[What do General Practitioners and Dentists Report about their Cooperation? A Qualitative Exploration]. / Was berichten Hausärzte und Zahnärzte über ihre Zusammenarbeit? Ergebnisse aus einer qualitativen Exploration.

OBJECTIVE: Against the background of well-described associations between oral and general health, the cooperation between general practitioners (GPs) and dentists is crucial. Besides treatment, this includes prevention. Administrative referral between these two professions is not provided by statute. Thus, the study addresses the question: How do dentists and GPs integrate the associations between oral and systemic health in daily routine? METHODS: A total of 28 semi-structured interviews were conducted with GPs and dentists from 3 structurally different regions in the Federal State of Baden-Wurttemberg. Participants were visited in their office. The interviews were recorded, transcribed and analysed by 2 dentists and sociologists using Mayrings' qualitative content analysis. RESULTS: Associations between general and oral health are partially known to both practitioners. However, contact between them is limited. GPs send patients directly to dentists, without contacting them - mainly due to a desolate dental status, rarely due to therapy-resistant headache or facial pain. Dentists contact GPs to clarify mainly medication or anticoagulation medications taken by patients prior to invasive procedures. Preventive aspects play a minor part. Consultation essentially depends on acquaintanceship. CONCLUSION: Separation by statute determines the cooperation. Oral cavity in daily care is demarcated. Holistic patient care is hindered by a lack of knowledge and daily routines.

[Psychosomatic Consultation in the Workplace--Description and Modelling of a New Health-Related Service]. / Psychosomatische Sprechstunde im Betrieb--Gestaltungsformen des Angebots.

GOAL OF THE STUDY: In Germany, mental disorders have increasing importance for disability and early retirement. However, patients may have to wait several months before becoming an appointment with a psycho(somatic) therapist. Accordingly, several companies initiated a "psychosomatic consultation in the workplace" (PCIW). This concept has been explored. METHODS: Qualitative data analysis (expert interviews with stakeholders, focus group interviews with occupational health physicians; Mayring's content analysis) focussed on the question of how the concept of a PCIW can be tailored to meet the employees' needs. RESULTS: Concepts and implementation of PCIW differed with regard to the aspects dissemination of information about the consultation, gatekeeping, place of the consultation, and number of appointments with the psycho(somatic) therapist. The concepts of PCIW may be described as more or less "restrictive" or "liberal". The interviewees emphasised the need for PCIW and discussed the involvement of the occupational health physician within this approach. PCIW proved of value. Yet, the interviewees were ambivalent regarding the fact that companies offer and pay for treatment which should be provided within standard health care. CONCLUSION: Shaping company-based elements of standard health care should respect setting-specific needs and involve in-company stakeholders into the process.

Southwest Oncology Group study S0413: a phase II trial of lapatinib (GW572016) as first-line therapy in patients with advanced or metastatic gastric cancer.

BACKGROUND: Lapatinib (GW572016) is a dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2/ErbB2), which are reported as overexpressed in 15%-45% of gastric cancers, making them potential targets. PATIENTS AND METHODS: The primary objective of this study was to assess response rate. Secondary objectives included overall survival (OS), toxicity, and the relationship of EGFR, ErbB2, and markers of angiogenesis with clinical outcome. Lapatinib was administered to chemonaive metastatic gastric cancer patients at a dose of 1500 mg orally daily for 28 days. RESULTS: The study enrolled 47 patients from February 2005 until May 2006. Four patients (9%) had a confirmed partial response (PR), 1 (2%) had an unconfirmed PR, and 10 (23%) had stable disease. Median (95% confidence interval) time to treatment failure was 1.9 (1.6-3.1) months and OS was 4.8 (3.2-7.4) months. Significant adverse events: one grade 4 cardiac ischemia/infarction, one grade 4 fatigue, and one grade 4 emesis. One treatment-related death was due to central nervous system ischemia. An exploratory analysis of markers revealed gene expression of HER2, interleukin (IL)-8 and genomic polymorphisms IL-8, and vascular endothelial growth factor correlated with OS. CONCLUSIONS: Lapatinib is well tolerated, with modest single-agent activity in advanced/metastatic gastric cancer patients. Potential molecular correlatives were identified which warrant further validation.

TP53 and gastric carcinoma: a review.

