Gorlin syndrome associated with small bowel carcinoma and mesenchymal proliferation of the gastrointestinal tract: case report and review of literature.

UNLABELLED: BACKGROUND AND CASE PRESENTATION: A patient with nevoid basal cell carcinoma syndrome (Gorlin syndrome) presented with two unusual clinical features, i.e. adenocarcinoma of the small bowel and extensive mesenchymal proliferation of the lower gastrointestinal tract. CONCLUSIONS: We discuss the possibility that these two features are pathogenetically linked to the formerly undescribed patient's PTCH germ line mutation.

The predictive value of genes of the TGF-beta1 pathway in multimodally treated squamous cell carcinoma of the esophagus.

BACKGROUND AND AIM: Pretherapeutic identification of esophageal squamous cell carcinomas (ESCCs) that are likely to respond to neoadjuvant chemoradiotherapy is important in the attempt to improve the prognosis for patients. In the present study, expression of members of the transforming growth factor-beta1 (TGF-beta1) signaling pathway was investigated in pretherapeutic biopsies from 97 ESCCs (cT3, cN0/+, cM0) in patients who underwent neoadjuvant chemoradiotherapy (45 Gy plus cisplatin and 5-fluorouracil) and subsequent esophagectomy in the setting of a single-center prospective treatment trial. MATERIALS AND METHODS: Expression of TGF-beta1 and its downstream effectors Smad4 and Smad7 was assessed using quantitative reverse transcription polymerase chain reaction from RNA prepared from pretherapeutic tumor biopsies. The presence of phosphorylated Smad2 was assessed immunohistochemically. RESULTS: Expression of TGF-beta1 (mean 7.8; range 0.0-25.7 arb. units), Smad4 (mean 0.1; range 0.0-0.4 arb. units), and Smad7 (mean 1.6; range 0.4-16.1 arb. units) varied substantially between the patients. Tumors with total or subtotal regression, as determined by histopathological examination after neoadjuvant chemoradiotherapy, showed significantly higher levels of Smad4 mRNA expression than tumors with minor or no regression (P = 0.032). TGF-beta1 and Smad7 mRNA expression as well as Smad2 protein expression were of no prognostic value. Expression of the four genes under analysis also showed no impact on the overall survival. In contrast, the overall survival correlated significantly with histopathological regression (P < 0.0001) and to a minor degree also with clinical regression grading (P = 0.0254). INTERPRETATION: Among the parameters analyzed, only Smad4 was found to have possible predictive value for esophageal squamous cell carcinoma in patients receiving neoadjuvant chemoradiotherapy.

Immunohistochemical detection of receptor tyrosine kinases c-kit, EGF-R, and PDGF-R in colorectal adenocarcinomas.

PURPOSE: The selective inhibition of tyrosine kinases is a promising strategy in the treatment of several human malignancies. This study aimed to clarify expression patterns of therapeutically addressable receptor tyrosine kinases in colorectal cancer. MATERIALS AND METHODS: In this study, we used tissue arrays to analyze 263 specimen of colorectal carcinoma for the expression of the tyrosine kinases c-kit (CD117), epidermal growth factor receptor (EGF-R), and platelet-derived growth factor receptor (PDGF-R). Staining patterns were then correlated with tumor stage and survival. RESULTS: Five tumors (1.9%) showed a strong expression of c-kit (CD117), while in 40 samples (15.2%), a weak/intermediate expression was observed. Positive staining did not correlate with histopathological parameters although a trend toward a better survival of c-kit-positive patients was observed. No positivity for PDGF-R was observed in 263 samples of colorectal carcinomas. Positive EGF-R expression was identified in 39 cases (15.2%), whereas 218 samples (84.8%) stained negative. CONCLUSIONS: Our study confirms that expression of the tyrosine kinases c-kit and PDGF-R are rare in colorectal carcinomas and do not correlate with tumor stage.

EUS-guided FNA of solid pancreatic masses: high yield of 2 passes with combined histologic-cytologic analysis.

