the presence of undetected cancer at the time of surgery. FDG-PET is a sensitive diagnostic tool that identifies tumors based on the increased uptake of glucose by tumor cells. To date, no survival results have been reported for patients who have actually had liver resection after being staged by FDG-PET. METHODS: Forty-three patients with metastatic colorectal cancer were referred for hepatic resection after conventional tumor staging with computed tomography. FDG-PET was performed on all patients. Laparotomy was performed on patients not staged out by PET. Resection was performed at the time of laparotomy unless extrahepatic disease or unresectable hepatic tumors were found. Patients were examined at intervals in the preoperative period. RESULTS: FDG-PET identified additional cancer not seen on computed tomography in 10 patients. Surgery was contraindicated in six of these patients because of the findings on FDG-PET. Laparotomy was performed in 37 patients. In all but two, liver resection was performed. Median follow-up in the 35 patients undergoing resection was 24 months. The Kaplan-Meier estimate of overall survival at 3 years was 77% and the lower 95% confidence limit of this estimate of survival was 60%. This figure is higher than 3-year estimate of survival found in previously published series. The 3-year disease-free survival rate was 40%. CONCLUSIONS: Preoperative FDG-PET lessens the recurrence rate in patients undergoing hepatic resection for colorectal metastases to the liver by detection of disease not found on conventional imaging.

Aged↗
PubMed2000

HER2/neu antisense targeting of human breast carcinoma.

Overexpression of the HER2/neu oncogene is observed in approximately 30% of human breast carcinoma specimens. HER2/neu overexpression is a negative prognostic factor in breast cancer patients. Cancer cells that overexpress HER2/neu may also be less sensitive to chemotherapy. In order to further define mechanisms by which HER2/neu overexpression drives neoplastic cell growth and chemoresistance, antisense oligonucleotides (ODNs) have been utilized to selectively down-regulate HER2/neu expression in human breast cancer cells. Such antisense ODNs suppress HER2/neu mRNA and protein levels in a dose-dependent, sequence-specific manner. Down-regulation of HER2/neu expression in HER2/neu overexpressing breast cancer cells inhibits cell cycle progression in G0/G1 and results in apoptotic cell death. In tissue culture studies, combined treatment of HER2/ neu overexpressing breast cancer cells with HER2/neu antisense ODNs and conventional chemotherapeutic agents results in synergistic inhibition of cancer cell growth and activation of apoptotic cell death mechanisms. These studies have been extended to demonstrate synergistic antitumor effects following systemic treatment with antisense ODNs plus doxorubicin in nude mice bearing human breast carcinoma xenografts. Collectively these findings demonstrate that HER2/neu overexpression stimulates anti-apoptotic cell survival mechanisms and suggest that HER2/neu antisense ODNs may be of use in cancer therapeutics.

Animals↗
PubMed2000

Down-regulation of HER2/neu expression induces apoptosis in human cancer cells that overexpress HER2/neu.

The HER2/neu oncogene is overexpressed in a significant fraction of human tumors; such overexpression is thought to play a role in the aberrant proliferation of cancer cells. The effects of HER2/neu-specific phosphorothioate antisense oligodeoxyribonucleotides on HER2/neu expression, tumor cell proliferation, and activation of apoptotic cell death pathways have been examined. Antisense treatment down-regulates HER2/neu expression in a dose-dependent and sequence-specific manner. HER2/neu antisense treatment specifically inhibits the growth of tumor lines that overexpress HER2/neu, but it has little effect on the growth of tumor cells that express low levels of HER2/neu. Down-regulation of HER2/neu expression is not only cytostatic, but it also results in the activation of apoptotic cell death pathways in cells that overexpress HER2/neu. These results suggest that, in addition to stimulating tumor cell proliferation, HER2/neu overexpression in cancer cells acts as an antiapoptotic cell survival factor.

Apoptosis↗
PubMed2000

The "hidden cystic duct" syndrome and the infundibular technique of laparoscopic cholecystectomy--the danger of the false infundibulum.

BACKGROUND: The "classical" biliary injury usually involves misidentification of the common bile duct as the cystic duct. The purpose of this study was to determine if the method of cholecystectomy, specifically the "infundibular technique," might be a contributing factor in this injury. STUDY DESIGN: Twenty-one operative notes of patients who were referred with injury to the common bile duct were examined. Notes were classified as to informativeness. Patient and operative variables potentially related to injury were searched for. RESULTS: Inflammation was the main patient variable associated with injury. The main operative variable was that in most of the injuries the cystic duct was isolated and divided as the first step in the procedure. Often the operative note contained a statement indicating that the surgeon believed that the "cystic" duct (actually the common bile duct) was emanating from the infundibulum of the gallbladder and that this was the anatomic rationale for identification of the cystic duct. In no case was the triangle of Calot completely dissected before injury. CONCLUSIONS: The cystic duct may be hidden in some patients having laparoscopic cholecystectomy, especially in the presence of inflammation. This may lead to the deceptive appearance of a false infundibulum that misleads the surgeon into identifying the common duct as the cystic duct. Biliary injury is more likely when cystic duct identification is made by relying solely on the appearance of the junction of the cystic duct with the infundibulum of the gallbladder, and this technique should be abandoned.

