Biomedical subjects

N K Altorki

Publications and source records attributed to N K Altorki.

At least 19 recordsLinked to original sources

PubMed1999

Curcumin inhibits cyclooxygenase-2 transcription in bile acid- and phorbol ester-treated human gastrointestinal epithelial cells.

We investigated whether curcumin, a chemopreventive agent, inhibited chenodeoxycholate (CD)- or phorbol ester (PMA)-mediated induction of cyclooxygenase-2 (COX-2) in several gastrointestinal cell lines (SK-GT-4, SCC450, IEC-18 and HCA-7). Treatment with curcumin suppressed CD- and PMA-mediated induction of COX-2 protein and synthesis of prostaglandin E2. Curcumin also suppressed the induction of COX-2 mRNA by CD and PMA. Nuclear run-offs revealed increased rates of COX-2 transcription after treatment with CD or PMA and these effects were inhibited by curcumin. Treatment with CD or PMA increased binding of AP-1 to DNA. This effect was also blocked by curcumin. In addition to the above effects on gene expression, we found that curcumin directly inhibited the activity of COX-2. These data provide new insights into the anticancer properties of curcumin.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed1999

Suppression of apoptosis does not foster neoplastic growth in Barrett's esophagus.

Esophageal adenocarcinoma often arises in association with metaplastic and dysplastic mucosa in Barrett's esophagus. Derangements in cell cycle control and apoptosis regulation might be responsible for the progression from metaplasia to dysplasia and adenocarcinoma We tested this hypothesis by performing cell cycle analysis, in situ detection of apoptosis, and evaluation for the immunohistochemical expression of proteins involved in proliferation (Ki-67), the control of apoptosis (bcl-2, bcl-x and bax), and cell cycle regulation (retinoblastoma and cyclin D1). We studied 17 randomly selected paraffin-embedded esophagectomy specimens that contained intestinal metaplasia without dysplasia, low-grade dysplasia, high-grade dysplasia, and esophageal adenocarcinoma Compared with gastric controls and intestinal metaplasia without dysplasia, high-grade dysplasia and esophageal adenocarcinoma demonstrated greater numbers of cells in S phase and G2 phase. Comparison of the proliferation index and the apoptotic rate in intestinal metaplasia without dysplasia, low-grade dysplasia, high-grade dysplasia, and esophageal adenocarcinoma showed a statistically significant trend that linked an increasing proliferation index and apoptotic rate with increasing histologic severity (P = .006 and P = .0002, respectively). A statistically significant linear association was found between bcl-x expression, bax expression, and the bcl-2-to-bax expression ratio versus increasing histologic severity (P = .0004, P = .007, and P = .03, respectively). These data support the hypothesis that neoplastic transformation of intestinal metaplastic epithelium in the esophagus might result from sequential changes in the expression of proteins involved in the control of apoptosis and the cell cycle. Furthermore, suppression of apoptosis does not seem to foster neoplastic growth in Barrett's esophagus. These observations will lead to a better understanding of the pathogenesis of esophageal adenocarcinoma and might contribute to enhancing the diagnostic accuracy when presented with dysplastic lesions.

Adenocarcinoma↗

PubMed1998

Human lung cancer antigens recognized by autologous antibodies: definition of a novel cDNA derived from the tumor suppressor gene locus on chromosome 3p21.3.

