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Biomedical subjects

N Altorki

Publications and source records attributed to N Altorki.

At least 19 recordsLinked to original sources
PubMed2001

Early lung cancer action project: initial findings on repeat screenings.

BACKGROUND: The Early Lung Cancer Action Project (ELCAP) was designed to evaluate the usefulness of annual computed tomography (CT) screening for lung carcinoma. With the baseline results having been reported previously, the focus of the current study was on the early results of the repeat screenings. METHODS: A cohort of 1000 high-risk individuals was recruited for baseline and annual repeat CT screening. At last follow-up, a total of 1184 annual repeat screenings had been performed. A positive result from the screening test was defined as newly detected, one to six noncalcified pulmonary nodules with interim growth. The diagnostic workup of the individuals was guided by recommendations supplied by the ELCAP investigators to the collaborating clinicians. RESULTS: Of the 1184 repeat CT screenings, the test result was positive in 30 (2.5%). In 2 of these 30 cases, the individual died (of an unrelated cause) before diagnostic workup and the nodule(s) resolved in another 12 individuals. In the remaining 16 individuals, the absence of further growth was documented by repeat CT in 8 individuals and further growth was documented in the remaining 8 individuals. All eight individuals with further nodular growth underwent biopsy and malignancy was diagnosed in seven. Six of these seven malignancies were nonsmall cell carcinomas (five of which were Stage IA and one of which was Stage IIIA) and the one small cell carcinoma was found to be of limited stage. The median size dimension of these malignancies was 8 mm. In another two subjects, symptoms prompted the interim diagnosis of lung carcinoma. Neither of these malignancies was nodule-associated but rather were endobronchial; one was a Stage IIB nonsmall cell carcinoma and the other was a small cell carcinoma of limited stage. CONCLUSIONS: False-positive screening test results are uncommon and usually manageable without biopsy; compared with no screening, such screenings permit diagnosis at substantially earlier and thus more curable stages. Annual repetition of CT screening is sufficient to minimize symptom-prompted interim diagnoses of nodule-associated malignancies.

Aged↗
PubMed2001

Immunohistochemical analysis of NY-ESO-1 antigen expression in normal and malignant human tissues.

NY-ESO-1, a member of the CT (cancer/testis) family of antigens, is expressed in normal testis and in a range of human tumor types. Knowledge of NY-ESO-1 expression has depended on RT-PCR detection of mRNA and there is a need for detecting NY-ESO-1 at the protein level. In the present study, a method for the immunochemical detection of NY-ESO-1 in paraffin-embedded tissues has been developed and used to define the expression pattern of NY-ESO-1 in normal tissues and in a panel of human tumors. No normal tissue other than testis showed NY-ESO-1 reactivity, and expression in testis was restricted to germ cells particularly spermatogonia. In human tumors, the frequency of NY-ESO-1 antigen expression corresponds with past analysis of NY-ESO-1 mRNA expression e.g., 20-30% of lung cancers, bladder cancers and melanoma, and no expression in colon and renal cancer. Co-typing of NY-ESO-1 antigen and mRNA expression in a large panel of lung cancers showed a good correlation. There is great variability in NY-ESO-1 expression in individual tumors, ranging from an infrequent homogeneous pattern of staining to highly heterogeneous antigen expression.

Antibodies, Monoclonal↗
PubMed2001

Detection of early-stage lung cancer: computed tomographic scan or chest radiograph?

OBJECTIVE: Computed tomography has recently been proposed as a useful method for the early detection of lung cancer. In this study we compared the stage distribution of lung cancers detected by a computed tomographic scan with that of lung cancers detected by a routine chest x-ray film. METHODS: Two groups of patients with biopsy-proven non-small cell lung cancer were reviewed. In the first group of 32 patients, the tumors were detected by a computed tomographic scan. In a second group (n = 101), the lung cancers were detected on routine chest x-ray films. Patients with pulmonary symptoms or a history of cancer were excluded. RESULTS: There was no difference in age, sex, or cell-type distribution between the 2 groups. A significantly greater number of patients undergoing a computed tomographic scan had stage IA disease compared with those having an x-ray film. Of the 32 patients in the group having a scan, 10 had tumors 1 cm or less in size versus 6 of 101 in the group having a chest radiograph. Additionally, there was a significant reduction in advanced stage disease in the group having a scan. CONCLUSIONS: In this retrospective study, a higher incidence of stage IA lung cancers and significantly fewer cases of more advanced disease were observed in patients screened with computed tomography than in those having a chest radiograph. These data suggest that computed tomographic screening may be of value in improving the survival of patients with non-small cell lung cancer.