In this article, we survey the major p53 (TP53) alterations identified in gastric carcinomas and their precursors. These include p53 expression, mutations, and loss of heterozygosity (LOH). Not only are the various abnormalities summarized, but in addition there is a survey of the literature with respect to the impact of these changes on patient prognosis and treatment response. The majority of published studies involve the immunohistochemical detection of the protein. These use different antibodies, different detection techniques, and different methods of interpretation. Therefore not surprisingly, the results of many of the studies are contradictory with one another. Overall, however, it appears that p53 alterations occur early in the development of gastric carcinoma, being present even in the nonneoplastic mucosa and they increase in frequency as one progresses along the pathway of gastric carcinoma development. p53 immunoreactivity is seen in 17%-90.7% of invasive gastric carcinomas. p53 alterations occur much more commonly in proximal lesions than in distal ones, suggesting that the molecular events leading to the development of gastric carcinoma may be very different in proximal vs. distal tumors. p53 mutations occur in 0%-77% of gastric carcinomas. The mutations are distributed widely across the gene from exons 4-11 with hot spots of mutation at codons 175, 248, 273, 282, 245, and 213. G:C>A:T transitions at CpG sites are the commonest type of mutation. At least 60% of carcinomas with mutations also exhibit p53 LOH.

A unique basal pattern of p53 expression in ulcerative colitis is associated with mutation in the p53 gene.

AIMS: The p53 protein is implicated in the control of cell proliferation, differentiation, and death. As part of a study characterizing p53 alterations in colonic mucosa of patients with ulcerative colitis, we identified a unique pattern of basal p53 immunoreactivity. METHODS AND RESULTS: Tissue samples (n=180) from 42 ulcerative colitis patients were evaluated for p53 alterations by immunohistochemistry, loss of heterozygosity analysis, polymerase chain reaction-single-strand conformation polymorphism and direct sequencing. In addition, the expression of the p53- associated proteins p21waf1/cip1 and MDM2 was evaluated immunohistochemically. Three basic patterns of p53 immunoreactivity were observed: (i) isolated immunoreactive cells in the crypt bases; (ii) strongly positive cells confined to the basal half of the glands; and (iii) diffusely staining cells. The basal staining pattern was observed in both non-neoplastic tissues and in some areas of dysplasia, and was associated with normal expression of p21waf1/cip1 in all cases, and with p53 mutation in seven of 11 cases. CONCLUSIONS: The basal pattern of p53 expression is associated with mutation in the p53 gene, and appears to be an early change in a subgroup of ulcerative colitis patients. The significance of this pattern of immunoreactivity and the mechanism by which it develops are discussed.

Heterotopic ovarian splenoma: report of a first case.

We present a case of ovarian splenoma, a form of heterotopic splenic hamartoma consisting of red pulp tissue. The hamartoma was located in ovarian stroma in an otherwise normal ovary. The histology showed interanastomosing vascular channels of splenic sinusoidal red pulp lined by cells that were immunoreactive for antibodies to von Willebrand antigen and CD8, findings consistent with splenic lining cells. The sinuses were lined by cuboidal to flattened cells with ovoid and grooved bland-looking nuclei. Ultrastructurally, the tumor cells showed Weibel-Palade bodies and lysosomes. To our knowledge, this is the first case of splenic tissue arising in an ovary, and it underlines the trend noted in the literature that splenic hamartoma,although a rare entity, can arise in many retroperitoneal organs, including the ovary.

Usefulness of colonoscopy with biopsy in the evaluation of patients with chronic diarrhea.

OBJECTIVE: Patients referred for chronic diarrhea frequently undergo endoscopic evaluation. There are limited data on the role for colonoscopy with biopsy and ileoscopy for patients with chronic diarrhea. METHODS: We reviewed the charts of 228 patients with chronic diarrhea evaluated by colonoscopy between November 1995 and March 1998. Chronic diarrhea was defined as loose, frequent bowel movements for a minimum of 4 wk. Patients were excluded if biopsies were not performed in normal colons, if they had undergone previous bowel surgery, a history of inflammatory bowel disease, HIV, or an inadequate colonoscopy. RESULTS: One hundred sixty-eight patients were included in the analysis, of whom 142 (85%) had ileoscopy. Colonoscopy and biopsy yielded a specific histological diagnosis in 52 (31%) patients. These included Crohn's disease (9), ulcerative colitis (7), lymphocytic colitis (10), collagenous colitis (3), ischemic colitis (3), infectious colitis (6), and miscellaneous diseases (14). Ileoscopy yielded significant findings in 3% of patients (four with Crohn's disease and one with infection). CONCLUSIONS: Colonoscopy and biopsy is useful in the investigation of patients with chronic diarrhea yielding a histological diagnosis in 31% of patients without a previous diagnosis. Ileoscopy complemented colonoscopy findings in a minority of patients with chronic diarrhea and was essential for a diagnosis in only two patients.

