Developments in esophageal surgery for adenocarcinoma: a comparison of two decades

<p>Abstract</p> <p>Background</p> <p>The objective of this study was to examine outcomes in patients undergoing esophageal resection for adenocarcinoma at our institution during a 20-year period and, in particular, to address temporal trends in long-term survival.</p> <p>Methods</p> <p>Out of 470 patients who underwent esophagectomy for malignancy between September 1985 and September 2005, a total number of 175 patients presented with esophageal adenocarcinoma. Patients enrolled in this study included AEG (adenocarcinoma of the esophagogastric junction) type I tumors only. Time trends were studied comparing two decades, 9/1985 to 9/1995 (DI) and 10/1995 to 9/2005 (DII).</p> <p>Results</p> <p>The overall survival was significantly more favourable in patients undergoing esophageal resection for adenocarcinoma in the recent time period (DII, 10/1995 to 9/2005) as compared to the early time period (DI, 9/1985 to 9/1995) (log rank test: p = 0.0329). Significant differences in the recent decade were seen based on lower ASA-classifications, earlier tumor stages, and the operative procedure with a higher frequency of transhiatal resections (p < 0.05). 30-day mortality improved from 8.3% to 3.1% during the 20-year time-interval, thus without statistical significance.</p> <p>Conclusion</p> <p>Based on our experience, overall survival is improving over time for adenocarcinoma of the esophagus. Factors that may play an important role in this trend include early diagnosis and improved patient selection through better preoperative staging, improved surgical technique with a tailored approach carefully evaluated by physiologic patient status, comorbidity and tumor extent.</p

Genome wide single cell analysis of chemotherapy resistant metastatic cells in a case of gastroesophageal adenocarcinoma

<p>Abstract</p> <p>Background</p> <p>Metastatic progression due to development or enrichment of therapy-resistant tumor cells is eventually lethal. Molecular characterization of such chemotherapy resistant tumor cell clones may identify markers responsible for malignant progression and potential targets for new treatment. Here, in a case of stage IV adenocarcinoma of the gastroesophageal junction, we report the successful genome wide analysis using array comparative genomic hybridization (CGH) of DNA from only fourteen tumor cells using a bead-based single cell selection method from a bone metastasis progressing during chemotherapy.</p> <p>Case presentation</p> <p>In a case of metastatic adenocarcinoma of the gastroesophageal junction, the progression of bone metastasis was observed during a chemotherapy regimen of epirubicin, oxaliplatin and capecitabine, whereas lung-, liver and lymph node metastases as well as the primary tumor were regressing. A bone marrow aspirate sampled at the site of progressing metastasis in the right iliac bone was performed, and single cell molecular analysis using array-CGH of Epithelial Specific Antigen (ESA)-positive metastatic cells, and revealed two distinct regions of amplification, 12p12.1 and 17q12-q21.2 amplicons, containing the KRAS (12p) and ERBB2 (HER2/NEU) (17q) oncogenes. Further intrapatient tumor heterogeneity of these highlighted gene copy number changes was analyzed by fluorescence in situ hybridization (FISH) in all available primary and metastatic tumor biopsies, and ErbB2 protein expression was investigated by immunohistochemistry.</p> <p>ERBB2 was heterogeneously amplified by FISH analysis in the primary tumor, as well as liver and bone metastasis, but homogenously amplified in biopsy specimens from a progressing bone metastasis after three initial cycles of chemotherapy, indicating a possible enrichment of erbB2 positive tumor cells in the progressing bone marrow metastasis during chemotherapy. A similar amplification profile was detected for wild-type KRAS, although more heterogeneously expressed in the bone metastasis progressing on chemotherapy. Correspondingly, the erbB2 protein was found heterogeneously expressed by immunohistochemical staining of the primary tumor of the gastroesophageal junction, while negative in liver and bone metastases, but after three initial cycles of palliative chemotherapy with epirubicin, oxaliplatin and capecetabine, the representative bone metastasis stained strongly positive for erbB2.</p> <p>Conclusion</p> <p>Global analysis of genetic aberrations, as illustrated by performing array-CGH analysis on genomic DNA from only a few selected tumor cells of interest sampled from a progressing bone metastasis, can identify relevant therapeutic targets and genetic aberrations involved in malignant progression, thus emphasizing the importance and feasibility of this powerful tool on the road to more personalized cancer therapies in the future.</p

Discovery of New Molecular Subtypes in Oesophageal Adenocarcinoma

A large number of patients suffering from oesophageal adenocarcinomas do not respond to conventional chemotherapy; therefore, it is necessary to identify new predictive biomarkers and patient signatures to improve patient outcomes and therapy selections. We analysed 87 formalin-fixed and paraffin-embedded (FFPE) oesophageal adenocarcinoma tissue samples with a reverse phase protein array (RPPA) to examine the expression of 17 cancer-related signalling molecules. Protein expression levels were analysed by unsupervised hierarchical clustering and correlated with clinicopathological parameters and overall patient survival. Proteomic analyses revealed a new, very promising molecular subtype of oesophageal adenocarcinoma patients characterised by low levels of the HSP27 family proteins and high expression of those of the HER family with positive lymph nodes, distant metastases and short overall survival. After confirmation in other independent studies, our results could be the foundation for the development of a Her2-targeted treatment option for this new patient subgroup of oesophageal adenocarcinoma