Serological analysis of a recombinant lung cancer cDNA expression library with the autologous patient serum led to the isolation of 20 clones representing 12 different genes: 4 of these were known genes, and the other 8 were previously unknown genes. Of the four known genes, aldolase A (NY-LU-1), previously shown to be overexpressed in lung cancer, was most frequently isolated. The other three genes were annexin XI, human HIV Rev-interacting protein Rip-1, and the human homologue of the ATP-binding arsA component of the bacterial arsenite transporter, all of which are known to be widely expressed in human tissues. Among the eight unknown genes, of most interest was NY-LU-12. Cloning of full-length NY-LU-12 showed that this cDNA was derived from the same gene as g16, a partially sequenced gene that mapped to the lung cancer tumor suppressor gene locus on chromosome 3p21. The reported g16 sequence, however, was significantly shorter (2433 versus 3591 bp). As a result of alternate splicing and subsequent frameshift, the reported g16 protein is 603 amino acids shorter than the NY-LU-12 product (1123 residues) at its COOH terminus and would therefore lack the epitopes recognized by the autologous serum. Analysis of the putative NY-LU-12 protein sequence predicted that it is a nuclear zinc finger protein with two RNA-binding domains, and Southern analysis showed that this gene is partially deleted in the lung cancer line NCI-H740 but not in nine other lung cancer lines. Screening of normal and cancer patient sera showed anti-NY-LU-12 seroreactivity in 2 of 21 allogeneic lung cancer patients but not in 24 patients with other tumors or in 16 sera from healthy donors. Comparison of NY-LU-12 cDNA from Lu15 tumor and normal lung tissue by DNA sequencing and/or single-strand conformation polymorphism analysis showed no evidence of mutation. Considering the high frequency of 3p21 alterations in lung cancer and the fact that the tumor suppressor gene or genes in this locus have not been identified, additional studies on the NY-LU-12 gene and its product are warranted.

Amino Acid Sequence↗

PubMed1998

Cardiac operations in patients with cirrhosis.

BACKGROUND: A retrospective review was performed to determine the outcome after cardiac operations in patients with a documented history of noncardiac cirrhosis. METHODS: The charts of patients admitted to the cardiothoracic surgical service between 1990 and 1996 were reviewed, and 13 patients with a preoperative history of cirrhosis were identified. The severity of preoperative liver disease was graded according to the criteria of Child. RESULTS: Most of the cases of cirrhosis were alcohol-related. Eight patients were classified as having Child class A and 5 as having Child class B cirrhosis. One hundred percent of patients with Child class B and 25% of those with Child class A cirrhosis had major complications. The postoperative chest tube output and transfusion requirements of these patients were approximately three times higher than average. The overall perioperative mortality rate was 31%. In patients with Child class B cirrhosis, the mortality rate was 80%. No patient with Child class A cirrhosis died. Deaths were related to gastrointestinal and septic complications, and not to cardiovascular failure. CONCLUSIONS: These findings suggest that patients with minimal clinical evidence of cirrhosis can tolerate cardiopulmonary bypass and cardiac surgical procedures, whereas those with more advanced liver disease should not be offered operation.

Aged↗

PubMed1998

Comprehensive multimodality blood conservation: 100 consecutive CABG operations without transfusion.

BACKGROUND: Despite the recent introduction of a number of technical and pharmacologic blood conservation measures, bleeding and allogeneic transfusion remain persistent problems in open heart surgical procedures. We hypothesized that a comprehensive multimodality blood conservation program applied algorithmically on the basis of bleeding and transfusion risk would provide a maximum, cost-effective, and safe reduction in postoperative bleeding and allogeneic blood transfusion. METHODS: One hundred consecutive patients undergoing coronary artery bypass grafting were prospectively enrolled in a risk factor-based multimodality blood conservation program (MMD group). To evaluate the relative efficacy and safety of this comprehensive approach, comparison was made with a similar group of 90 patients undergoing coronary artery bypass grafting to whom the multimodality blood conservation program was not applied but in whom an identical set of transfusion guidelines was enforced (control group). To evaluate the cost effectiveness of the multimodality program, comparison was also made between patients in the MMD group and a consecutive series of contemporaneous, diagnostic-related group-matched patients. RESULTS: One hundred consecutive patients in the MMD group underwent coronary artery bypass grafting without allogeneic transfusion. This compared favorably with the control population in whom a mean of 2.2 +/- 6.7 units of allogeneic blood was transfused per patient (34 patients [38%] received transfusion). In addition, the volume of postoperative blood loss at 12 hours in the control group was almost double that of the MMD group (660 +/- 270 mL versus 370 +/- 180 mL [p < 0.001]). Total costs for the MMD group in each of the three major diagnostic-related groups were equivalent to or significantly less than those in the consecutive series of diagnostic-related group-matched patients. CONCLUSIONS: Comprehensive risk factor-based application of multiple blood conservation measures in an optimized, integrated, and algorithmic manner can significantly decrease bleeding and need of allogeneic transfusion in coronary artery bypass grafting in a safe and cost-effective manner.