Gastrointestinal neuroendocrine/neuroectodermal tumors.

This article reviews the cause and clinical and pathologic features of gastrointestinal carcinoid tumors and small cell carcinomas. Their pathogenesis and molecular features are reviewed. Tumor arrays within a given site, as in the stomach, are compared with one another to highlight their histologic features and differing biologies. General treatment guidelines are also provided.

The Vienna classification of gastrointestinal epithelial neoplasia.

BACKGROUND: Use of the conventional Western and Japanese classification systems of gastrointestinal epithelial neoplasia results in large differences among pathologists in the diagnosis of oesophageal, gastric, and colorectal neoplastic lesions. AIM: To develop common worldwide terminology for gastrointestinal epithelial neoplasia. METHODS: Thirty one pathologists from 12 countries reviewed 35 gastric, 20 colorectal, and 21 oesophageal biopsy and resection specimens. The extent of diagnostic agreement between those with Western and Japanese viewpoints was assessed by kappa statistics. The pathologists met in Vienna to discuss the results and to develop a new consensus terminology. RESULTS: The large differences between the conventional Western and Japanese diagnoses were confirmed (percentage of specimens for which there was agreement and kappa values: 37% and 0.16 for gastric; 45% and 0.27 for colorectal; and 14% and 0.01 for oesophageal lesions). There was much better agreement among pathologists (71% and 0.55 for gastric; 65% and 0.47 for colorectal; and 62% and 0.31 for oesophageal lesions) when the original assessments of the specimens were regrouped into the categories of the proposed Vienna classification of gastrointestinal epithelial neoplasia: (1) negative for neoplasia/dysplasia, (2) indefinite for neoplasia/dysplasia, (3) non-invasive low grade neoplasia (low grade adenoma/dysplasia), (4) non-invasive high grade neoplasia (high grade adenoma/dysplasia, non-invasive carcinoma and suspicion of invasive carcinoma), and (5) invasive neoplasia (intramucosal carcinoma, submucosal carcinoma or beyond). CONCLUSION: The differences between Western and Japanese pathologists in the diagnostic classification of gastrointestinal epithelial neoplastic lesions can be resolved largely by adopting the proposed terminology, which is based on cytological and architectural severity and invasion status.

Histochemical and immunohistochemical characterization of foamy histiocytes (muciphages and xanthelasma) of the rectum.

Despite being relatively common in the rectum, foamy histiocytes have received scant attention as to the antecedent lesion that causes them to form or their histologic characterization on the types of muco-substances they accumulate. One-hundred consecutive tissue sections of the rectum from an equal number of patients were reviewed for the presence of foamy histiocytes, evaluated for their associated histologic features, and examined histochemically for five types of mucin. Immunohistochemical and electron microscopic studies were performed. Forty (40%) of the rectal biopsy tissues contained foamy histiocytes. Patients presented with diarrhea, hematochezia, intestinal habit change, constipation, hemorrhoids, and abdominal pain. Endoscopically, 19 patients were thought to have rectal nodules or polyps. Histologically, 25 of the patients had regenerative changes in the adjacent mucosa and 14 had hyperplastic changes. In 36 patients (90%), the foamy histiocytes were located superficially in the lamina propria. Associated changes indicated that they are found in areas that are subject to an injury that is in a healing phase. These changes included mild fibrosis and chronic inflammation of lamina propria with mild architectural distortion. Thirty-five (88%) cases showed staining for D-PAS, Alcian blue stain pH 2.5, and the cocktail Alcian blue stain/PAS. Mucicarmine was positive in 25 (63%) cases. The Alcian blue stain pH 1.0 was positive in 19 (59%) of 32 cases. Ultrastructural studies showed electron-dense globules. Two cases were histologically identical to the other 38 but they did not stain for any mucin. Ultrastructural features disclosed clear vacuoles and thus represent a xanthelasma of the rectum. The foamy cells in all cases were confirmed to be histiocytes by immunohistochemistry and electron microscopy. Although muciphages and xanthelasma of the rectum may mimic polyps endoscopically, they are not related to any specific symptom or clinical finding, despite the fact that they probably represent remnants of a previous injury. Muciphages contain neutral, weakly acidic or strongly acidic mucin. The main type of acidic mucin is sialomucin with a smaller component of sulfated mucin.

Alterations in exon 4 of the p53 gene in gastric carcinoma.