BACKGROUND: EUS-guided FNA (EUS-FNA) is an established tissue-acquisition technique, with most studies concentrating on cytologic analyses of specimens, with only few data existing on histologic assessment. OBJECTIVE: To assess the sensitivity of a combined analysis of histologic followed by cytologic tissue diagnosis. DESIGN: A retrospective 3-center study. METHODS: In consecutive patients undergoing FNA of solid pancreatic masses, core specimens were harvested for histology; residual tissue was examined cytologically. Only unequivocally positive results were regarded as malignant. Criterion standards were positive results from EUS-FNA or other histologic findings, or, if negative, clinical follow-up data (minimum 12 months). RESULTS: Among 192 patients (110 men; mean age 63 years) with mostly pancreatic-head masses (72.4%), overall, adequate tissue was obtained in 98.9% of all cases, with a mean of 1.88 needle passes and an overall sensitivity of 82.9% (95% CI, 76.0%-88.5%). Histology and subsequent cytology provided adequate tissue and sensitivities of 86.5% and 60%, and 92.7% and 68.1%, respectively. Excluding cases with inadequate specimens, sensitivities rose by 4% to 10%. Histology showed a trend for superiority over cytology only in characterizing nonadenocarcinoma tumor types. No differences in sensitivity were found between the centers involved. LIMITATIONS: Retrospective design, different processing of cytologic specimens. CONCLUSIONS: At EUS-FNA in pancreatic masses, combined histologic-cytologic analysis achieved a sensitivity of more than 80%, despite a low number of needle passes and may thus save time. Histology alone did not reach higher sensitivity than cytology. In particular situations, eg, rare tumors, histology may still be required.

Prognostic implications of BAX protein expression and microsatellite instability in all non-metastatic stages of primary colon cancer treated by surgery alone.

PURPOSE: This study examined whether the apoptosis-related protein, BAX, or the microsatellite-instability phenotype provide prognostic information in patients with resected colon cancer. METHODS: A total of 371 stage I-III patients that previously underwent radical surgery were included (mean follow-up 51.8 months). BAX expression was examined by immunohistochemical staining; high-frequency microsatellite instability (MSI+) was determined by assessing the specific marker, BAT26, using single-strand conformation polymorphism (SSCP)-based analysis. RESULTS: High BAX expression was found in 66.4% of patients. MSI+ tumors were observed in 14.8% of 344 patients. Univariate analysis showed that unlike MSI, low BAX expression was significantly correlated with poor disease-specific overall survival (OS) in stages I-III (p = 0.04). Multivariate subgroup analyses revealed that unlike MSI, low BAX was an independent predictor for OS in stage II (p = 0.009); however, in stages I or III, BAX or MSI were not independent predictors of OS. CONCLUSIONS: In stage II colon cancer treated with surgery alone, BAX protein expression may be a predictor for prognosis.

Patterns of alphavbeta3 expression in primary and metastatic human breast cancer as shown by 18F-Galacto-RGD PET.

UNLABELLED: The integrin alpha(v)beta(3) is a key player in angiogenesis and metastasis. Our aim was to study the uptake patterns of the alpha(v)beta(3)-selective PET tracer (18)F-galacto-RGD in invasive ductal breast cancer. METHODS: Sixteen patients with primary (n = 12) or metastasized breast cancer (n = 4) were examined with (18)F-galacto-RGD PET. Standardized uptake values (SUVs) were derived by region-of-interest analysis, and immunohistochemistry of alpha(v)beta(3) expression was performed (n = 5). RESULTS: (18)F-Galacto-RGD PET identified all invasive carcinomas, with SUVs from 1.4 to 8.7 (mean +/- SD, 3.6 +/- 1.8; tumor-to-blood and tumor-to-muscle ratios, 2.7 +/- 1.6 and 6.2 +/- 2.2, respectively). Lymph-node metastases were detected in 3 of 8 patients (mean SUV, 3.3 +/- 0.8). SUVs in distant metastases were heterogeneous (2.9 +/- 1.4). Immunohistochemistry confirmed alpha(v)beta(3) expression predominantly on microvessels (5/5) and, to a lesser extent, on tumor cells (3/5). CONCLUSION: Our results suggest generally elevated and highly variable alpha(v)beta(3) expression in human breast cancer lesions. Consequently, further imaging studies with (18)F-galacto-RGD PET in breast cancer patients for assessment of angiogenesis or planning of alpha(v)beta(3)-targeted therapies are promising.