Characterization of the innate immune response to chronic aspiration in a novel rodent model

<p>Abstract</p> <p>Background</p> <p>Although chronic aspiration has been associated with several pulmonary diseases, the inflammatory response has not been characterized. A novel rodent model of chronic aspiration was therefore developed in order to investigate the resulting innate immune response in the lung.</p> <p>Methods</p> <p>Gastric fluid or normal saline was instilled into the left lung of rats (n = 48) weekly for 4, 8, 12, or 16 weeks (n = 6 each group). Thereafter, bronchoalveolar lavage specimens were collected and cellular phenotypes and cytokine concentrations of IL-1alpha, IL-1beta, IL-2, IL-4, IL-6, IL-10, GM-CSF, IFN-gamma, TNF-alpha, and TGF-beta were determined.</p> <p>Results</p> <p>Following the administration of gastric fluid but not normal saline, histologic specimens exhibited prominent evidence of giant cells, fibrosis, lymphocytic bronchiolitis, and obliterative bronchiolitis. Bronchoalveolar lavage specimens from the left (treated) lungs exhibited consistently higher macrophages and T cells with an increased CD4:CD8 T cell ratio after treatment with gastric fluid compared to normal saline. The concentrations of IL-1alpha, IL-1beta, IL-2, TNF-alpha and TGF-beta were increased in bronchoalveolar lavage specimens following gastric fluid aspiration compared to normal saline.</p> <p>Conclusion</p> <p>This represents the first description of the pulmonary inflammatory response that results from chronic aspiration. Repetitive aspiration events can initiate an inflammatory response consisting of macrophages and T cells that is associated with increased TGF-beta, TNF-alpha, IL-1alpha, IL-1beta, IL-2 and fibrosis in the lung. Combined with the observation of gastric fluid-induced lymphocyitic bronchiolitis and obliterative bronchiolitis, these findings further support an association between chronic aspiration and pulmonary diseases, such as obliterative bronchiolitis, pulmonary fibrosis, and asthma.</p

Mucin pattern reflects the origin of the adenocarcinoma in Barrett's esophagus: a retrospective clinical and laboratorial study

<p>Abstract</p> <p>Background</p> <p>Mucin immunoexpression in adenocarcinoma arising in Barrett's esophagus (BE) may indicate the carcinogenesis pathway. The aim of this study was to evaluate resected specimens of adenocarcinoma in BE for the pattern of mucins and to correlate to the histologic classification.</p> <p>Methods</p> <p>Specimens were retrospectively collected from thirteen patients who underwent esophageal resection due to adenocarcinoma in BE. Sections were scored for the grade of intestinal metaplasia. The tissues were examined by immunohistochemistry for MUC2 and MUC5AC antibodies.</p> <p>Results</p> <p>Eleven patients were men. The mean age was 61 years old (varied from 40 to 75 years old). The tumor size had a mean of 4.7 ± 2.3 cm, and the extension of BE had a mean of 7.7 ± 1.5 cm. Specialized epithelium with intestinal metaplasia was present in all adjacent mucosas. Immunohistochemistry for MUC2 showed immunoreactivity in goblet cells, while MUC5AC was extensively expressed in the columnar gastric cells, localizing to the surface epithelium and extending to a variable degree into the glandular structures in BE. Tumors were classified according to the mucins in gastric type in 7/13 (MUC5AC positive) and intestinal type in 4/13 (MUC2 positive). Two tumors did not express MUC2 or MUC5AC proteins. The pattern of mucin predominantly expressed in the adjacent epithelium was associated to the mucin expression profile in the tumors, p = 0.047.</p> <p>Conclusion</p> <p>Barrett's esophagus adenocarcinoma shows either gastric or intestinal type pattern of mucin expression. The two types of tumors developed in Barrett's esophagus may reflect the original cell type involved in the malignant transformation.</p

Anatomical classification of the shape and topography of the stomach

The aim of the study was to present the classification of anatomical variations of the stomach, based on the radiological and historical data. In years 2006–2010, 2,034 examinations of the upper digestive tract were performed. Normal stomach anatomy or different variations of the organ shape and/or topography without any organic radiologically detectable gastric lesions were revealed in 568 and 821 cases, respectively. Five primary groups were established: abnormal position along longitudinal (I) and horizontal axis (II), as well as abnormal shape (III) and stomach connections (IV) or mixed forms (V). The first group contains abnormalities most commonly observed among examined patients such as stomach rotation and translocation to the chest cavity, including sliding, paraesophageal, mixed-form and upside-down hiatal diaphragmatic hernias, as well as short esophagus, and the other diaphragmatic hernias, that were not found in the evaluated population. The second group includes the stomach cascade. The third and fourth groups comprise developmental variations and organ malformations that were not observed in evaluated patients. The last group (V) encloses mixed forms that connect two or more previous variations