Adult↗
PubMed2001

Should en bloc esophagectomy be the standard of care for esophageal carcinoma?

OBJECTIVE: To determine the impact of radical node dissection on the recurrence patterns and survival rates of patients with carcinoma of the esophagus. SUMMARY BACKGROUND DATA: The role of esophagectomy with radical lymphadenectomy in the treatment of esophageal cancer is controversial. Most centers favor a limited operation with no attempt at nodal clearance. However, disease recurrence and patient survival rates remain dismal with or without preoperative therapy. The authors postulate that a more radical node dissection would reduce local failure rates and enhance survival. METHODS: One hundred eleven patients with esophageal cancer underwent en bloc esophagectomy with radical lymph node dissection between 1988 and 1998. In 90% of patients the procedure was applied nonselectively and without any preoperative therapy. Patients were prospectively followed up for recurrence patterns and survival. RESULTS: The 5-year survival rate including noncancer deaths was 40%. The 5-year survival rates for patients with stage 1, 2A, 2B, 3, and 4 disease were 78%, 72%, 0%, 39%, and 27%, respectively. Forty percent of patients had node-negative disease (5-year survival rate, 75%), and 60% had nodal metastases (5-year survival rate, 26%). Recurrence occurred in 39% of patients and was local in only 8%. CONCLUSIONS: Radical esophagectomy results in superior overall and stage-specific 5-year survival rates. Extensive node dissection has a positive impact on survival rates, particularly in patients with nodal metastases.

Adult↗
PubMed2001

Acidic fibroblast growth factor is expressed sequentially in the progression from Barrett's esophagus to esophageal adenocarcinoma.

Acidic fibroblast growth factor 1 (FGF-1) is sequentially accumulated in Barrett's esophagus and its expression in glandular dysplasias is independent of esophageal adenocarcinoma. This suggests that FGF-1 immunohistochemistry could be used as an adjunct to the routine histopathologic diagnosis of dysplasia in Barrett's esophagus. The data also underscore the important role of fibroblast growth factors in tumorigenesis.

Adenocarcinoma↗
PubMed2001

Early lung cancer action project: a summary of the findings on baseline screening.

PURPOSE: The Early Lung Cancer Action Project (ELCAP) is designed to evaluate baseline and annual repeat screening by low radiation dose computed tomography (low-dose CT) in persons at high-risk for lung cancer. METHODS: Since starting in 1993, the ELCAP has enrolled 1,000 asymptomatic persons, 60 years of age or older, with at least 10 pack-years (1 pack per day for 10 years, or 2 packs per day for 5 years) of cigarette smoking, no prior cancer, and medically fit to undergo thoracic surgery. After a structured interview and informed consent, baseline chest radiographs and low-dose CT were obtained on each subject. The diagnostic work-up of screen-detected noncalcified pulmonary nodules (NCN) was guided by ELCAP recommendations which included short-term high-resolution CT follow-up for the smallest nodules. Baseline RESULTS: On low-dose CT at baseline compared to chest radiography, NCN were detected three times as commonly (23% versus 7%), malignancies four times as commonly (2.7% versus 0.7%), and stage I malignancies six times as commonly (2.3% versus 0.4%). Of the 27 CT-detected cancers, 96% (26/27) were resectable; 85% (23/27) were stage I, and 83% (19 of the 23 stage I) were not seen on chest radiography. Following the ELCAP recommendations, biopsies were performed on 28 of the 233 subjects with NCN; 27 had a malignant and one a benign NCN. Another three individuals underwent biopsy outside of the ELCAP recommendations; all had benign NCNS: No one had thoracotomy for a benign nodule. CONCLUSION: Baseline CT screening for lung cancer provides for detecting the disease at earlier and presumably more commonly curable stages in a cost-effective manner.