Expression of EpCam and villin in Barrett's esophagus and in gastric cardia.

In the current study we aimed to clarify the potential of EpCAM and villin as in vivo biomarkers for both Barrett esophagus (BE)-associated neoplasia and BE versus cardiac mucosa. Immunohistochemical staining in BE with various degrees of intraepithelial neoplasia (IN), Barrett carcinoma (BC) and in normal cardiac mucosa (CM) revealed a lack of EpCam and villin in squamous esophageal epithelium. All specimens of IN and BC showed EpCam with varying staining intensities. In 57% of CM samples a weak signal was detected; the remainder displayed strong EpCam expression. Villin was found in 97% of BE specimens and in all those with IN; 37% of BC and 75% of CM specimens were~also positive. We conclude that expression of EpCam and villin differs only between squamous epithelium and BE. Determination of these proteins does not allow discrimination between different degrees of neoplasia or between esophageal intestinal metaplasia and cardiac mucosa.

Cyclin D1 expression is induced by viral BARF1 and is overexpressed in EBV-associated gastric cancer.

Approximately 10% of gastric carcinomas (GC) worldwide are associated with Epstein-Barr virus (EBV). GC is one of the most frequent human malignancies associated with EBV. The latent expression of the EBV-oncogene BARF1 is restricted to epithelial malignancies. To investigate the underlying BARF1-related mechanisms of oncogenic epithelial transformation, we analyzed gene expression profiles of a BARF1-transfected epithelial (HaCaT+) and the corresponding BARF1-negative (HaCaT-) cell line by cDNA microarray analysis. Real-time PCR was performed to confirm the cDNA microarray results. In addition, immunohistochemistry and fluorescence in situ hybridization were performed on a tissue microarray of 181 GC including 11 EBV-associated GC. Among other genes cyclin D1 expression was significantly upregulated in HaCaT+ on the transcriptional and protein level. Cyclin D1 protein expression in GC revealed a significant overexpression of cyclin D1 in EBV-associated GC (p<0.012) but not in EBV-negative GC. Cyclin D1 FISH showed that cyclin D1 overexpression was not due to gene amplification in EBV-associated GC. Cyclin D1 is induced in HaCaT+ by BARF1 and is overexpressed in EBV-associated GC indicating an interaction of viral BARF1 and cyclin D1.

[18F]galacto-RGD positron emission tomography for imaging of alphavbeta3 expression on the neovasculature in patients with squamous cell carcinoma of the head and neck.

PURPOSE: [(18)F]Galacto-RGD has been developed for positron emission tomography (PET)-imaging of alphavbeta3 expression, a receptor involved in angiogenesis and metastasis. Our aim was to study the feasibility of PET imaging with [(18)F]Galacto-RGD in patients with squamous cell carcinoma of the head and neck (SCCHN). EXPERIMENTAL DESIGN: Eleven patients with primary diagnosis of SCCHN were examined. After injection of 140 to 200 MBq [(18)F]Galacto-RGD, static emission scans 60 min post injection from the head to the abdomen (n = 11) and dynamic scans >60 min covering the tumor region (n = 6) for kinetic modeling were acquired. Standardized uptake values (SUV) were measured in tumors, muscle and oral mucosa. Immunohistochemistry was done using an alphavbeta3-specific antibody (n = 7). Image fusion with magnetic resonance imaging and/or computed tomography (CT) scans (n = 8) and calculation of tumor subvolumes based on SUVs was done using the iPlan software (BrainLAB). RESULTS: [(18)F]Galacto-RGD PET identified 10 of 12 tumors, with SUVs ranging from 2.2 to 5.8 (mean, 3.4 +/- 1.2). Two tumors <5 mm were missed. Tumor/blood and tumor/muscle ratios were 2.8 +/- 1.1 and 5.5 +/- 1.6, respectively. Tumor kinetics was consistent with a two-tissue compartmental model with reversible specific binding. Immunohistochemistry confirmed alphavbeta3 expression in all tumors with alphavbeta3 being located on the microvessels in all specimens and additionally on tumor cells in one specimen. Image fusion of [(18)F]Galacto-RGD PET with magnetic resonance imaging/multislice CT and definition of tumor subvolumes was feasible in all cases. CONCLUSIONS: [(18)F]Galacto-RGD PET allows for specific imaging of alphavbeta3 expression in SCCHN with good contrast. Image fusion and definition of tumor subvolumes is feasible. This technique might be used for the assessment of angiogenesis and for planning and response evaluation of alphavbeta3-targeted therapies.