Algorithms↗

PubMed1998

Massive hiatal hernias: the anatomic basis of repair.

OBJECTIVES: In the repair of giant hiatal hernias, controversy persists as to whether an antireflux repair is required and whether a Collis gastroplasty is necessary. This study was undertaken to determine the location of the gastroesophageal junction in giant hiatal hernias with an intrathoracic stomach, as well as the outcome after repair without a Collis gastroplasty. METHODS: Fifty-two patients were evaluated for a giant hiatal hernia, of whom 47 underwent surgical correction. Preoperative evaluation included esophagoscopy (n = 45), gastrointestinal series (n = 40), esophageal manometry (n = 20), and 24-hour pH testing (n = 13). The dominant clinical features were acute chest or abdominal pain (72%), heartburn (53%), and gastrointestinal bleeding (49%). The gastroesophageal junction was located in the mediastinum in 77% of patients, in the abdomen in 17%, and was not determined in 6%. Twenty-eight patients (59%) had clinical or objective evidence of reflux. Reduction with an antireflux repair without a gastroplasty was done in 47 (Belsey, n = 28; Nissen, n = 19). An excellent or good result was achieved in 38 patients (90%) with a median follow-up of 45 months. CONCLUSIONS: These results, obtained without a Collis gastroplasty, are equivalent to those obtained by an antireflux repair with an esophageal lengthening procedure. The frequent location of the gastroesophageal junction in the mediastinum suggests that these massive hernias often are the result of progressive enlargement of a sliding component. An antireflux repair is therefore necessary in the majority of patients.

Aged↗

PubMed1998

Flavopiridol mediates cell cycle arrest and apoptosis in esophageal cancer cells.

Esophageal adenocarcinoma (SKGT-2, SKGT-4, and SKGT-5) and epidermoid carcinoma (HCE-4) cells containing variable retinoblastoma (Rb), cyclin D1, p16, and p53 expression patterns were exposed to the synthetic flavone, flavopiridol. The IC50 was approximately 100-150 nM for each of these cell lines. Exposure of esophageal carcinoma cells to 300 nM flavopiridol induced cell cycle arrest and apoptosis, resulting in a 90% inhibition of proliferation relative to that of nontreated cells after a 5-day exposure to the drug. Western blot analysis revealed diminution of cyclin D1, Rb, and p107 protein levels after flavopiridol exposure. Whereas cell cycle arrest and overall growth inhibition did not correlate in any obvious manner with the genotype of these cell lines, apoptosis seemed to be more pronounced in SKGT-2 and SKGT-4 cells that lack Rb expression. Pretreatment of esophageal cancer cells with 9-cis-retinoic acid did not substantially potentiate flavopiridol activity in these cell lines. Although the precise mechanism of flavopiridol-mediated cytotoxicity has not been fully defined, this drug is an attractive agent for molecular intervention in esophageal cancers and their precursor lesions; further evaluation of flavopiridol in this clinical context is warranted.

Antineoplastic Agents↗

PubMed1997

En bloc esophagectomy improves survival for stage III esophageal cancer.

