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Objective: The aim was to determine the prevalence of metastases to the cervical and recurrent laryngeal cervicothoracic (CT) nodes as well as survival and recurrence patterns after esophagectomy with three-field lymph node dissection (TFD) in patients with predominately adenocarcinoma (AC) of the esophagus., Background: Although esophagectomy with TFD is commonly practiced in Japan and Southeast Asia for squamous cell cancer (SCC) of the esophagus, there are only a handful of reports about its' utilization and survival benefit in North American patients., Methods: This is a retrospective case series of patients who had an esophagectomy with TFD. The primary outcomes of interest were the prevalence of nodal metastases to the CT nodes as well as overall survival (OS) and disease-free survival. Secondary outcomes included time to recurrence, recurrence patterns, operative morbidity as well as 30 and 90-day mortality., Results: Two hundred forty-two patients with esophageal cancer (AC: 67%) underwent esophagectomy with TFD. Metastases to the CT nodes were present in 56 patients (23%: AC 20% and SCC 30%). Positive CT nodes were present in 14% of pT1/T2 tumors and 30% of pT3 tumors. For the 56 patients with CT positive nodes, 5-year OS was 25% (AC:16%; SCC:39%). Fifteen of 56 (26.7%) patients with metastases to the CT nodes were alive and disease-free at a minimum of 5 years postoperatively. Ten-year OS was 43% for all patients with SCC and 28% for patients with AC., Conclusions: Metastases to the CT nodes are common in both SCC and AC of the esophagus and may be present in at least 14% of early lesions. Five-year survival is encouraging particularly for patients with esophageal SCC cancer., Competing Interests: N.A. received grants or contracts from AstraZeneca, Jansen Pharmaceuticals, the National Cancer Institute, New York Genome Center P1000 and the US Department of Defense; and received honoraria from AstraZeneca and Regeneron. J.P. has leadership and ownership interest in Angiocrine Bioscience, TMRW, and Viewpoint Medical. J.V.-V. received research grants from Kadmon Pharmaceuticals and Stony Wold-Herbert Fund. The remaining authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

The care of patients with oesophageal cancer or of individuals who have an elevated risk of oesophageal cancer has changed dramatically. The epidemiology of squamous cell and adenocarcinoma of the oesophagus has diverged over the past several decades, with a marked increase in incidence only for oesophageal adenocarcinoma. Only in the past decade, however, have molecular features that distinguish these two forms of the disease been identified. This advance has the potential to improve screening for oesophageal cancers through the development of novel minimally invasive diagnostic technologies predicated on cancer-specific genomic or epigenetic alterations. Surgical techniques have also evolved towards less invasive approaches associated with less morbidity, without compromising oncological outcomes. With improvements in multidisciplinary care, advances in radiotherapy and new tools to detect minimal residual disease, certain patients may no longer even require surgical tumour resection. However, perhaps the most anticipated advance in the treatment of patients with oesophageal cancer is the advent of immune-checkpoint inhibitors, which harness and enhance the host immune response against cancer. In this Review, we discuss all these advances in the management of oesophageal cancer, representing only the beginning of a transformation in our quest to improve patient outcomes., (© 2023. Springer Nature Limited.)

Purpose: Epigenetic silencing of tumor suppressor genes (TSG) is an acquired abnormality observed in cancer and is prototypically linked to DNA methylation. We postulated that pretreatment (priming) with 5-azacitidine would increase the efficacy of chemotherapy by reactivating TSGs. This study was conducted to identify a tolerable dose of 5-azacitidine prior to EOX (epirubicin, oxaliplatin, capecitabine) neoadjuvant chemotherapy in patients with locally advanced esophageal/gastric adenocarcinoma (EGC). Experimental Design: Eligible patients had untreated, locally advanced, resectable EGC, ECOG 0-2, and adequate organ function. 5-Azacitidine (V, 75 mg/m 2 ) was given subcutaneously for 3 (dose level, DL 1) or 5 (DL 2) days prior to each 21-day cycle of EOX (E, 50 mg/m 2 ; O, 130 mg/m 2 ; X, 625 mg/m 2 twice daily for 21 days). Standard 3+3 methodology guided V dose escalation. DNA methylation at control and biomarker regions was measured by digital droplet, bisulfite qPCR in tumor samples collected at baseline and at resection. Results: All subjects underwent complete resection of residual tumor (R0). Three of the 12 patients (25%) achieved a surgical complete response and 5 had partial responses. The overall response rate was 67%. The most common toxicities were gastrointestinal and hematologic. Hypomethylation of biomarker genes was observed at all dose levels and trended with therapeutic response. Conclusions: Neoadjuvant VEOX was well-tolerated with significant clinical and epigenetic responses, with preliminary evidence that priming with V prior to chemotherapy may augment chemotherapy efficacy. The recommended phase II trial schedule is 5-azacitidine 75 mg/m 2 for 5 days followed by EOX chemotherapy every 21 days. Clin Cancer Res; 23(11); 2673-80. ©2016 AACR ., (©2016 American Association for Cancer Research.)