Differentiation between pancreaticobiliary and upper gastrointestinal adenocarcinomas: is analysis of cytokeratin 17 expression helpful?

Metastatic adenocarcinoma of unknown primary site, eg, to lymph nodes, liver, or lung, may originate from many organs. Microscopic differentiation of adenocarcinomas from the pancreaticobiliary and upper gastrointestinal tracts may be difficult because of shared histologic and immunohistologic features. A high prevalence of cytokeratin (CK)17 expression in pancreaticobiliary adenocarcinoma was reported, and preliminary data indicate infrequent or missing expression in gastric adenocarcinoma. The prevalence of CK17 expression in gastric cardiac and esophageal adenocarcinomas has not been studied. We studied CK17 expression in tissue microarrays of 67 distal gastric, 71 gastric cardiac, and 46 esophageal adenocarcinomas and compared it with expression in 55 pancreatic, 23 extrahepatic bile duct, and 49 colorectal adenocarcinomas. CK17 expression was as follows: pancreatic, 88%; bile duct, 59%; esophageal, 30%; distal gastric, 28%; gastric cardiac, 27%; and colorectal adenocarcinoma, 6%. These differences were statistically significant for all tumor types except in comparisons of esophageal, cardiac, and distal gastric adenocarcinoma. The prevalence of CK17 expression in pancreatic and extrahepatic bile duct adenocarcinomas is substantially higher than in upper gastrointestinal tract and colorectal adenocarcinomas. However, in individual cases of adenocarcinoma of unknown primary site, CK17 results alone are insufficient to differentiate the analyzed tumor entities.

Regulation of thrombomodulin expression in human vascular smooth muscle cells by COX-2-derived prostaglandins.

There is concern that cyclooxygenase (COX)-2 inhibitors may promote atherothrombosis by inhibiting vascular formation of prostacyclin (PGI2) and an increased thrombotic risk of COX-2 inhibitors has been reported. It is widely accepted that the prothrombotic effects of COX-2 inhibitors can be explained by the removal of platelet-inhibitory PGI2. Using microarray chip technology, we have previously demonstrated that thrombomodulin (TM) mRNA is upregulated in cultured human coronary artery smooth muscle cells by the stable prostacyclin mimetic iloprost. This study is the first to demonstrate a stimulation of the expression of functionally active thrombomodulin in human smooth muscle cells by prostaglandins, endogenously formed via the COX-2 pathway. Because TM is an important inhibitor of blood coagulation, these findings provide a novel platelet-independent mechanism to explain the prothrombotic effects of COX-2 inhibitors. The full text of this article is available online at http://circres.ahajournals.org.

Positron emission tomography using [18F]Galacto-RGD identifies the level of integrin alpha(v)beta3 expression in man.

PURPOSE: The integrin alpha(v)beta3 plays a key role in angiogenesis and tumor cell metastasis and is therefore an important target for new therapeutic and diagnostic strategies. We have developed [18F]Galacto-RGD, a highly alpha(v)beta3-selective tracer for positron emission tomography (PET). Here, we show, in man, that the intensity of [18F]Galacto-RGD uptake correlates with alpha(v)beta3 expression. EXPERIMENTAL DESIGN: Nineteen patients with solid tumors (musculoskeletal system, n = 10; melanoma, n = 4; head and neck cancer, n = 2; glioblastoma, n = 2; and breast cancer, n = 1) were examined with PET using [18F]Galacto-RGD before surgical removal of the tumor lesions. Snap-frozen specimens (n = 26) were collected from representative areas with low and intense standardized uptake values (SUV) of [18F]Galacto-RGD. Immunohistochemistry was done using the alpha(v)beta3-specific antibody LM609. Intensity of staining (graded on a four-point scale) and the microvessel density of alpha(v)beta3-positive vessels were determined and correlated with SUV and tumor/blood ratios (T/B). RESULTS: Two tumors showed no tracer uptake (mean SUV, 0.5 +/- 0.1). All other tumors showed tracer accumulation with SUVs ranging from 1.2 to 10.0 (mean, 3.8 +/- 2.3; T/B, 3.4 +/- 2.2; tumor/muscle ratio, 7.7 +/- 5.4). The correlation of SUV and T/B with the intensity of immunohistochemical staining (Spearman's r = 0.92; P < 0.0001) as well as with the microvessel density (Spearman's r = 0.84; P < 0.0001) were significant. Immunohistochemistry confirmed lack of alpha(v)beta3 expression in normal tissue (benign lymph nodes, muscle) and in the two tumors without tracer uptake. CONCLUSIONS: Molecular imaging of alpha(v)beta3 expression with [18F]Galacto-RGD in humans correlates with alpha(v)beta3 expression as determined by immunohistochemistry. PET with [18F]Galacto-RGD might therefore be used as a new marker of angiogenesis and for individualized planning of therapeutic strategies with alpha(v)beta3-targeted drugs.

