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Biomedical subjects

H J Stein

Publications and source records attributed to H J Stein.

At least 19 recordsLinked to original sources
PubMed2007

Lack of EGFR gene mutations in exons 19 and 21 in esophageal (Barrett's) adenocarcinomas.

Epidermal growth factor receptor is over-expressed in several tumors and is the target for the tyrosine kinase inhibitor gefitinib. This receptor is also over-expressed in esophageal adenocarcinomas. In non-small cell lung cancer, specific somatic mutations residing in the epidermal growth factor receptor tyrosine kinase in the activation loop and the glycine-rich P-loop, are responsible for an enhanced sensitivity toward gefitinib. We analyzed exons 19 and 21 coding for the receptor tyrosine kinase of the epidermal growth factor gene in 105 samples of esophageal (Barrett's) adenocarcinoma by denaturing high-pressure liquid chromatography. We found only one silent mutation in exon 19 of adenine to guanine in codon 754 leading to a substitution of K to K, the rest of the sample being wild-type genotype. In conclusion, mutations within the tyrosine kinase domain of EGFR associated with sensitivity of non-small cell lung cancer patients to gefitinib are not present in esophageal (Barrett's) adenocarcinoma.

Adenocarcinoma↗
PubMed2007

Squamous cell carcinoma and Zenker diverticulum.

Squamous cell carcinoma in a Zenker diverticulum is a very rare condition. We report a case of a patient with a Zenker carcinoma, who was primarily functionally inoperable and therefore received neoadjuvant radiochemotherapy before cardiac bypass surgery. After a complicated course with cardiogenic shock and myocardial infarction, a re-evaluation of functional risk analysis and the tumor situation revealed operability. Subsequently, partial hypopharyngectomy and partial cervical esophageal resection with lymphadenectomy was performed. Reconstruction of the gastrointestinal continuity was made by interposition of a free small bowel graft and microvascular anastomosis. The postoperative course showed a small anastomotic leakage of the hypopharyngeal-small bowel anastomosis, which was successfully treated conservatively.

Aged↗
PubMed2006

Precision measurement of the quasifree pn-->dvarphi reaction close to threshold.

The quasifree pn-->dvarphi reaction has been studied at the Cooler Synchrotron COSY-Jülich, using the internal proton beam incident on a deuterium cluster-jet target and detecting a fast deuteron in coincidence with the K+K- decay of the varphi meson. The energy dependence of the total and differential cross sections are extracted for excess energies up to 80 MeV by determining the Fermi momentum of the target neutron on an event-by-event basis. Though these cross sections are consistent with s-wave production, the kaon angular distributions show the presence of p waves at quite a low energy. Production on the neutron is found to be stronger than on the proton but not by as much as for the eta meson.

Journal Article↗
PubMed2006

The prognostic impact of O6-Methylguanine-DNA Methyltransferase (MGMT) promotor hypermethylation in esophageal adenocarcinoma.

Promotor hypermethylation is a common event in human cancer. O6-Methylguanine-DNA Methyltransferase (MGMT) is a gene involved in DNA repair, which is methylated in a variety of cancer types. In colorectal cancer and lung cancer, hypermethylation of MGMT has been correlated with p53 mutation. In the present study, 132 samples of esophageal adenocarcinoma and 58 samples of normal esophageal tissue were investigated for MGMT hypermethylation status by methylation-specific real-time PCR and results were correlated to clinicopathological parameters, patient's survival, p53 mutation and expression of p53 protein and MGMT protein. In the carcinomas, hypermethylation of MGMT was found in 63.6% of cases and loss of MGMT protein expression in 48.5% of cases. Furthermore, MGMT hypermethylation was found in 5.7% of normal esophageal smooth muscle tissue, in 20.0% of esophageal squamous epithelium and in 61.5% of nonneoplastic Barrett's mucosa. In the carcinomas, hypermethylation of the MGMT gene was correlated with loss MGMT protein expression (p < 0.0001) and with high tumor differentiation (p = 0.0079). In contrast, no correlation between MGMT hypermethylation, Lauren's classification, WHO classification, tumor size, gender, age, pT category and pN category, and p53 status was found. Neither MGMT hypermethylation nor loss of MGMT protein expression was correlated with patient's survival. In conclusion, MGMT hypermethylation in esophageal adenocarcinoma is a frequent event that is associated with loss of MGMT protein expression but not with patient's outcome.