Clinical Trials as Topic↗
PubMed2000

Staging and the surgical management of lung cancer.

Small cell lung cancer remains a nonsurgical disease with the majority (80%) of cases presenting in higher stages. The primary treatment modalities for small cell lung cancer are radiation therapy and systemic chemotherapy, often administered concomitantly. This article focuses on the staging and surgical management of non-small-cell lung cancer.

Carcinoma, Non-Small-Cell Lung↗
PubMed2000

Monoclonal antibody MA454 reveals a heterogeneous expression pattern of MAGE-1 antigen in formalin-fixed paraffin embedded lung tumours.

Cancer/testis (CT) antigens such as those encoded by the MAGE-gene family are expressed in a wide variety of malignant neoplasms. In normal tissues, expression is generally restricted to testis. Current knowledge of the expression pattern of CT antigens is mainly based on mRNA analysis. Little is known about actual protein expression. We previously developed MA454, a monoclonal antibody (mAb) to MAGE-1 recombinant protein. By employing antigen retrieval techniques, we show that MA454 is reactive on formalin-fixed paraffin-embedded tissues. Immunohistochemical (IHC) analysis of a normal tissue panel revealed staining solely in germ cells of testes. A series of 59 lung tumours was co-typed for MAGE-1 expression by RT-PCR and by immunohistochemistry with MA454. MA454 was positive in 19/59 cases (32%). MAGE-1 mRNA was found in 17 of the 54 cases (32%) available for RT-PCR. Of the 19 MA454-reactive tumours, 15 showed a highly heterogeneous pattern of expression. The other 4 MA454 positive cases revealed immunoreactivity in >25% of tumour areas. Of the 53 cases typed for both, mRNA and protein expression, 48 co-typed whereas 5 cases were discrepant, a likely consequence of heterogeneous MAGE-1 expression. The predominantly focal expression of MAGE-1 suggests that this antigen might not be sufficient as a sole target for immunotherapeutic approaches.

Antibodies, Monoclonal↗
PubMed1999

Inhibition of cyclooxygenase-2 gene expression by p53.

Oncogenes enhance the expression of cyclooxygenase (Cox)-2, but interactions between tumor suppressor genes and Cox-2 have not been studied. In the present work, we have compared the levels of Cox-2 and the production of prostaglandin E2 in mouse embryo fibroblasts that do not express any p53 ((10)1) versus the same cell line ((10. 1)Val5) engineered to overexpress wild-type (wt) p53 at 32 degrees C or mutant p53 at 39 degrees C. Cells expressing wt p53 showed about a 10-fold decrease in synthesis of prostaglandin E2 compared with those expressing mutant p53. Levels of Cox-2 protein and mRNA were markedly suppressed by wt p53 but not by mutant p53. Nuclear run-offs revealed decreased rates of Cox-2 transcription in cells expressing wt p53. The activity of the Cox-2 promoter was reduced by 85% in cells expressing wt p53 but was reduced only by 30% in cells expressing mutant p53 compared with cells null for p53. The effect of p53 on the suppression of Cox-2 promoter activity was localized to the first 40 base pairs 5' from the transcription start site. Electrophoretic mobility shift assay revealed that p53 competed with TATA-binding protein for binding to mouse Cox-2 or human Cox-2 promoter extending from -50 to +52 base pairs. The results of this study suggest that interactions between p53 and Cox-2 could be important for understanding why levels of Cox-2 are undetectable in normal cells and increased in many tumors.

Animals↗
PubMed1998

Dihydroxy bile acids activate the transcription of cyclooxygenase-2.