OBJECTIVE: The role of en bloc esophagectomy in the surgical treatment of patients with locally advanced esophageal cancer is not well defined. This report attempts to elucidate its impact on survival, in comparison with less extensive resection, among patients with stage III disease. METHODS: A prospectively established database was retrospectively analyzed. RESULTS: One hundred twenty-eight patients underwent esophagectomy for carcinoma of the thoracic esophagus between 1988 and 1996 (78 underwent en bloc resection and 50 underwent standard resection). The 30-day and hospital mortality rates were 3.9% and 5.4%, respectively, comparable for the two procedures. Fifty-four patients had stage III disease. Overall 4-year survival was 34.5% after en bloc resection, with a median survival of 27 months (n = 33), and 11% after standard resection (n = 21), with a median survival of 12 months (p = 0.007). Among patients with stage III disease undergoing a complete resection, 4-year survivals were 36.7% and 0% after en bloc and standard resections, respectively (p = 0.001). Eighty-six of 128 patients had nodal metastasis. Three-year survivals for patients with NI disease were 33.9% and 13% after en bloc and standard resections, respectively (p = 0.02). CONCLUSION: Among patients with stage III esophageal cancer, en bloc resection appears to significantly improve survival compared with lesser resections. This improvement in survival may be attributable to resection of nodal disease.

Actuarial Analysis↗

PubMed1997

Expression of acidic fibroblast growth factor in Barrett's esophagus and associated esophageal adenocarcinoma.

OBJECTIVE: Adenocarcinoma of the esophagus is generally attributed to the neoplastic transformation of intestinal metaplastic lesions (Barrett's esophagus). On the basis of our preliminary data that showed significant acidic fibroblast growth factor mRNA and protein expression in adenocarcinoma of the esophagus, we studied expression of fibroblast growth factor in esophageal adenocarcinoma and its precursor lesions, intestinal metaplasia, low-grade dysplasia, and high-grade dysplasia. Fibroblast growth factor belongs to a family of polypeptides that are involved in differentiation and cellular proliferation. METHODS: We examined 30 esophagectomy specimens that were resected for adenocarcinoma (n = 27) and high-grade dysplasia (n = 3). After confirmation of the diagnosis by routine light microscopy, the index lesions (invasive carcinomas) and adjoining Barrett's mucosa were evaluated with a monoclonal antibody against human acidic fibroblast growth factor. The results are expressed with the use of an immunoreactive score that allows distinction between weak, moderate, and strong immunoreactivity. RESULTS: Adenocarcinoma demonstrated a moderate-to-strong mean immunoreactive score of 8. In contrast, high-grade dysplasia demonstrated a weak-to-moderate mean score of 4.5, which was significantly different (p < 0.05). Intestinal metaplasia and low-grade dysplasia displayed even weaker expression of fibroblast growth factor, with a negligible immunoreactive score less than 1 (p < 0.005). Seventy-five percent of evaluable cases demonstrated an increasing degree of fibroblast growth factor expression in the spectrum of lesions ranging from metaplasia to dysplasia and carcinoma. CONCLUSIONS: These data indicate that in patients with adenocarcinoma arising in association with Barrett's esophagus, fibroblast growth factor is generally sequentially accumulated in the progression from metaplasia to neoplasia. This progression may affect future investigation into the role of fibroblast growth factors in tumorigenesis and, possibly, the application of fibroblast growth factor immunohistochemistry to diagnosis.

Adenocarcinoma↗

PubMed1997

Occult cervical nodal metastasis in esophageal cancer: preliminary results of three-field lymphadenectomy.

The extent of lymphadenectomy for carcinoma of the thoracic esophagus remains debatable. A prospective study was initiated in August 1994 to evaluate the patterns of nodal spread after esophagectomy with three-field lymph node dissection. The hospital mortality rate was 3.3%. Nodal metastases occurred in 73% (22/30) of patients. The most commonly affected nodal groups were the lesser curvature nodes (57%), parahiatal nodes (42%), and the right recurrent nodes (35%). Cervical nodal metastasis occurred in 10 patients (35%) irrespective of tumor location or T status. The cervical field of dissection was as likely as the mediastinum to be a site of nodal disease. These findings should be considered when the operative strategy for esophageal carcinoma is planned.

Adult↗

PubMed1997

Extent of resection and lymphadenectomy in early Barrett's cancer.