Coexpression of cyclooxygenases (COX-1, COX-2) and vascular endothelial growth factors (VEGF-A, VEGF-C) in esophageal adenocarcinoma.

Cyclooxygenases (COX), especially COX-2, are considered to be involved in carcinogenesis. Our study was initiated to test whether expression of COX isoforms (COX-1 and COX-2) is linked to expression of potent inducers of angiogenesis [vascular endothelial growth factor (VEGF)-A] and lymphangiogenesis (VEGF-C) in esophageal adenocarcinoma. One hundred twenty-three esophageal adenocarcinomas were investigated by means of quantitative reverse transcription-PCR for expression of COX-1, COX-2, VEGF-A, and VEGF-C. Additionally, COX-2 protein expression was determined using immunohistochemistry. Three esophageal cancer cell lines (OE-33, OSC-1, and OSC-2) were treated with COX-inhibiting substances (diclofenac, rofecoxib, and SC-560) and the effect on expression of the four genes was determined. COX-2 protein expression was found in all carcinomas under analysis. RNA expression levels of COX-1 and COX-2 varied markedly in carcinoma tissues and correlated significantly with each other (P < 0.001, r = 0.726). Furthermore, COX expression correlated with expression of VEGF-A (COX-1: P < 0.001, r = 0.753; COX-2: P < 0.001, r = 0.764) and VEGF-C (COX-1: P < 0.001, r = 0.778; COX-2: P < 0.001; r = 0.613). Exposure of esophageal cancer cell lines OE-33, OSC-1, and OSC-2 with three COX-inhibiting substances (diclofenac, rofecoxib, and SC-560) resulted in significantly reduced expression of VEGF-A and VEGF-C. In conclusion, our data suggest that both COX isoforms may be involved in the pathogenesis of esophageal adenocarcinoma, as they are linked to the expression of important modulators of angiogenesis (VEGF-A) and lymphangiogenesis (VEGF-C).

Increased risk of ischemic bowel complications during treatment with bevacizumab after pelvic irradiation: report of three cases.

PURPOSE: To assess the rate of severe bowel complications during treatment with the anti-vascular endothelial growth factor monoclonal antibody bevacizumab. METHODS AND MATERIALS: We performed a retrospective evaluation of bevacizumab-associated severe intestinal adverse events from our institutional database. RESULTS: A total of 33 patients started treatment with bevacizumab at our institution during the first 6 months after its approval in Germany. Three patients (9%) presented with severe bowel complications: two with acute ischemic colitis and one with gastrointestinal perforation with a fatal outcome. All 3 patients had undergone radiotherapy directed to the pelvis before treatment with bevacizumab. None of the 30 patients without bowel complications had been pretreated with infradiaphragmatic irradiation. Histologic evaluation of bowel biopsies and resection specimens revealed severe ischemic bowel damage as the pathophysiologic background of the clinical findings. CONCLUSION: This report contributes to the pathophysiologic clarification of bevacizumab-induced bowel complications and points to a potentially increased risk of severe ischemic damage during treatment with bevacizumab in patients who have undergone previous radiotherapy.

Lack of prognostic impact of p53 gene mutation and p53 phosphorylation at serine 15 in multimodally treated adenocarcinomas of the gastroesophageal junction.