Adenocarcinoma↗
PubMed2006

Near-threshold production of phi mesons in pp collisions.

The pp-->ppphi reaction has been studied at the Cooler Synchrotron COSY-Jülich, using the internal beam and ANKE facility. Total cross sections have been determined at three excess energies epsilon near the production threshold. The differential cross section closest to threshold at epsilon=18.5 MeV exhibits a clear S wave dominance as well as a noticeable effect due to the proton-proton final-state interaction. Taken together with data for ppomega production, a significant enhancement of the phi/omega ratio of a factor 8 is found compared to predictions based on the Okubo-Zweig-Iizuka rule.

Journal Article↗
PubMed2006

Expression of cyclo-oxygenase 1 and 2, prostaglandin E synthase and transforming growth factor beta1, and their relationship with vascular endothelial growth factors A and C, in primary adenocarcinoma of the small intestine.

BACKGROUND: Primary adenocarcinomas of the small intestine are rare. The prostaglandin biosynthetic pathway plays a major role in carcinogenesis and is linked with angiogenesis in various tumours. Promotion of tumour growth by transforming growth factor (TGF) beta may be mediated through the prostaglandin pathway. METHODS: Expression of cyclo-oxygenase (COX) 1 and 2, prostaglandin E synthase (PGES), TGF-beta1 and vascular endothelial growth factor (VEGF) A and C genes was analysed in 54 primary adenocarcinomas of the small intestine and corresponding normal intestinal mucosa. All patients had undergone surgical resection without previous antineoplastic therapy. Target gene expression was analysed at the mRNA level by reverse transcriptase-polymerase chain reaction and correlated with clinicopathological parameters as well as survival. COX-2 protein expression was examined by immunohistochemistry. RESULTS: Expression of COX-2 protein was detected immunohistochemically in 98 per cent of the carcinomas. COX-1, COX-2, VEGF-A, VEGF-C, PGES and TGF-beta1 mRNA expression varied markedly in different tumours, but all were overexpressed compared with levels in normal intestinal mucosa. There were significant associations between levels of COX-1, COX-2, TGF-beta1 and PGES mRNAs and those of VEGF-A and VEGF-C. CONCLUSION: Correlations between levels of mRNA for COX-1, COX-2, TGF-beta1 and PGES and those for proangiogenic factors VEGF-A and VEGF-C suggest a role for these factors in the propagation of primary adenocarcinomas of the small intestine.

Adenocarcinoma↗
PubMed2006

[Limited surgical resection versus local endoscopic therapy of early cancers of the esophagogastric junction].

BACKGROUND: Adenocarcinomas of the esophagogastric junction (especially Barrett's cancers) are increasingly diagnosed at early stages. The current standard treatment - radical resection with extensive lymphadenectomy - has been challenged. Limited resection or endoscopic mucosal ablation have been proposed as less invasive alternatives. METHODS: Available data regarding limited surgical resections and endoscopic interventional procedures are evaluated with respect to short- and long-term results (mortality, morbidity, oncologic adequacy, quality of life). RESULTS: Limited resection of the esophagogastric junction has been proven as safe (low morbidity and mortality) and oncologically adequate procedure (low rate of recurrence/excellent long-term survival) with good quality of life. The procedure meets the oncological requirements (R0-resection, complete resection of potentially tumor-infiltrated lymph nodes and the entire precancerous Barrett's esophagus). Reconstruction with interposition of a pedicled isoperistaltic jejunal loop prevents reflux and is crucial for achieving good postoperative quality of life. In contrast, endoscopic mucosal resection (EMR) carries the risk of high recurrence rates (at least 30 %). This has to be regarded as an effect of the frequent incomplete resection, multicentric tumor growth, the persistence of precancerous Barrett's mucosa and persistence of gastroesophageal reflux. Consequently, from the oncological view point, EMR is only suited for unicentric mucosal tumors (T1a) in short segments of Barrett's esophagus. Reliable preoperative identification of such tumors is, however, currently not possible. CONCLUSION: For adequately selected patients with early Barrett's cancer, limited resection of the esophagogastric junction is an appropriate procedure. Endoscopic mucosa resection (EMR) might gain importance as staging tool.