Biomarker analysis of cetuximab plus oxaliplatin/leucovorin/5-fluorouracil in first-line metastatic gastric and oesophago-gastric junction cancer: results from a phase II trial of the Arbeitsgemeinschaft Internistische Onkologie (AIO)

<p>Abstract</p> <p>Background</p> <p>The activity of the epidermal growth factor receptor (EGFR)-directed monoclonal antibody cetuximab combined with oxaliplatin/leucovorin/5-fluorouracil (FUFOX) was assessed in first-line metastatic gastric and oesophago-gastric junction (OGJ) cancer in a prospective phase II study showing a promising objective tumour response rate of 65% and a low mutation frequency of <it>KRAS </it>(3%). The aim of the correlative tumour tissue studies was to investigate the relationship between <it>EGFR </it>gene copy numbers, activation of the EGFR pathway, expression and mutation of E-cadherin, V600E BRAF mutation and clinical outcome of patients with gastric and OGJ cancer treated with cetuximab combined with FUFOX.</p> <p>Methods</p> <p>Patients included in this correlative study (<it>n </it>= 39) were a subset of patients from the clinical phase II study. The association between <it>EGFR </it>gene copy number, activation of the EGFR pathway, abundance and mutation of E-cadherin which plays an important role in these disorders, BRAF mutation and clinical outcome of patients was studied. <it>EGFR </it>gene copy number was assessed by FISH. Expression of the phosphorylated forms of EGFR and its downstream effectors Akt and MAPK, in addition to E-cadherin was analysed by immunohistochemistry. The frequency of mutant V600E BRAF was evaluated by allele-specific PCR and the mutation profile of the E-cadherin gene <it>CDH1 </it>was examined by DHPLC followed by direct sequence analysis. Correlations with overall survival (OS), time to progression (TTP) and overall response rate (ORR) were assessed.</p> <p>Results</p> <p>Our study showed a significant association between increased <it>EGFR </it>gene copy number (≥ 4.0) and OS in gastric and OGJ cancer, indicating the possibility that patients may be selected for treatment on a genetic basis. Furthermore, a significant correlation was shown between activated EGFR and shorter TTP and ORR, but not between activated EGFR and OS. No V600E BRAF mutations were identified. On the other hand, an interesting trend between high E-cadherin expression levels and better OS was observed and two <it>CDH1 </it>exon 9 missense mutations (A408V and D402H) were detected.</p> <p>Conclusion</p> <p>Our finding that increased <it>EGFR </it>gene copy numbers, activated EGFR and the E-cadherin status are potentially interesting biomarkers needs to be confirmed in larger randomized clinical trials.</p> <p>Trial registration</p> <p>Multicentre clinical study with the European Clinical Trials Database number 2004-004024-12.</p

Location-Specific Epigenetic Regulation of the Metallothionein 3 Gene in Esophageal Adenocarcinomas

Metallothionein 3 (MT3) maintains intracellular metal homeostasis and protects against reactive oxygen species (ROS)-induced DNA damage. In this study, we investigated the epigenetic alterations and gene expression of the MT3 gene in esophageal adenocarcinomas (EACs).Using quantitative bisulfite pyrosequencing, we detected unique DNA methylation profiles in the MT3 promoter region. The CpG nucleotides from -372 to -306 from the transcription start site (TSS) were highly methylated in tumor (n = 64) and normal samples (n = 51), whereas CpG nucleotides closest to the TSS (-4 and +3) remained unmethylated in all normal and most tumor samples. Conversely, CpG nucleotides in two regions (from -139 to -49 and +296 to +344) were significantly hypermethylated in EACs as compared to normal samples [FDR<0.001, -log10(FDR)>3.0]. The DNA methylation levels from -127 to -8 CpG sites showed the strongest correlation with MT3 gene expression (r = -0.4, P<0.0001). Moreover, the DNA hypermethylation from -127 to -8 CpG sites significantly correlated with advanced tumor stages and lymph node metastasis (P = 0.005 and P = 0.0313, respectively). The ChIP analysis demonstrated a more repressive histone modification (H3K9me2) and less active histone modifications (H3K4me2, H3K9ace) in OE33 cells than in FLO-1 cells; concordant with the presence of higher DNA methylation levels and silencing of MT3 expression in OE33 as compared to FLO-1 cells. Treatment of OE33 cells with 5-Aza-deoxycitidine restored MT3 expression with demethylation of its promoter region and reversal of the histone modifications towards active histone marks.In summary, EACs are characterized by frequent epigenetic silencing of MT3. The choice of specific regions in the CpG island is a critical step in determining the functional role and prognostic value of DNA methylation in cancer cells