PURPOSE: As inactivation of p53 may be correlated with poor response of tumors to chemo- and/or radiotherapy the presence of p53 mutations in exons 5-8 was determined in adenocarcinomas of the gastroesophageal junction (GEJ). As p53 protein phosphorylation at serine 15 indicates stabilization and protection against mdm-2 the presence of this phosphorylation state was subsequently evaluated. METHODS: Mutations in exons 5-8 were analyzed by denaturing high pressure liquid chromatography (DHPLC) and subsequent sequence analysis in pretherapeutic biopsies of 38 adenocarcinomas of the GEJ that had undergone multimodal treatment in the course of a prospective multicentric phase III trial. The presence of p53 protein phosphorylation at serine 15 was evaluated by immunohistochemistry. RESULTS: Mutations in the DNA binding region were found in 23 samples and were only weakly associated with worse 2-year survival (P=0.083). Phosphorylation at serine 15 of p53 was detected in 14 samples, being neither associated with p53 mutation nor with patient's survival. CONCLUSION: This allows the conclusion that the determination of these two parameters does not help to select patients who do profit from multimodal treatment for adenocarcinomas of the GEJ.

The histological appearance of oesophageal adenocarcinoma--an analysis based on 215 resection specimens.

The current study was performed to determine whether the histopathological appearance of oesophageal adenocarcinoma (AC) differs significantly from that of cardiac or gastric AC. Therefore, HE-stained slides of 215 primarily resected oesophageal AC, 108 cardiac and 184 gastric AC were classified according to a variety of clinico-pathologic parameters. According to Lauren's classification, oesophageal AC (1.4%) less frequently belonged to the diffuse type than cardiac (2.8%) and gastric AC (23.9%; p<0.0001). Tubular and papillary AC, as defined by the WHO classification, were more frequent among oesophageal (94.4%) than among cardiac (87.0%) and gastric AC (59.2%; p<0.0001). Solid carcinomas, according to Carneiro's classification, were less frequent among oesophageal (2.8%) than among cardiac (10.2%) and gastric AC (9.2%; p<0.0001). Oesophageal AC were graded more frequently G1/G2 (53.9%) than cardiac (30.6%) and gastric AC (27.7%; p<0.0001). Among oesophageal AC, Lauren's classification (p=0.0067), Carneiro's classification (p=0.0170), tumour grade (p=0.0005), lymphatic vessel invasion (p<0.0001) but not WHO classification were histological predictors of postoperative survival. In conclusion, oesophageal AC displays the same histological spectrum as cardiac and gastric AC. However, the relative proportion of differentiated, gland-forming carcinomas is significantly more frequent in the oesophagus than in the cardia and in the stomach.

Esophageal squamous cell carcinoma with entirely intramural growth pattern.

Esophageal cancers are predominantly carcinomas, which are-due to their origin from the epithelial lining-visible by endoluminal view. We report in this study about the rare case of an esophageal squamous cell cancer with an unusual, entirely intramural growth pattern. The diagnosis could only be established postoperatively, because all preoperative biopsies had failed to demonstrate the tumor. The entirely intramural growth pattern of esophageal squamous cell cancer is an exceedingly rare variant, with only one previously reported case. Nevertheless, clinicians, radiologists, and pathologists should be aware of the potential existence of this condition, especially when clinical and imaging results suggest a malignant tumor that cannot be proven on biopsies. Surgical exploration must be considered under these circumstances.

Expression and nuclear localization of Snail, an E-cadherin repressor, in adenocarcinomas of the upper gastrointestinal tract.

Transcriptional E-cadherin down-regulation can be mediated by Snail, a zinc finger transcription factor. To be able to examine nuclear Snail immunoreactivity in archival human cancers, we established a monoclonal antibody against the purified human Snail protein. The specificity of the selected rat antibody Sn9H2 was demonstrated by Western blot analysis using extracts from different cell lines and by immunofluorescence and immunohistochemistry of primary tissues. Subsequently, a series of 340 adenocarcinomas of the upper gastrointestinal tract, including tumours from the oesophagus (n=154), cardia (n=102) and stomach (n=84), arranged in tissue microarrays, were examined for Snail expression and were correlated to E-cadherin expression and clinico-pathological parameters. Nuclear Snail immunoreactivity was seen in 27 tumours (7.9%) and tended to be more frequent in oesophageal adenocarcinomas (11.1%) than in cardiac (6.9%) or gastric (3.6%) carcinomas (p=0.0428). In 35% of the Snail-positive cases, E-cadherin immunoreactivity was lost. No correlation was found for nuclear Snail expression and tumour grade, Lauren's classification, WHO classification, tumour stage and tumour size. The pattern of Snail expression observed with our new hybridoma, Sn9H2, which is currently the only antibody that reacts with endogenous nuclear (active) Snail, suggests only a minor role of Snail in tumours of the upper gastrointestinal tract.