Adenocarcinoma↗
PubMed2006

Prognostic significance of expression patterns of c-erbB-2, p53, p16INK4A, p27KIP1, cyclin D1 and epidermal growth factor receptor in oesophageal adenocarcinoma: a tissue microarray study.

AIMS: To correlate immunohistochemical expression patterns and prognosis in oesophageal adenocarcinoma. METHODS: The expression of c-erbB-2, p53, p16INK4A, p27KIP1, cyclin D1 and epidermal growth factor receptor (EGFR) was studied in a series of 137 primarily resected oesophageal adenocarcinoma samples. The expression analysis on protein level was performed on routine paraffin wax-embedded material, with immunohistochemical staining of the samples, assembled on a tissue microarray. The results were correlated with clinicopathological features (pT, pN and G) and survival. RESULTS: 22 (16%) tumours showed an overexpression of the c-erbB-2 oncoprotein. Expression of EGFR was observed in 72 (55%) cases, accumulation of p53 in 68 (52%) cases and of cyclin D1 in 102 (77%) cases. Loss of p16INK4A expression was observed in 101 (76%) cases and low expression of p27KIP1 in 91 (71%) cases. Expression of these proteins did not correlate with tumour stage, grade, Lauren's or World Health Organization classification or lymph node status. On univariate survival analysis, more advanced tumour stage (p = 0.002), lymph node involvement (p = 0.003), high tumour grade (p = 0.017) and lack of EGFR expression (p = 0.034) were found to be associated with poorer survival. On multiple regression analysis, only tumour stage (p = 0.03) and lymph node involvement (p = 0.004) were shown to have an association with the survival of the patient. CONCLUSION: The immunohistochemical expression of c-erbB-2 oncoprotein, cylin D1, p16INK4A, p27KIP1, p53 and EGFR in most oesophageal adenocarcinomas suggests their implication in the pathogenesis of this entity. None of the molecular markers assessed, however, was of prognostic value. Identification of any marker superior to or even approaching the prognostic value of conventional histopathological markers (pT and pN) was therefore not possible.

Adenocarcinoma↗
PubMed2005

Preferred location for the development of esophageal adenocarcinoma within a segment of intestinal metaplasia.

BACKGROUND: Barrett's metaplasia is the predominant precursor for the development of esophageal adenocarcinoma. This precancerous lesion has become the focus of various surveillance programs aimed at detecting earlier and therefore potentially curable lesions. However, sampling error by missing invasive cancer lesions is a common problem. This study aimed to identify preferred locations within a segment of Barrett's mucosa for the development of esophageal adenocarcinoma. METHODS: The study group consisted of 213 patients with histologically proven esophageal adenocarcinoma. Of those, there were 134 cases of early cancer and 79 cases of locally advanced lesions. These patients received neoadjuvant chemotherapy. The frequency of intestinal metaplasia and the location of the tumor occurrence within the segment of intestinal metaplasia were assessed. RESULTS: Intestinal metaplasia was found in 83% of the early lesions and in 98% of the advanced tumors after neoadjuvant chemotherapy. In 82.2% of the cases, the tumor was located at the distal margin of the intestinal metaplasia in patients with early tumor manifestations. The remaining tumor mass after neoadjuvant therapy also was located predominantly at the distal margin of the segment of intestinal metaplasia (85% of the cases). CONCLUSIONS: The results demonstrate that almost all adenocarcinomas of the esophagus are based on the development of a segment of intestinal metaplasia. The distal margin of Barrett's mucosa seems to be the most vulnerable location for the development of invasive cancer.

Adenocarcinoma↗
PubMed2005

Surgery for early stage esophageal adenocarcinoma.

