Variation by stage in the effects of prediagnosis weight loss on mortality in a prospective cohort of esophageal cancer patients.

Cancer cachexia is increasingly recognized as a poor prognostic marker for various tumor types. Weight loss in esophageal cancer is multifactorial, as patients with bulky tumors also have reduced ability to eat. We aimed to investigate the relationship between prediagnosis weight loss and mortality in esophageal cancer and to determine whether these associations vary with tumor stage. We conducted a prospective cohort study of esophageal cancer patients at two tertiary centers. We recorded baseline patient characteristics including medications, smoking, body mass index, and weight loss in the year prior to diagnosis, and collected data on treatment and outcomes. We used Cox regression modeling to determine the associations between percent weight loss and outcomes. The main outcome of interest was all-cause mortality; secondary endpoints were esophageal cancer-specific mortality and development of metastases. We enrolled 134 subjects, the majority of whom had adenocarcinoma (82.1%); median percent weight loss was 4.7% (IQR: 0%-10.9%). Increasing percent weight loss was not associated with all-cause mortality (ptrend = 0.36). However, there was evidence of significant interaction by tumor stage (p = 0.02). There was a strong and significant association between prediagnosis weight loss and mortality in patients with T stages 1 or 2 (adjusted HR 8.26 for highest versus lowest tertile, 95%CI 1.11-61.5, ptrend = 0.03) but not for T stages 3 or 4 (ptrend = 0.32). Body mass index one year prior to diagnosis was not associated with mortality. Prediagnosis weight loss was associated with increased all-cause mortality only in patients with early stage esophageal cancer. This suggests that tumor-related cachexia can occur early in esophageal cancer and represents a poor prognostic marker.

Cigarette smoke mediates epigenetic repression of miR-217 during esophageal adenocarcinogenesis.

Although microRNAs (miRs) have been implicated in the pathogenesis of various human malignancies, limited information is available regarding mechanisms by which these noncoding RNAs contribute to initiation and progression of tobacco-induced esophageal cancers. In this study, array and quantitative reverse transcriptase-PCR techniques were used to examine miR expression in immortalized esophageal epithelia (IEE) and esophageal adenocarcinoma (EAC) cells cultured in normal media with or without cigarette smoke condensate (CSC). Under relevant exposure conditions, CSC significantly decreased miR-217 expression in these cells. Endogenous levels of miR-217 expression in cultured EAC cells (EACC)/primary EACs were significantly lower than those observed in IEE/ paired normal esophageal tissues. RNA crosslink immunoprecipitation, quantitative reverse transcriptase-PCR (qRT-PCR) and immunoblot experiments demonstrated direct interaction of miR-217 with kallikrein 7 (KLK7), encoding a putative oncogene not previously implicated in EAC. Repression of miR-217 correlated with increased levels of KLK7 in primary EACs, particularly those from smokers. Chromatin and methylated DNA immunoprecipitation experiments demonstrated that CSC-mediated repression of miR-217 coincided with DNMT3b-dependent hypermethylation and decreased occupancy of nuclear factor 1 within the miR-217 genomic locus. Deoxyazacytidine induced miR-217 expression and downregulated KLK7 in EACC; deoxyazacytidine also attenuated CSC-mediated miR-217 repression and upregulation of KLK7 in IEE and EACC. Overexpression of miR-217 significantly decreased, whereas overexpression of KLK7 increased proliferation, invasion and tumorigenicity of EACC. Collectively, these data demonstrate that epigenetic repression of miR-217 contributes to the pathogenesis of EAC via upregulation of KLK7 and suggest that restoration of miR-217 expression may be a novel treatment strategy for these malignancies.

Surgical management of chylothorax.