Adolescent↗
PubMed2000

Pancreaticoduodenectomy for lymphoepithelial cyst of the pancreas.

Lymphoepithelial tumors of the pancreas are rare cystic tumors characterized by the presence of a keratinizing squamous epithelium and a dense lymphoid infiltrate on histologic examination. This case report describes the first lymphoepithelial tumor to be resected from the pancreatic head by pancreaticoduodenectomy. This case is also the first in which the cyst was found to be secondarily infected. The radiologic and clinicopathologic features of these unusual tumors are discussed.

Humans↗
PubMed1999

Shared antigenic epitopes and pathobiological functions of anti-p185(her2/neu) monoclonal antibodies.

We have studied two anti-p185 antibodies: the monoclonal antibody 7. 16.4 and rhuMAb 4D5, which were raised against the the ectodomain of rat (p185(neu)), and the human (p185(her2/neu)) homolog, respectively. Studies on the structure of these two antibodies indicate that they share structural similarity in the variable region, especially the CDR3 region, which determines the antibody-antigen interaction. Further studies by flow cytometry revealed that 7.16.4 can compete with rhuMAb4D5 for binding to the cell surface p185(her2/neu), suggesting that these two antibodies share an epitope on the p185 receptor. Furthermore, 7.16.4 can also inhibit proliferation and transformation caused by p185(her2/neu). Moreover the rhuMAb 4D5 binds to the rat p185(neu). With the observation that 7.16.4 positively stains human breast cancer tissues that overexpress p185(her2/neu), 7.16.4 may be useful for the pathological diagnosis and therapy of human tumors.

3T3 Cells↗
PubMed1999

Synergistic antitumor effects of HER2/neu antisense oligodeoxynucleotides and conventional chemotherapeutic agents.

BACKGROUND: The HER2/neu oncogene is overexpressed in a substantial fraction of human tumors. HER2/neu overexpressing tumors may be intrinsically resistant to chemotherapy. The present study examined the ability of antisense-mediated downregulation of HER2/neu expression to enhance the antitumor effects of conventional chemotherapeutic agents against human tumor cells that overexpress HER2/neu. METHODS: The effects of HER2/neu antisense oligodeoxynucleotides (ODNs) on the growth inhibitory and proapoptotic activity of several distinct chemotherapeutic agents were examined in vitro. In vivo effects of HER2/neu antisense ODNs in combination with doxorubicin hydrochloride were assessed by examining the growth of human tumor xenografts implanted into nude mice. RESULTS: The proliferation of tumor cell lines that overexpress HER2/neu was inhibited by antisense ODNs in combination with conventional chemotherapeutic agents in an additive or synergistic fashion. Such combination therapy also demonstrated synergistic activation of apoptosis. HER2/neu antisense ODNs in combination with doxorubicin hydrochloride demonstrated synergistic antitumor effects in vivo as well. CONCLUSIONS: Downregulation of HER2/neu expression can enhance the sensitivity of human cancer cells, which overexpress HER2/neu to the cytotoxic effects of chemotherapy. Antisense ODNs targeting the HER2/neu gene may play a role in cancer therapy.

Animals↗
PubMed1999

Management of diagnostic dilemmas of the pancreas by ultrasonographically guided laparoscopic biopsy.

INTRODUCTION: Pancreatic lesions may be difficult to diagnose because of small size or inaccessibility. Such lesions are being seen with increasing frequency because of advances in pancreatic imaging techniques. In the past 18 months we have evaluated 14 patients whose pancreatic lesions could not be diagnosed by traditional means, including percutaneous biopsy. METHODS: With the patient under general anesthesia, the anterior surface of the pancreas was exposed by a three-trocar laparoscopic technique. The lesion was located by laparoscopic ultrasonography. A core biopsy needle was inserted into the lesion under simultaneous visual and ultrasonographic guidance using picture-in-picture techniques. RESULTS: The main diagnostic dilemma encountered was the differentiation of pancreatic cancer from pancreatitis. Other conditions were lymphoma and renal cell carcinoma. Excellent tissue samples were obtained, allowing diagnosis and planning of treatment in all cases. Operative time ranged from 1 to 4 hours, and length of stay ranged from 1 to 3 days. Blood transfusions were not required, and there were no complications. Alcohol nerve block was performed laparoscopically in one patient in this group after the diagnosis was made by frozen section. CONCLUSIONS: Direct ultrasonographically guided laparoscopic biopsy provides rapid, safe diagnosis of pancreatic lesions.

Adult↗
PubMed1998

Antisense oligonucleotides specific for the HER2/neu oncogene inhibit the growth of human breast carcinoma cells that overexpress HER2/neu.