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.

Despite advances in treatment, long-term outcomes for esophageal cancer remain poor, with overall survival rates of between 15% and 35%. Poor long-term survival reflects locoregionally advanced disease or metastatic disease at presentation. Among patients undergoing surgical resection, 40% to 50% have stage III disease. Surgery alone results in poor locoregional control and poor long-term outcomes, with survival rates ranging from 10% to 30%. Induction therapy combining surgery with chemotherapy with or without radiotherapy attempts to improve long-term survival in these patients. This article examines the merits of various modalities of induction therapy for patients with locally advanced esophageal cancer., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: To determine the prevalence of occult cervical nodal metastases in patients with squamous cell cancer and adenocarcinoma of the esophagus, and to determine the impact of esophagectomy with three-field lymph node dissection on survival and recurrence rates., Summary Background Data: Although esophagectomy with three-field lymph node dissection is commonly practiced in Japan, its role in the surgical management of esophageal cancer in the United States, especially in patients with esophageal adenocarcinoma, is essentially unknown., Methods: This is a prospective observational study of esophagectomy with three-field lymphadenectomy. Eighty patients underwent resection between August 1994 and April 2001. Clinicopathological information and follow-up data were collected on all patients until death or June 2001., Results: Hospital mortality and morbidity rates were 5% and 46%, respectively. Metastases to the recurrent laryngeal and/or deep cervical nodes occurred in 36% of patients irrespective of cell type (adenocarcinoma 37%, squamous 34%) or location within the esophagus (lower third 32%, middle third 60%). Overall 5-year and disease-free survival rates were 51% and 46%, respectively. Sixty-nine percent presented with nodal metastases. The 5-year survival rate for node-negative patients was 88%; that for those with nodal metastases was 33%. The 5-year survival rate in patients with positive cervical nodes was 25% (squamous 40%, adenocarcinoma 15%)., Conclusions: Esophagectomy with three-field lymph node dissection can be performed with a low mortality and reasonable morbidity. Unsuspected metastases to the recurrent laryngeal and/or cervical nodes are present in 36% of patients regardless of cell type or location within the esophagus. Thirty percent of patients were upstaged, mainly from stage III to stage IV. An overall 5-year survival rate of 51% suggests a true survival benefit beyond that achieved solely on the basis of stage migration.

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.

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.

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.

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.

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.

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.

In the United States, the incidence of esophageal adenocarcinoma has risen faster than any other malignancy in recent years, and now represents the most common histologic type of esophageal cancer observed in major institutions. The precise etiology of this malignancy, and the epidermiologic variables responsible for its dramatically rising incidence, remains obscure. Elucidation of the molecular biology of malignant transformation in Barrett's esophagus may improve the management of patients with advanced esophageal adenocarcinomas. Furthermore, appreciation of the molecular events associated with esophageal adenocarcinomas. Furthermore, appreciation of the molecular events associated with esophageal adenocarcinogenesis may facilitate early detection of occult carcinomas, and enable therapeutic interventions designed to prevent these otherwise highly lethal neoplasms.

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.

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.

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.

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.

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.

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.

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.

Adenocarcinomas of the proximal and distal stomach have significant clinical and biological differences. A study was undertaken to determine if a difference in the incidence of mutated ras oncogenes exists between proximal (gastroesophageal junction or cardia) and distal (body or antrum) gastric tumors, and to assess the overall incidence in gastric cancers from non-Asian patients. Deoxyribonucleic acid from 28 primary gastric adenocarcinomas were analyzed for point mutations in codons 12, 13, and 61 of the Ha-ras, Ki-ras, and N-ras protooncogenes using polymerase-catalyzed chain reaction methodology. Twelve tumors were located at the gastroesophageal junction or cardia, and 16 in the body or antrum. Mutated ras genes were detected in 2 of 28 tumors for an overall incidence of 7%. The mutations occurred in codon 61 of the N-ras gene in a proximal gastric cancer and in codon 12 of the Ki-ras gene in a distal gastric cancer. These data indicate that mutations in ras genes are an uncommon event in primary gastric cancers and that there is no meaningful difference in the incidence of ras mutations in proximal and distal stomach cancers.

Adenocarcinoma arising in association with the columnar-lined esophagus is now recognized with increasing frequency. The incidence of malignant degeneration in Barrett's esophagus, its etiology, and pathogenesis are all issues of ongoing debate. The role of gastroesophageal reflux in driving the malignant change remains unproven. Surgical resection is the treatment of choice; however, prognosis is generally poor. Surveillance of patients with non-malignant Barrett's esophagus permits detection of early lesions where resection results in excellent long-term survival.