BACKGROUND: Chylothorax remains an uncommon but challenging clinical problem. Thoracic duct ligation is the treatment of choice for postsurgical patients. However, the optimal treatment for traumatic patients is unclear. We wanted to examine the outcomes of patients with high output or recurrent chylothorax who were treated by surgical means. METHODS: From December 1992 to April 2008, 29 patients underwent surgical procedures for high output (> 1 L/day) (16) or recurrent chylothorax (13). We analyzed these patients to determine the surgical approach, perioperative complications, and outcomes of the treatment approach. RESULTS: Of the 29 patients, 12 patients developed chylothorax following esophagectomy, in 5 patients it resulted from lymphoproliferative disorders, in 2 patients following ascending aneurysm repair, in 2 after trauma, in 3 following lung resection, and in 1 patient respectively from coronary artery bypass grafting (CABG), thymectomy for thymoma, vasculitis, and metastatic lung cancer, while 1 patient had no clear etiology. The median age of patients was 61 (range 20-79) years. 22 patients initially underwent thoracic duct ligation, 6 had talc pleurodesis, and one underwent bilateral pleuroperitoneal shunt placement. Approaches for thoracic duct ligation included: right thoracotomy (16), left thoracotomy (3), VATS (2), and right thoracotomy together with laparotomy (1). There were no intraoperative complications or deaths within 30 days or during postoperative hospitalization. The success rate after initial thoracic duct ligation was 95 % (21/22). One patient needed re-exploration after ligation with resolution of chylothorax after the second operation. The success rate after pleurodesis was 83 % (5/6). One patient after pleurodesis needed subsequent thoracic duct ligation for resolution of bilateral chylothoraces. All patients in this series had resolution of chylothorax. CONCLUSIONS: Thoracic duct ligation is the treatment of choice for high output or recurrent chylothorax with a 96 % success rate. Surgical pleurodesis is effective in some cases and may be an option for marginal patients.

Preoperative chemotherapy for esophageal cancer with paclitaxel and carboplatin: results of a phase II trial.

OBJECTIVE: Paclitaxel has one of the highest response rates when used as a single agent in patients with esophageal cancer. The combination of paclitaxel and carboplatin has been shown to be a well-tolerated and safe regimen in non-small cell lung cancer. The objective of this study was to determine the efficacy of preoperative paclitaxel and carboplatin in patients with carcinoma of the esophagus. PATIENTS AND METHODS: A phase II trial was initiated in January 1999 and concluded in January 2001. All patients had potentially resectable disease (including clinical T4 lesions). Patients with stage I disease and those with visceral metastases were excluded. All underwent preoperative computed tomography scanning and endosonography for staging. Paclitaxel (200 mg/m(2)) and carboplatin (area under the curve = 6) were given on days 1 and 22. Esophagectomy was carried out on weeks 6 to 8. RESULTS: Twenty-six (11 epidermoid, 15 adenocarcinoma) patients completed the trial. Median age was 61.5 and 85% were men. Preoperative staging showed: stage IIA, 6 patients; stage IIB, 1 patient; and stage III, 19 patients. All patients completed their preoperative chemotherapy. There was no unexpected chemotherapy-related toxicity. A major clinical response was achieved in 16 patients (61%: 19% complete, 42% partial). Resectability was 77% (20/26). A complete pathologic response was seen in 11% of all patients and in 25% of those with epidermoid cancer. Hospital mortality and morbidity were 4 and 27%, respectively. Overall 3-year survival was 48% (64% for resected patients, median not reached). All 6 unresectable patients died within 6 months of exploration. CONCLUSION: Paclitaxel-carboplatin combination is a safe and well-tolerated regimen for esophageal cancer with clinical response rates comparable to historical controls. This regimen may be especially suitable for patients with epidermoid cancer, who had a 25% pathological complete response in this report.

Celecoxib, a selective cyclo-oxygenase-2 inhibitor, enhances the response to preoperative paclitaxel and carboplatin in early-stage non-small-cell lung cancer.

PURPOSE: Preclinical studies suggest that treatment with a selective cyclo-oxygenase-2 (COX-2) inhibitor may augment the antitumor effects of chemotherapy. In this study, patients with non-small-cell lung cancer (NSCLC) were preoperatively treated with celecoxib in combination with chemotherapy. End points were toxicity, response rates, and measurement of intratumoral levels of prostaglandin E2 (PGE2). METHODS: In this phase II trial, 29 patients with stages IB to IIIA NSCLC were treated with two preoperative cycles of paclitaxel and carboplatin, as well as daily celecoxib, followed by surgical resection. Levels of PGE2 in the primary tumors and adjacent normal lung tissue were compared in 17 study patients versus 13 controls, who received preoperative paclitaxel/carboplatin without celecoxib. RESULTS: All patients completed preoperative chemotherapy, and 26 completed preoperative celecoxib. The overall clinical response rate was 65% (48% with partial response; 17% with complete response). Grade 3 or 4 neutropenia was observed in 18 patients (62%). Twenty-eight patients were explored and underwent complete resection of their tumors. There were no complete pathologic responses, but seven patients (24%) had minimal residual microscopic disease. The addition of celecoxib to a regimen of paclitaxel and carboplatin abrogated the marked increase in levels of PGE2 detected in primary tumors after treatment with paclitaxel and carboplatin alone. CONCLUSION: In comparison with historically reported response rates, these data suggest that the addition of a selective COX-2 inhibitor may enhance the response to preoperative paclitaxel and carboplatin in patients with NSCLC. Moreover, treatment with celecoxib 400 mg twice daily was sufficient to normalize the increase in PGE2 levels found in NSCLC patients after treatment with paclitaxel and carboplatin. Confirmatory trials are planned.