The HER2/neu oncogene encodes a cell surface protein which plays a role in growth factor-stimulated mitogenic signaling. HER2/neu is overexpressed in 30-40% of human breast carcinomas. This study tested the hypothesis that inhibiting HER2/neu expression using a phosphorothioate antisense (AS) oligonucleotide would inhibit the growth of breast cancer cells that overexpress this gene. A human breast carcinoma cell line, BT474, which overexpresses the HER2/neu oncogene was exposed to AS, sense (S), or scrambled antisense (SC) phosphorothioate oligonucleotides in tissue culture. Treatment with AS oligonucleotides specifically downregulated HER2/neu mRNA expression and resulted in lower levels of the HER2/neu protein product, p185; control oligonucleotides had no such effect. AS oligonucleotide treatment significantly inhibited the in vitro growth of BT474 cells, whereas S and SC controls had little effect on BT474 growth. HER2/neu AS oligonucleotide treatment had no effect on the growth of a distinct breast cancer line, MCF7, which expresses low levels of the HER2/neu oncogene. Breast carcinoma cells which overexpress the HER2/neu gene appear to be dependent on continued expression of this oncogene for cell growth. AS oligonucleotide pharmaceuticals which interfere with the expression of the HER2/neu oncogene may be of use in the therapy of some patients with breast carcinoma.

Breast Neoplasms↗
PubMed1997

Evolution and current status of the Whipple procedure: an update for gastroenterologists.

The Whipple procedure has undergone a remarkable gradual evolution in the last 20 years, of which many gastroenterologists are unaware. Improvements in staging, particularly staging laparoscopy with ultrasonography, have reduced the incidence of negative laparotomies. The forbidding mortality of pancreaticoduodenectomy, approximately 20% just a generation ago, has decreased precipitously in high-volume referral centers. Near zero mortality rates are now common. Morbidity and length of stay have also been reduced. Cardiac and pulmonary complications have been markedly reduced, whereas others such as pancreatic fistula still remain a problem. Modifications of the procedure have been introduced to improve long-term outcome of pancreatic cancer and to lessen digestive sequelae. Total pancreatectomy and large regional excisions did not improve results. However, 5-year survival rates of 20% are now reported by several centers for adenocarcinoma of the pancreas, and long-term survival rates for other periampullary tumors are approximately 40%. Pylorus-sparing procedures can be performed and may lessen postoperative sequelae. The clinical consequences of improved results are that large numbers of procedures are being performed at specialty centers, providing the opportunity to perform clinical trials, and that the procedure is used more widely, for instance, in benign diseases such as chronic pancreatitis.

Gastroenterology↗
PubMed1995

Molecular cloning and chromosomal localization of the human homologue of a B-lymphocyte specific protein tyrosine kinase (blk).

A cDNA encoding the human homologue of the murine protein tyrosine kinase, blk, has been cloned from a human B-lymphocyte cDNA library by cross-species hybridization using the murine blk cDNA as a probe. The sequence of the 2608 bp human blk cDNA clone contains an open reading frame encoding a predicted 505 amino acid protein with SH3, SH2 and catalytic domains that contain consensus sequences of the src protein tyrosine kinase family. Comparison of human and murine blk sequences indicated that they share 86% amino acid identity, the most conserved region being the catalytic domain (93% identity). Like the murine blk gene human blk is expressed only in B lymphocytes. The human blk gene was mapped to chromosome 8 at p22-23.

Amino Acid Sequence↗
PubMed1995

Prevention of breast tumour development in vivo by downregulation of the p185neu receptor.

Certain strains of transgenic mice that express the rat neu oncogene (neuT) in mammary epithelial cells develop breast tumours at an average of 44 weeks of age. In this study, intraperitoneal injection of a monoclonal anti-receptor antibody specific for the rat neuT oncogene product dramatically affected tumour development in these transgenic mice in a dose-dependent manner. A significant proportion (50%) of mice, when injected with anti-receptor antibodies, did not develop tumours even after 90 weeks of age. The phosphotyrosine levels of the membrane fraction of breast tissues in the anti-receptor antibody-treated mice were almost completely abolished when a higher dose of antibodies was used. This study demonstrates, for the first time, that immunologic manipulation of an oncogene product can effectively prevent the development of tumours in a rodent transgenic model.

Animals↗
PubMed1988

Monoclonal antibodies reactive with distinct domains of the neu oncogene-encoded p185 molecule exert synergistic anti-tumor effects in vivo.

The neu oncogene encodes a 185,000 dalton transmembrane glycoprotein, p185. The current study examined the effects of p185-specific monoclonal antibody administration on the tumorigenic growth of neu-transformed NIH3T3 cells implanted into nude mice. Treatment with anti-p185 monoclonal antibodies of the IgG1, IgG2a, IgG2b subclasses was able to profoundly inhibit the growth of neu-transformed cells. Furthermore, while none of these antibodies individually was able to cause complete eradication of tumors, the administration of mixtures of antibodies reactive with two distinct regions on the p185 molecule resulted in synergistic anti-tumor effects and complete eradication of tumors in a substantial fraction of the treated animals. The effect was oncogene specific, since the growth of ras transformed cells was not influenced by anti p185 antibodies. These results demonstrate that antibodies reactive with multiple domains of a tumor antigen can exert synergistic anti-tumor effects, and suggest that therapy with monoclonal antibodies specific for the neu oncogene product may play a role in cancer treatment.

Animals↗