The recognition of Barrett's esophagus as a premalignant condition has led to aggressive endoscopic screening protocols aimed at detecting adenocarcinoma in this organ. This policy has resulted in an increasing number of patients who present with 'early Barrett's cancer'. In the existing literature, very little data address patients with these lesions and, therefore, no consistent definition of early Barrett's cancer currently exists. Additionally, the extent of resection and lymphadenectomy that should be performed is not known. We define early Barrett's cancer as clinical T1N0M0 adenocarcinoma. We perform en bloc esophagectomy with radical lymphadenectomy for these lesions because current data suggest that a more radical operation may improve survival in patients with esophageal cancer. It is also the only way to stage adequately the tumour and is associated with morbidity and mortality rates comparable to less radical, 'standard' resections in experienced hands. Barrett's esophagus is associated with invasive adenocarcinoma in 40% of patients who undergo esophagectomy for the preoperative diagnosis of high-grade dysplasia. The existing literature suggests these lesions may represent the earliest subset of Barrett's cancer and that a standard, less radical resection may suffice for these patients.

Adenocarcinoma↗

PubMed1997

Is Barrett's esophagus the precursor of most adenocarcinomas of the esophagus and cardia? A biochemical study.

OBJECTIVE: To obtain biochemical evidence that Barrett's esophagus (BE) is the precursor of most adenocarcinomas (Adc) of the esophagus and cardia. SUMMARY BACKGROUND DATA: Based on morphologic data, BE was previously proposed as the precursor of most Adc of the esophagus. This hypothesis would receive strong support if biochemical evidence were found to demonstrate a pattern common to BE and Adc of the esophagus and cardia. METHODS: We studied the presence of intestinal-type proteins sucrase-isomaltase (SI) and crypt Cell Antigen (CCAg) in BE, Barrett's Adc, and esophageal-cardial Adc without BE. In each case specimens were collected from normal esophagus, stomach, tumor, and BE mucosa when present. To study related conditions, five specimens of peptic esophagitis and of squamous cell carcinoma were also analyzed. An indirect immunofluorescence technique was employed and sections were analyzed with laser confocal microscopy imaging. RESULTS: Most Barrett's mucosa specimens stained positively for SI (93%) and CCAg (89%). These proteins were detected in BE independently of the type of metaplasia, the coexistence of dysplasia, or the presence of associated Adc. SI and CCAg were present in 25 (96%) and 24 (92%) of the cases of Adc respectively. No statistical difference was detected in SI and CCAg expression between Adc samples with and without BE, between BE and Adc samples with or without BE, and between tumors located in the esophagus versus the cardia. No staining for these proteins was detected in stomach or esophageal mucosa, in submucosal glands of the esophagus, in peptic esophagitis or squamous cell carcinoma. CONCLUSION: These data show that BE and Adc of the esophagus and cardia have a similar phenotype and support the hypothesis that most of these tumors probably originate from preexisting BE.

Adenocarcinoma↗

PubMed1997

Pitfalls and complications of colon interposition.

Colon interposition is a complex operation that requires meticulous technique and attention to detail. In experienced hands, the colon is a valuable conduit for esophageal reconstruction, particularly in patients with benign disease.

Colon↗

PubMed1996

Intraoperative autologous blood donation preserves red cell mass but does not decrease postoperative bleeding.

BACKGROUND: Postoperative bleeding and transfusion remain a source of morbidity and cost after open heart operations. The benefit of the acute removal and reinfusion of fresh autologous blood around the time of cardiopulmonary bypass-a technique known as intraoperative autologous donation (IAD)-has not been universally accepted. We sought to more clearly evaluate the effects of IAD on allogeneic transfusion and postoperative bleeding by removing, preserving, and reinfusing a calculated maximum volume of fresh autologous whole blood. METHODS: Ninety patients undergoing coronary artery bypass grafting or valvular operations were prospectively randomized to either have (IAD group) or not have (control group) calculated maximum volume IAD performed. Treatment was otherwise identical. Transfusion guidelines were uniformly applied to all patients. RESULTS: An average volume of 1,540 +/- 302 mL of fresh autologous blood was removed and reinfused in the IAD group. Postoperative hematocrits were significantly greater at 12 and 24 hours postoperatively in the IAD group versus the control group despite a significant decrease in both the percentage of patients in whom allogeneic red blood cells were transfused (17% versus 52%; p < 0.01) and the number of red blood cell units transfused per patient per group (0.28 +/- 0.66 and 1.14 +/- 1.19 units; p < 0.01). Conversely, chest tube output, incidence of excessive postoperative bleeding, postoperative prothrombin time, and platelet and coagulation factor transfusion requirement did not differ between groups. CONCLUSIONS: These results indicate that intraoperative autologous donation serves to preserve red blood cell mass. Its routine use in eligible patients is therefore justified. However, the removal and reinfusion of an individually calculated maximum volume of fresh autologous blood had no effect on postoperative bleeding or platelet and coagulation factor transfusion requirement. This lack of hemostatic effect belies the beliefs of many about the primary action of IAD, helps to delineate the optimal way in which to perform IAD, and carries implications regarding the use of allogeneic platelet and coagulation factors for the treatment of early postoperative bleeding.