Duodenal reflux induces cyclooxygenase-2 in the esophageal mucosa of rats: evidence for involvement of bile acids.

BACKGROUND & AIMS: Reflux of duodenal contents including bile acids is believed to contribute to esophageal injury and Barrett's esophagus. Cyclooxygenase (COX)-2, an inducible form of COX, has been implicated in both inflammation and carcinogenesis. In this study, we investigated the effects of bile acids and duodenal reflux on COX-2 expression in cultured esophageal cells and tissue, respectively. METHODS: Immunoblotting and Northern blotting were used to assess the effects of bile acids on COX-2 expression in esophageal cell lines. Immunoblotting and immunohistochemistry were performed to evaluate the effects of duodenal reflux on COX-2 expression and cell proliferation in esophageal tissue. RESULTS: Unconjugated bile acids were about fivefold more potent inducers of COX-2 messenger RNA, COX-2 protein, and prostaglandin synthesis than conjugated bile acids. Acidifying the culture medium sensitized esophageal cells to bile acid-mediated induction of COX-2. The induction of COX-2 by bile acids was mediated by phosphatidylinositol-3 kinase and extracellular signal-regulated kinase 1/2 mitogen-activated protein kinases. In experimental animals, duodenoesophageal reflux led to esophagitis, marked thickening of the esophageal mucosa, and enhanced expression of COX-2. Increased immunoreactivity for Ki-67 and cyclin D1 indicated that enhanced cell proliferation contributed to mucosal thickening. CONCLUSIONS: Reflux of duodenal contents into the esophagus led to increased COX-2 expression and mucosal thickening. Bile acids are likely to contribute to these effects.

Inducible prostaglandin E synthase is overexpressed in non-small cell lung cancer.

An inducible microsomal form of human prostaglandin E synthase (mPGES) was recently identified. This enzyme converts the cyclooxygenase (COX) product, prostaglandin (PG) H2, to PGE2, a prostanoid that has been implicated in carcinogenesis. Increased amounts of PGE2 are detected in many types of cancer, but the underlying mechanism is not fully understood. Hence, we compared amounts of mPGES in 19 paired samples (tumor and adjacent normal tissue) of non-small cell lung cancer (NSCLC). By immunoblot analysis, mPGES was overexpressed in about 80% of NSCLCs. Immunohistochemistry localized the expression of mPGES to neoplastic epithelial cells. COX-2 was also commonly up-regulated in these tumors; marked differences in the extent of up-regulation of mPGES and COX-2 were observed in individual tumors. Cell culture was used to define the underlying mechanism(s) that accounts for up-regulation of mPGES in NSCLC. As reported previously for COX-2, levels of mPGES mRNA and protein were increased in NSCLC cell lines containing mutant Ras as compared with a nontumorigenic bronchial epithelial cell line. Nuclear run-offs revealed increased rates of mPGES transcription in the transformed cell lines. Overexpression of Ras caused a severalfold increase in mPGES promoter activity in nontransformed cells. Tumor necrosis factor-alpha induced mPGES and COX-2 in NSCLC cell lines but had no effect on the expression of either enzyme in a nontumorigenic bronchial epithelial cell line. Consistent with prior observations for COX-2, these data suggest that both cellular transformation and cytokines contribute to the up-regulation of mPGES in NSCLC.

Cyclo-oxygenase 2: a pharmacological target for the prevention of cancer.