Bile acids, endogenous promoters of gastrointestinal cancer, activate protein kinase C (PKC) and the activator protein-1 (AP-1) transcription factor. Because other activators of PKC and AP-1 induce cyclooxygenase-2 (COX-2), we determined the effects of bile acids on the expression of COX-2 in human esophageal adenocarcinoma cells. Treatment with the dihydroxy bile acids chenodeoxycholate and deoxycholate resulted in an approximately 10-fold increase in the production of prostaglandin E2 (PGE2). Enhanced synthesis of PGE2 was associated with a marked increase in the levels of COX-2 mRNA and protein, with maximal effects at 8-12 and 12-24 h, respectively. In contrast, neither cholic acid nor conjugated bile acids affected the levels of COX-2 or the synthesis of PGE2. Nuclear run-off assays and transient transfections with a human COX-2 promoter construct showed that induction of COX-2 mRNA by chenodeoxycholate and deoxycholate was due to increased transcription. Bile acid-mediated induction of COX-2 was blocked by inhibitors of PKC activity, including calphostin C and staurosporine. Treatment with bile acid enhanced the phosphorylation of c-Jun and increased binding of AP-1 to DNA. These data are important because dihydroxy bile acid-mediated induction of COX-2 may explain, at least in part, the tumor-promoting effects of bile acids.

Bile Acids and Salts↗
PubMed1998

Outcome analysis of 245 CarboMedics and St. Jude valves implanted at the same institution.

BACKGROUND: Thromboembolism and valve-related death are major complications associated with prosthetic valve implants, but it is difficult to evaluate the relative incidence of these complications based on studies in which the implantation of only one valve is reported from any given institution. We therefore report the outcome of patients implanted at our institution during the same time period with either the recently released CarboMedics (CM) or the St. Jude Medical (SJ) valve prostheses. METHODS: Between October 1994 and January 1996, 245 consecutive patients received either SJ (116 patients) or CM (129 patients) valves at our institution. Follow up of these patients was 99.6% complete, for a total of 318.5 cumulative patient-years (median follow-up, 1.4 years). RESULTS: The 30-day mortality rates for SJ and CM implants were 3.4% and 3.1%, respectively. Actuarial survival and freedom from valve related mortality rates at 1.5 years for SJ and CM valves were 94%+/-2% versus 86%+/-3% (p = 0.03) and 100% versus 94%+/-2% (p = 0.005), respectively. There was no structural valve failure for either implant, but there were five thrombosed valves in the CM group and none in the SJ group (p = 0.04). All thrombosed valves were mitral (four mitral valve replacement, one aortic and mitral valve replacement). Two of the thrombosed valves were successfully explanted, whereas the three remaining patients died. Freedom from a thromboembolic event in the mitral position at 1.5 years, including thrombosed valves was 97%+/-3% and 83%+/-5% for SJ and CM valves, respectively (p = 0.04). CONCLUSIONS: The results of this study suggest that further evaluation of thromboembolic outcomes after CM compared with SJ valve implantation is warranted.

Aortic Valve↗
PubMed1998

Retrograde autologous priming for cardiopulmonary bypass: a safe and effective means of decreasing hemodilution and transfusion requirements.

OBJECTIVES: The obligatory hemodilution resulting from crystalloid priming of the cardiopulmonary bypass circuit represents a major risk factor for blood transfusion in cardiac operations. We therefore examined whether retrograde autologous priming of the bypass circuit would result in decreased hemodilution and red cell transfusion. METHODS: Sixty patients having first-time coronary bypass were prospectively randomized to cardiopulmonary bypass with or without retrograde autologous priming. Retrograde autologous priming was performed at the start of bypass by draining crystalloid prime from the arterial and venous lines into a recirculation bag (mean volume withdrawal: 880 +/- 150 ml). Perfusion and anesthetic techniques were otherwise identical for the two groups. The hematocrit value was maintained at a minimum of 16% and 23% during and after cardiopulmonary bypass, respectively, in all patients. Patients were well matched for all preoperative variables, including established transfusion risk factors. Subsequent hemodynamic parameters, pressor requirements, and fluid requirements were equivalent in the two groups. RESULTS: The lowest hematocrit value during cardiopulmonary bypass was 22% +/- 3% versus 20% +/- 3% in patients subjected to retrograde autologous priming and in control patients, respectively (p = 0.002). One (3%) of 30 patients subjected to retrograde autologous priming had intraoperative transfusion, and seven (23%) of 30 control patients required transfusion during the operation (p = 0.03). The number of patients receiving any homologous red cell transfusions in the two groups during the entire hospitalization was eight of 30 (27%; retrograde autologous priming) versus 16 of 30 (53%; control) (p = 0.03). CONCLUSIONS: These data suggest that retrograde autologous priming is a safe and effective means of significantly decreasing hemodilution and the number of patients requiring red cell transfusion during cardiac operations.