Association of pretherapeutic expression of chemotherapy-related genes with response to neoadjuvant chemotherapy in Barrett carcinoma.

PURPOSE: We analyzed pretherapeutic gene expression patterns of patients with locally advanced adenocarcinomas of the esophagus with regard to response to neoadjuvant chemotherapy. EXPERIMENTAL DESIGN: Pretherapeutic, paraffin-embedded, formalin-fixed endoscopic esophageal tumor biopsies of 38 patients with locally advanced esophageal adenocarcinomas (Barrett adenocarcinoma) were included. All patients underwent two cycles of cisplatin and 5-fluorouracil (5-FU) therapy with or without additional paclitaxel followed by abdominothoracal esophagectomy. RNA expression levels of 5-FU metabolism-associated genes thymidylate synthase, thymidine phosphorylase, dihydropyrimidine dehydrogenase, methylenetetrahydrofolate reductase, MAP7, and ELF3, of platinum- and taxane-related genes caldesmon, ERCC1, ERCC4, HER-2/neu, and GADD45, and of multidrug resistance gene MRP1 were determined using real-time reverse transcriptase-PCR. Expression levels were correlated with response to chemotherapy, histopathologically assessed in surgically resected specimens. RESULTS: Responding patients showed significantly higher pretherapeutic expression levels of MTHFR (P = 0.012), caldesmon (P = 0.016), and MRP1 (P = 0.007). In addition, patients with high pretherapeutic MTHFR and MRP1 levels had a survival benefit after surgery (P = 0.013 and P = 0.015, respectively). Additionally, investigation of intratumoral heterogeneity of gene expression of relevant genes (MTHFR, caldesmon, HER-2/neu, ERCC4, and MRP1), verified in nine untreated Barrett adenocarcinomas by examination of five distinct tumor areas, revealed no significant heterogeneity in gene expression indicating that expression profiles obtained from biopsy material may yield a representative genetic expression profile of total tumor tissue. CONCLUSIONS: Our results indicate that determination of mRNA levels of few genes may be useful for the prediction of the success of neoadjuvant chemotherapy in individual cancer patients with locally advanced Barrett adenocarcinoma.

Noninvasive visualization of the activated alphavbeta3 integrin in cancer patients by positron emission tomography and [18F]Galacto-RGD.

BACKGROUND: The integrin alphavbeta3 plays an important role in angiogenesis and tumor cell metastasis, and is currently being evaluated as a target for new therapeutic approaches. Several techniques are being studied to enable noninvasive determination of alphavbeta3 expression. We developed [(18)F]Galacto-RGD, a (18)F-labeled glycosylated alphavbeta3 antagonist, allowing monitoring of alphavbeta3 expression with positron emission tomography (PET). METHODS AND FINDINGS: Here we show by quantitative analysis of images resulting from a small-animal PET scanner that uptake of [(18)F]Galacto-RGD in the tumor correlates with alphavbeta3 expression subsequently determined by Western blot analyses. Moreover, using the A431 human squamous cell carcinoma model we demonstrate that this approach is sensitive enough to visualize alphavbeta3 expression resulting exclusively from the tumor vasculature. Most important, this study shows, that [(18)F]Galacto-RGD with PET enables noninvasive quantitative assessment of the alphavbeta3 expression pattern on tumor and endothelial cells in patients with malignant tumors. CONCLUSIONS: Molecular imaging with [(18)F]Galacto-RGD and PET can provide important information for planning and monitoring anti-angiogenic therapies targeting the alphavbeta3 integrins and can reveal the involvement and role of this integrin in metastatic and angiogenic processes in various diseases.