Current treatment recommendations for early esophageal adenocarcinoma range from radical esophagectomy with extensive lymphadenectomy, limited surgical resection with/without regional lymphadenectomy to endoscopic mucosectomy or ablation. A comparison of treatment associated morbidity, tumor recurrence rates, and functional outcome suggests that none of these alternatives can be universally recommended. Rather, an individualized strategy should be employed based on depth of tumor penetration into the mucosa/submucosa, presence of lymph node metastases, multicentricity of tumor growth, length of the underlying Barrett mucosa and comorbidity of the affected patient. Endoscopic mucosectomy may suffice for an isolated focus of high-grade neoplasia or mucosal cancer, provided the neoplasia and underlying Barrett mucosa can be removed completely. Surgical resection is the treatment of choice for tumors invading the submucosa, multicentric tumors and recurrence after endoscopic mucosectomy. The extent of surgical resection must be guided by the length of the Barrett mucosa. In most instances a complete tumor resection and removal of the entire Barrett mucosa can be achieved by a limited transabdominal approach, and therefore subtotal esophagectomy may not be necessary. Application of the sentinel node technology may in the future allow to limit systematic lymphadenectomy to the rather small subgroup of patients who in fact have lymph node metastases.

Adenocarcinoma↗
PubMed2005

[Diagnosis and therapy of weakly-acid/non-acidic gastroesophageal reflux disease].

The therapy of gastroesophageal reflux disease (GERD) is uncomplicated in most cases. However, 20 % of GERD patients suffer from reflux-associated symptoms under therapy with proton pump inhibitors (PPI). The cause of this resistance to PPI-therapy remains unclear. Today, the most discussed theory is the presence of the non- or weakly acidic reflux. Objective measurements of the weakly/non-acidic reflux are available since the development of intraluminal impedance monitoring in combination with pH-monitoring. The therapy of weakly/non-acidic GERD is not well established, so far. In the course of clinical studies the therapeutic spectrum (i. e. modification of the medical therapy, endoscopic anti-reflux procedures or surgical therapy) has to be tested.

Baclofen↗
PubMed2005

Measurement of the analyzing power in p-->d-->(p p)n with a fast forward 1S0 proton pair.

A measurement of the analyzing power A(y) of the p-->d--> (p p) + n reaction was carried out at the ANKE spectrometer at COSY at beam energies of 0.5 and 0.8 GeV by detection of a fast forward proton pair of small excitation energy E(pp) < 3 MeV. The S-wave dominance in the fast diproton is experimentally demonstrated in this reaction. While at T(p) = 0.8 GeV the measured analyzing power almost vanishes, it rises to nearly unity at T(p) = 0.5 GeV for neutrons emitted at theta(c.m.)(n) = 167 degrees. The results are compared with a model taking into account one-nucleon exchange, single scattering, and Delta(1232) excitation in the intermediate state. The model describes fairly well the unpolarized cross section obtained earlier and the analyzing power at 0.8 GeV; it fails to reproduce A(y) at 0.5 GeV.

Journal Article↗
PubMed2005

[Barrett's esophagus].

INTRODUCTION: It is widely accepted that long segments of Barrett's esophagus are caused by end-stage gastroesophageal reflux disease (GERD), but little is known about the correlation of severity of GERD and extent of metaplasia. METHODS: Twenty normal volunteers and 142 patients with different extent of intestinal metaplasia (39 with intestinal metaplasia limited to the esophagogastric junction, 48 with short segments of Barrett's esophagus, and 55 with long segments) underwent manometry and combined pH-bilirubin monitoring. RESULTS: The extent of intestinal metaplasia correlated to the exposition of gastric and duodenal juice in the esophagus and inversely with a competent lower esophageal sphincter. CONCLUSIONS: The extent of intestinal metaplasia is related to the severity of GERD.

Adult↗
PubMed2005

[Abdomino-right-thoracic esophagectomy with intrathoracic anastomosis in Barrett's cancer].