Aged↗
PubMed1995

Amplification of HER-2/neu gene in human gastric adenocarcinomas: correlation with primary site.

Adenocarcinomas of the proximal stomach including the gastroesophageal junction are extremely virulent cancers which are increasing rapidly in incidence. Stage-for-stage proximal gastric cancers have a worse prognosis than do tumors of the body or antrum of the stomach. To further explore biological differences based on site, we studied 80 patients with locally advanced primary tumours of the proximal (n = 40) and distal stomach (n = 40) for amplification of the HER-2/neu proto-oncogene. None of 40 patients with proximal lesions had overexpression of HER-2/neu, whereas four of 40 (10%) distal adenocarcinomas had a 16-24-fold gene amplification (P = 0.04). In the adenocarcinomas from two patients, gene rearrangements were found in addition to amplification. HER-2/neu gene product p185 over-expression was found only in the amplified cases. All four patients with distal tumors and amplification had rapid progression of disease (median survival: 4.3 months). While it is unclear why HER-2/neu amplification is seen only in distal tumors, these data further support the hypothesis that biological differences between proximal and distal lesions are present. As is the case for other tumours, HER-2/neu amplification is associated with a poor prognosis for the individual patient.

Adenocarcinoma↗
PubMed1994

Defining the invasive phenotype of proximal gastric cancer cells.

BACKGROUND: Adenocarcinoma of the proximal stomach is now the most rapidly rising cancer among men in the United States. The development of metastases is the major cause of morbidity and mortality for this aggressive disease. The mechanisms by which tumor cells invade the basement membrane are unknown for this disease. We have identified and established 5 invasive and noninvasive adenocarcinoma cell lines arising from the proximal stomach, which can be used to examine the mechanisms involved in tumor cell invasion. METHODS: The expression of factors associated with tumor cell attachment, proteolysis, and inhibition of proteolysis was determined by reverse transcription of mRNA to cDNA and subsequent amplification by the polymerase chain reaction. In addition, cells were examined for morphologic changes by scanning electron microscopy. RESULTS: Invasive proximal gastric cancer cells express the 72-kD form of collagenase type IV, whereas the noninvasive cells do not. Other factors examined (including the laminin receptor, cathepsin B, cathepsin L, urokinase-type plasminogen activator, and tissue inhibitor metalloproteinases) are expressed by both invasive and noninvasive gastric cancer cells, whereas collagenase type IV 92-kD form is not expressed by any of the cells examined. In addition, scanning electron microscopy revealed that all the invasive cell lines exhibit long cytoplasmic extensions. The noninvasive cells express short cytoplasmic projections and are rounder than the invasive proximal gastric cancer cell lines. CONCLUSIONS: There are distinct phenotypic differences between invasive and noninvasive proximal gastric cancer cell lines both at the level of expression of mRNA for collagenase Type IV 72-kD and at the level of scanning electron microscopy with the expression of cytoplasmic projections. Clinical outcome may be associated with these phenotypic differences.

Adenocarcinoma↗
PubMed1993

Characterization of cell lines established from human gastric-esophageal adenocarcinomas. Biologic phenotype and invasion potential.