Adult↗

PubMed1996

Primary inflammatory fibrosarcoma of the esophagus.

Primary sarcomas of the esophagus are rare. We report the radiologic, surgical, and pathologic findings of a primary inflammatory fibrosarcoma of the esophagus in a 33-year-old woman, and review the prognostic features and management options of this tumor.

Adult↗

PubMed1995

The mutational status of p53 protein in gastric and esophageal adenocarcinoma cell lines predicts sensitivity to chemotherapeutic agents.

Resistance to chemotherapy remains a serious problem in the successful treatment of gastric and esophageal cancers. DNA-damaging agents alter levels of p53 protein in several cell types and it has been speculated that regulation of p53 can be involved in the resistance or sensitivity of cancer cells to some chemotherapeutic drugs, depending on whether cells have mutant or wild-type p53; however, little is known about the relationship of p53 to drug sensitivity in gastric/esophageal cancers. Here we have examined human gastric/esophageal adenocarcinoma cell lines for p53 mutational status, chemosensitivity to 5-fluorouracil, mitomycin C, and cis-dichlorodiammineplatinum(II), alteration in p53 levels following exposure of cells to these drugs, and the mechanisms involved in regulating p53 levels. Our results indicate that wild-type p53 protein levels increase after treatment with each of these drugs via either post-translational and/or translational mechanisms and that this increase in wild-type p53 appears to be required for effective chemotherapeutic growth control of gastric/esophageal adenocarcinoma cells. In contrast, gastric/esophageal cancer cells expressing either mutated p53 protein or no p53 protein are more resistant to the growth-inhibitory effects of these drugs, despite the fact that drug exposure can also increase mutant p53 levels by a translational mechanism. Thus, these data indicate that the mutational status of p53 is predictive of chemosensitivity of gastric and esophageal adenocarcinomas, and suggest a mechanism in which p53 protein contributes to the cellular response to chemotherapy.

Adenocarcinoma↗

PubMed1994

Esophageal carcinoma with airway invasion. Evolution and choices of therapy.

In order to define the evolution of airway invasion by esophageal cancer, we reviewed 53 patients presenting with (group A) or without (group B) tracheoesophageal fistulae. Patients in group A were treated by esophageal bypass (4), esophageal diversion (4), expectant therapy (4), or esophageal prosthesis (1). The median survival was 4 months. Group B patients were treated by esophageal resection (18), esophageal bypass (4), or radiation therapy (13), depending on the extent of local disease. Bronchoscopy was a valuable tool for predicting resectability. Surgical resection, when possible, yielded better palliation. There were 4 long-term survivors in group B.

Adenocarcinoma↗

PubMed1994

Extended resections in the management of esophageal carcinoma.

The survival rate of patients with carcinoma of the esophagus is dismal. Improvement could be achieved only by earlier diagnosis and radical resection techniques to remove the esophagus and its draining lymphatic bed. En bloc esophagectomy and esophagectomy with three-field lymph node dissection are practiced in some centers in North America, Europe, and Japan. Survival rates with these techniques are better than those obtained with standard resection techniques.

Esophageal Neoplasms↗