The modified technique of abdomino-right-thoracic esophagectomy (the Lewis-Tanner approach) is increasingly being favoured as the surgical procedure of choice in patients with resectable adenocarcinoma of the distal esophagus, so-called Barrett's cancer. The technical details of this procedure and the reconstruction of gastrointestinal continuity using a gastric tube with high intrathoracic anastomosis are illustrated, as they have proved useful in our own practice during recent years.

Abdomen↗
PubMed2005

[Esophagectomy as therapeutic principle for squamous cell esophageal cancer].

The fatalistic approach towards surgical therapy of esophageal squamous cell cancer has been replaced in recent years by a more differentiated view. This was triggered by the establishment of individualized therapeutic modalities based on tumor stage, tumor location, general patient status, and comorbidity. Despite advances in nonsurgical therapy of squamous cell esophageal cancer, esophagectomy remains the central therapeutic modality. Primary subtotal en-bloc esophagectomy with lymphadenectomy is the only curative option with a high likelihood of success for resectable tumors (uT1-3 categories) located below the level of the tracheal bifurcation and for early more proximal tumors. In patients with locally advanced tumors at or above the level of the tracheal bifurcation, surgical resection can still cure those who respond to neoadjuvant radiochemotherapy. Preoperative "conditioning" of risk patients, surgical safety strategies in risk situations, and standardization of both the operative procedure and the perioperative management have resulted in a marked reduction of the previously substantial postoperative mortality to below 3% in experienced centers. In our own experience of 900 esophagectomies for squamous cell esophageal cancer, the 5-year survival rate rose from about 20% to more than 50% in the last two decades. Esophagectomy thus has become a safe operation and remains the only therapeutic option offering cure for a substantial proportion of patients with squamous cell cancer of the esophagus.

Adenocarcinoma↗
PubMed2005

Surgical strategies for early esophageal adenocarcinoma.

The need for extensive surgical resection for early-stage esophageal adenocarcinoma has been challenged by the increasing frequency of early detection in patients with Barrett's esophagus undergoing surveillance endoscopy. Limited endoscopic or surgical procedures are promoted as alternatives to radical esophagectomy and lymphadenectomy in such patients. Currently available data show that limited surgical resection of the distal esophagus with regional lymphadenectomy and interposition of an isoperistaltic jejunal segment is a safe and oncologically adequate procedure in this situation and provides good quality of life. This is in contrast to endoscopic ablation or endoscopic mucosal resection, which are associated with high tumour recurrence rates and persistence of premalignant Barrett esophagus. New technologies for accurate prediction of the presence and pattern of lymphatic spread-e.g. sentinel node techniques and artificial neural networks-may allow a further reduction of the invasiveness of surgical resection without compromising cure rates.

Adenocarcinoma↗
PubMed2005

COX2 expression, angiogenesis, proliferation and survival in Barrett's cancer.

OBJECTIVES: To examine COX2 expression and its relation to angiogenesis, Ki67 and Bcl2 expression in Barrett's cancer. METHODS: Specimens from 48 R0-resected Barrett's adenocarcinoma were immunostained for cyclooxygenase 2 (COX2), CD 31 and alpha-sm actin to discriminate between mature and immature vessels, Mib-1 and Bcl2. COX2 staining, angiogenesis, Ki67 expression and Bcl2 expression were also measured. RESULTS: COX2 expression was increased in 25 of 48 cases. There was no significant correlation between COX2 expression and age, sex and tumor differentiation. A significant association was found between lymph node positive cases and elevated COX2 expression (p=0.008). The percentage of Ki67 positive cancer cells was 43.8% (range 15.4-67.5%) in the low COX2 group and 57.8% (range 12.0-84.6%) in the high COX2 group. The difference was statistically significant (p=0.046). The median neovascularisation coefficient in the low COX2 group was 11.68 (range 8.22-43.64) and 25.47 (range 8-38.3) in the high COX2 group. The difference was statistically significant (p=0.012). A significant difference in survival was observed between patients in the COX2 low category when compared with the COX2 high category (log-rank test p=0.013). CONCLUSIONS: Elevated COX2 expression is associated with lymph-node metastases and reduced survival in Barrett's cancer. This appears to be related to the induction of angiogenesis and proliferation.

Barrett Esophagus↗