BACKGROUND: Gastric carcinoma is one of the most common malignancies worldwide, with an overall survival of about 10%. Improvement in therapy awaits better understanding of the biologic behavior of this tumor. Establishment of cell lines permits detailed analysis of the biology of gastric cancer. The authors report on the establishment and characterization of five cell lines arising from primary proximal gastric and distal esophageal adenocarcinomas. METHODS: Cultures of epithelial cells from adenocarcinomas of the proximal stomach or adenocarcinoma of the lower esophagus were established. Gastric cancer cell lines were analyzed for doubling times, anchorage-independent growth, tumorigenic and metastatic potential in nu/nu mice, expression of keratin proteins by indirect immunofluorescence, invasive potential in a Boyden Chamber, and growth factor production by reverse transcription of mRNA in cDNA and subsequent amplification by the polymerase chain reaction. RESULTS: Five cell lines were derived from primary gastric adenocarcinomas of the proximal stomach and from Barrett esophagus. All five cell lines were tumorigenic but not metastatic in vivo. None were capable of anchorage independent growth in vitro. Two lines were highly invasive in the Boyden chamber assay, whereas two lines were minimally or noninvasive. All five cell lines expressed RNA transcripts specific for the growth factors TGF beta 1, TGF beta 2, TGF beta 3, TGF alpha, and platelet-derived growth factor A, whereas subsets of cell lines expressed transcripts for aFGF, bFGF, FGF-5, Hst, and platelet-derived growth factor B. CONCLUSIONS: Five cell lines derived from primary gastric-esophageal adenocarcinomas were established in tissue culture. These cell lines show differences in morphologic features, growth potential, and invasiveness. These newly established gastric cancer cell lines should prove useful for a wide range of studies attempting to decipher the biology of proximal gastric adenocarcinoma.

Adenocarcinoma↗
PubMed1993

Reoperative coronary artery bypass surgery. Improved preservation of myocardial function with retrograde cardioplegia.

BACKGROUND: Cardiac-related mortality remains high for reoperative coronary artery bypass graft surgery (rCABG) compared with first-time surgery (fCABG). Retrograde cardioplegia (RC) has been suggested but not proven to improve the results for rCABG. METHODS AND RESULTS: We therefore reviewed the records of 240 consecutive patients who had undergone rCABG at our institution since 1988. The interval to reoperation was 9.1 +/- 4.2 years (mean +/- SD), with a range from 0.2 to 18 years. Only 46% of grafts were patent at the time of rCABG. The incision to cardiopulmonary bypass (CPB), incision to cross-clamp (XCL), and XCL per graft time intervals were significantly prolonged compared with 100 consecutive fCABG patients operated on during the same time period. Blood utilization was also significantly increased in rCABG compared with fCABG patients. Overall operative mortality was 5.8% and 0% for rCABG and fCABG patients, respectively (P < .05). High-risk criteria (emergency surgery, angina at rest requiring intravenous nitroglycerin or intra-aortic balloon pump [IABP] support [urgent surgery], recent [<21 days] myocardial infarction, or ejection fraction < 30%) were noted in 136 rCABG patients (57%) and 28 fCABG patients (28%) (P < .001). Profound postoperative myocardial dysfunction (postoperative IABP dependence) occurred in only one of 104 low-risk patients (1%), compared with 14 of 136 high-risk patients (10%) (P < .005). Operative mortality was noted in 13 high-risk patients (9.5%) compared with one low-risk patient (1%) (P < .005). RC was used in 80 patients without complication. Postoperative IABP dependence developed in only 2 of 53 high-risk/RC patients (3.8%) compared with 12 of 83 high-risk/non-RC patients (14.5%) (P < .05). At follow-up, rCABG and fCABG patients enjoyed similar symptomatic improvement. CONCLUSIONS: We conclude that retrograde cardioplegia, possibly by minimizing the increased ischemia associated with rCABG, improves the results of rCABG, specifically in regard to preventing profound myocardial dysfunction in high-risk patients.

Coronary Artery Bypass↗
PubMed1990

11p13-15 is a specific region of chromosomal rearrangement in gastric and esophageal adenocarcinomas.

In a cytogenetic analysis of 9 gastric and lower esophageal adenocarcinomas, we detected nonrandom rearrangements involving the region 11p13-15 in 8, thus identifying for the first time a specific chromosomal lesion in these tumors. In addition, rearrangements involving 3p21, translocations among the D group chromosomes, and i(5p) were each observed in more than half of the cases. The overall pattern of aberrations encountered in adenocarcinomas of gastric and lower esophageal origin was similar, suggesting that the tumors arising at these anatomical sites are biologically related. We also encountered cytogenetic evidence for gene amplification in the form of homogeneously staining regions and double-minute chromosomes in primary as well as metastatic lesions, which is consistent with amplification of a number of cellular oncogenes in these tumors detected by others and us at the molecular level. These cytogenetic findings are discussed in relation to nonrandom chromosome abnormalities and gene amplification reported in other types of adenocarcinoma.

Adenocarcinoma↗