Understanding the mechanisms underlying carcinogenesis provides insights that are necessary for the development of therapeutic strategies to prevent cancer. Chemoprevention--the use of drugs or natural substances to inhibit carcinogenesis - is an important and rapidly evolving aspect of cancer research. We discuss evidence that cyclooxygenase 2 (COX 2), an inducible form of the enzyme, is a potential pharmacological target to prevent cancer. Key data implicating a causal relation between increased activity of COX 2 and carcinogenesis and possible mechanisms of action of COX 2 in this context are covered. Importantly, selective COX 2 inhibitors appear to be safe enough in human beings to allow large-scale clinical testing in healthy people. Several chemoprevention trials using selective COX 2 inhibitors are underway.

Inhibition of cyclooxygenase-2: an approach to preventing cancer of the upper aerodigestive tract.

Multiple lines of evidence suggest that cyclooxygenase-2 (COX-2), an inducible form of COX, represents a potential pharmacologic target to prevent cancer. Key data suggesting a causal relationship between increased COX-2 activity and carcinogenesis and possible mechanisms of action of COX-2 in this context will be discussed. The possibility that COX-2 represents a pharmacological target for preventing upper aerodigestive cancers (head and neck, lung) will be emphasized. Importantly, clinical trials have been initiated to assess the chemopreventive properties of selective COX-2 inhibitors.

Early lung cancer action project: annual screening using single-slice helical CT.

The advent of helical CT imaging held promise for the early diagnosis, and thereby, for enhanced curability of lung cancer--a highly fatal disease. In 1993, the Early Lung Cancer Action Project (ELCAP) was initiated and experimentally screened a cohort of 1,000 high-risk persons. Here we summarize the results of the baseline and annual repeat CT screening of these 1,000 subjects. CT-based screening (compared to traditional radiology) was clearly shown to enhance the detection of lung cancer at earlier and more curable stages. A discussion follows of the meaning of the results and possible future screening protocols.

Three-field lymphadenectomy for esophageal cancer.

Esophagectomy with three-field lymph node dissection can be performed with a mortality and morbidity similar to that of less extensive operations. Approximately one third of patients will have previously unsuspected metastasis to the recurrent laryngeal nodes. This pattern of spread seems to be independent of cell type or tumor location. The impact of the procedure on patient survival is unclear; however, our early results are encouraging.

Long-term outcome after resection for bronchial carcinoid tumors.

OBJECTIVES: We sought to determine the long-term survival of patients treated for bronchial carcinoid tumors and whether lesser resections have had an effect on outcomes. METHODS: We conducted a retrospective, multi-institutional review of patients treated surgically for primary bronchial carcinoid tumors since 1980. Operative approach, pathologic stage, histology, surgical complications, tumor recurrence, and long-term survival were assessed. RESULTS: There were 50 men and 89 women with a mean age of 52.2+/-17.4 and 58.9+/-13.3 years, respectively (P=0.021). Men were more likely to be current or former smokers than were women. Operations included lobectomy or bilobectomy in 110, pneumonectomy in four, wedge resection in 22, and bronchial sleeve resection only in three patients; resection was performed thoracoscopically in six patients. One patient died postoperatively. Stages were I, 121; II, nine; III, six; and IV, three. Typical carcinoid tumors were stage I in 100 and more advanced (stages II-IV) in nine, whereas atypical carcinoid tumors were stage I in 18 and more advanced in eight (P=0. 002). Median follow-up was 43 months (range 1-149) during which 21 (15%) patients died (four from recurrent cancer) and 19 patients (14%) were lost to follow-up. Recurrent cancer developed in 2/98 patients with typical and 5/25 patients with atypical subtypes (P<0. 001; log-rank test). The likelihood of recurrence was related to histological subtype (relative risk 7.9 for atypical carcinoid; 95% confidence interval 1.4-43.5). Five-year survival was 88% for stage I patients and was 70% for patients with more advanced stages. When stratified by stage, survival was related to age (relative risk=1.9 for a 10 year increase in age; 95% confidence interval 1.2-2.9) and possibly to the histological subtype, but not to patient gender, year of operation, or type of operation performed. CONCLUSIONS: Either major lung resection or wedge resection is appropriate treatment for patients with early stage typical bronchial carcinoid tumors. Survival is favorable for early stage tumors regardless of histological subtype. Local recurrence is more common among patients with atypical subtypes, suggesting that a formal resection may improve long-term outcome.

Serological identification of embryonic neural proteins as highly immunogenic tumor antigens in small cell lung cancer.

Serological analysis of expression cDNA libraries (SEREX) derived from two small cell lung cancer (SCLC) cell lines using pooled sera of SCLC patients led to the isolation of 14 genes, including 4 SOX group B genes (SOX1, SOX2, SOX3, and SOX21) and ZIC2. SOX group B genes and ZIC2 encode DNA-binding proteins; SOX group B proteins regulate transcription of target genes in the presence of cofactors, whereas ZIC2 is also suspected to be a transcriptional regulator. These genes are expressed at early developmental stages in the embryonic nervous system, but are down-regulated in the adult. Although SOX2 mRNA can be detected in some adult tissues, ZIC2 is expressed only in brain and testis, and SOX1, SOX3, and SOX21 transcripts are not detectable in normal adult tissues. Of SCLC cell lines tested, 80% expressed ZIC2 mRNA, and SOX1, SOX2, and SOX3 expression was detected in 40%, 50%, and 10%, respectively. SOX group B and ZIC2 antigens elicited serological responses in 30-40% of SCLC patients in this series, at titers up to 1:10(6). In sera from 23 normal adults, no antibody was detected against SOX group B or ZIC2 proteins except for one individual with low-titer anti-SOX2 antibody. Seroreactivity against SOX1 and 2 was consistently higher titered than SOX3 and 21 reactivity, suggesting SOX1 and/or SOX2 as the main antigens eliciting anti-SOX responses. Although paraneoplastic neurological syndromes have been associated with several SCLC antigens, neurological symptoms have not been observed in patients with anti-SOX or anti-ZIC2 antibodies.

Expression of cancer-testis antigens in lung cancer: definition of bromodomain testis-specific gene (BRDT) as a new CT gene, CT9.

In an effort to define new cancer-testis (CT) genes, we investigated whether BRDT, a testis-restricted member of the RING3 family of transcriptional regulators, is also expressed in cancer. Standard RT-PCR expression analysis detected BRDT transcripts in 12 of 47 cases of non-small cell lung cancer and single cases of both squamous cell carcinoma of the head and neck (1/12) and esophagus (1/12) but not in melanoma or in cancers of the colon, breast, kidney and bladder. Typing of 33 non-small cell lung cancers for coexpression of a panel of CT antigens revealed a high incidence (60%) of MAGE-3 mRNA expression, followed by MAGE-1 (36%), CT7/MAGE-C1 (30%), CT10 (30%), SSX4 (23%), BRDT (21%), NY-ESO-1 (21%) and HOM-MEL-40/SSX2 (15%). The coexpression pattern of these antigens provides a foundation for developing a polyvalent lung cancer vaccine.

Early Lung Cancer Action Project: overall design and findings from baseline screening.

BACKGROUND: 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 people at high risk of lung cancer. We report the baseline experience. METHODS: ELCAP has enrolled 1000 symptom-free volunteers, aged 60 years or older, with at least 10 pack-years of cigarette smoking and no previous cancer, who were medically fit to undergo thoracic surgery. After a structured interview and informed consent, chest radiographs and low-dose CT were done for each participant. The diagnostic investigation of screen-detected non-calcified pulmonary nodules was guided by ELCAP recommendations, which included short-term high-resolution CT follow-up for the smallest non-calcified nodules. FINDINGS: Non-calcified nodules were detected in 233 (23% [95% CI 21-26]) participants by low-dose CT at baseline, compared with 68 (7% [5-9]) by chest radiography. Malignant disease was detected in 27 (2.7% [1.8-3.8]) by CT and seven (0.7% [0.3-1.3]) by chest radiography, and stage I malignant disease in 23 (2.3% [1.5-3.3]) and four (0.4% [0.1-0.9]), respectively. Of the 27 CT-detected cancers, 26 were resectable. Biopsies were done on 28 of the 233 participants with non-calcified nodules; 27 had malignant non-calcified nodules and one had a benign nodule. Another three individuals underwent biopsy against the ELCAP recommendations; all had benign non-calcified nodules. No participant had thoracotomy for a benign nodule. INTERPRETATION: Low-dose CT can greatly improve the likelihood of detection of small non-calcified nodules, and thus of lung cancer at an earlier and potentially more curable stage. Although false-positive CT results are common, they can be managed with little use of invasive diagnostic procedures.

mdm-2 expression correlates with wild-type p53 status in esophageal adenocarcinoma.

Several immunohistochemical studies showed that p53 protein is expressed in 50 to 80% of esophageal adenocarcinomas (EAs). Mutations of this tumor suppressor gene are present in 40 to 70% of EAs, so it is possible that p53 expression might occur as a result of mechanisms other than gene mutation. The human homologue of the murine double minute-2 gene (mdm-2) is a known regulator of p53 activity, and its expression results in stabilization of the wild-type p53 protein and loss of its tumor suppressor function. In this study, we evaluated the frequency of mdm-2 amplification and expression in EA and investigated the relationship between mdm-2 expression and p53 mutation. Thirty-three resection specimens of EAs and associated Barrett's esophagus were evaluated by immunohistochemical methods for p53 and mdm-2 expression. Sixteen of these cases were also evaluated for p53 mutations with use of polymerase chain reaction, single-strand conformational polymorphism, and DNA sequencing and for mdm-2 amplification with a differential polymerase chain reaction-based amplification analysis. Overexpression of p53 was present in 23 EAs (70%), and 18 EAs (55%) overexpressed mdm-2. p53 mutation was observed in 7 (43%) of 16 cases, whereas mdm-2 gene amplification was not detected in any. To summarize, we found substantial discordance of p53 immunohistochemical features and mutation in EA. Significant expression of mdm-2 occurred only in cases with wild-type p53, whereas all of the cases with p53 mutation showed little if any expression of mdm-2. Also, mdm-2 expression in cases with p53 overexpression but without p53 mutation exceeded mdm-2 expression in cases with p53 overexpression and p53 gene mutation. In cases without p53 mutation, overexpression of mdm-2 occurred in 50% of cases and might be responsible for stabilization of p53 protein and possible loss of tumor suppressor function.

Acidic fibroblast growth factor is progressively increased in the development of oesophageal glandular dysplasia and adenocarcinoma.

AIMS: To determine by immunohistochemistry and amplification of cDNA the relationship between fibroblast growth factor (FGF) expression and progressive changes in Barrett's oesophagus associated with oesophageal adenocarcinoma (OA). The FGFs are potent mitogens that possess angiogenic properties and the capability to regulate growth and differentiation of various cell types. They have also been implicated in the development and progression of numerous solid tumours, including some carcinomas of the aerodigestive tract, such as nasopharyngeal carcinoma and pancreatic adenocarcinoma. MATERIAL AND RESULTS: We studied the expression of the two prototypic FGFs, acidic FGF (FGF-1) and basic FGF (FGF-2), in OA and OA precursor lesions, including intestinal metaplasia (IM), low-grade dysplasia (LGD) and high-grade dysplasia (HGD). Fresh tissue from 10 OAs and four associated HGDs was available for the determination of FGF-1 and FGF-2 mRNA expression accomplished by the PCR amplification of cDNA. Using immunohistochemistry, we studied the expression of the FGF-1 and FGF-2 proteins in archival, paraffin-embedded tissue that was available from 17 oesophageal resection specimens that included OAs and OA precursor lesions. As compared to gastric fundic mucosal controls, OAs and HGDs showed significantly enhanced expression of FGF-1 mRNA and protein. IMs and LGDs showed significantly lesser degrees of FGF-1 immunoreactivity that were not increased over controls. In contrast, both the overall percentage of FGF-2-reactive OAs and the overall FGF-2 protein expression, assessed using an immunoreactivity score, are comparable to FGF-2 expression in controls. CONCLUSIONS: It appears that FGF-2 is ubiquitously expressed in OA and in normal oesophageal and gastric mucosa while significant FGF-1 expression is essentially restricted to HGD and OA. Our data also suggest that FGF-1 is sequentially upregulated in the progression from metaplasia to dysplasia and adenocarcinoma.

The rationale for radical resection.

Radical esophagectomy results in survival rates exceeding those obtained by standard techniques and comparable with or possibly better than survival rates following combined modality therapy. The benefits of radical resection include improved surgical staging, superior local control, and a higher probability of achieving an R0 resection.

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.

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.