BACKGROUND & AIMS: Our long-term goal was to evaluate the role of p53 in the prognosis of gastric cancer. We previously showed a discrepancy between p53 expression and the presence of mutations when only exons 5-9 were examined. We then evaluated exon 4. METHODS: DNA was sequenced from 217 gastric cancers to detect exon 4 alterations. Codon 72 was examined by restriction enzyme digestion. RESULTS: Mutations were present in 3.2% of tumors. In addition, 2 polymorphic sites were found at codons 36 and 72. Polymorphisms at codon 36 were only found in 2 patients. In contrast, the codon 72 polymorphism was very frequent. The genotype frequency was arg/arg (54%), arg/pro (33%), and pro/pro (14%). The genotype of the polymorphic site varied with race (P = 0.001): 64% of whites had the arg/arg genotype, compared with 24% of blacks. The difference in genotype by site, sex, or histological tumor type was not statistically significant (P = 0.067). CONCLUSIONS: There are several exon 4 alterations in gastric cancers. These include the rare mutations and the very rare codon 36 polymorphism. The most common change is the codon 72 polymorphism, the genotype of which differs significantly with race. The more common arg/arg genotype in whites may explain why whites are more prone to develop cardiac cancer, whereas the more common proline allele in blacks may explain why they are more prone to develop antral cancers. Further studies are required to determine whether the codon 72 polymorphism affects patient predisposition to gastric cancer.

Microsatellite instability and K-ras mutations in patients with ulcerative colitis.

Patients with inflammatory bowel disease (IBD), particularly ulcerative colitis (UC), have an increased incidence of colorectal carcinoma. The underlying mechanism is unknown, but we postulated that microsatellite instability (MSI) might predispose the colonic mucosa of UC patients to mutations, thereby increasing their cancer risk. We also sought to determine the frequency of K-ras mutations, to determine whether MSI predisposed to K-ras mutations and to compare the molecular phenotype of biopsy and resection specimens in the same patient. We also sought to determine whether molecular alterations found in biopsy specimens presaged their presence in subsequent resection specimens. Two hundred fifty-eight specimens from 52 patients were examined for K-ras mutations by direct sequencing. Seventy-one of the specimens were neoplastic. MSI was evaluated after polymerase chain reaction (PCR) amplification using primers directed at 8 microsatellite loci. Of the patients, 18.2% had K-ras mutations, and 30.8% had MSI in at least 1 locus. Of K-ras mutations, 81.8% were G to A substitutions involving the second nucleotide of codons 12 or 13. Only 0.7% of the samples showed a high level of MSI. No relationship existed between MSI and K-ras mutations, even in the 2 samples with high-level MSI. The numbers are small, but it appeared that MSI in biopsies failed to predict its presence in resection specimens. In contrast, K-ras mutations present in biopsy specimens tended to predict their presence in resections. K-ras mutations were found predominantly in neoplastic mucosae, whereas MSI was found predominantly in regenerative mucosae. The lack of any relationship between MSI and K-ras mutations suggests that MSI in the UC replicative mucosa does not predispose to colonic neoplasia via a K-ras-mediated pathway. This is probably related to the fact that the MSI is generally low-level MSI.

American Joint Committee on Cancer Prognostic Factors Consensus Conference: Colorectal Working Group.

BACKGROUND: The American Joint Committee on Cancer (AJCC), which regularly reviews TNM staging systems, established a working party to develop recommendations for colorectal carcinoma. METHODS: A multidisciplinary consensus conference using published literature developed an arbitrary classification system of prognostic marker value (Category I, IIA, IIB, III, and IV), which forms the framework for this report. RESULTS: The working party concluded that several T categories should be subdivided: pTis into intraepithelial carcinoma (pTie) and intramucosal carcinoma (pTim); pT1 into pT1a and pT1b corresponding to the absence or presence of blood or lymphatic vessel invasion, respectively; and pT4 into pT4a and pT4b according to the absence or presence of tumor involving the surface of the specimen, respectively. The working party also recommended that TNM groups be stratified based on the presence or absence of elevated serum levels of carcinoembryonic antigen (CEA) (>/= 5 ng/mL) on preoperative clinical examination. In addition, the working party also concluded that carcinoma of the appendix should be excluded from the colorectal carcinoma staging system because of fundamental differences in natural history. CONCLUSIONS: The TNM categories and stage groupings for colorectal carcinoma published in the current AJCC manual have clinical and academic value. However, a few categories require subdivision to provide increasing discrimination for individual patients. The serum marker CEA should be added to the staging system, whereas multiple other factors should be recorded as part of good clinical practice. Although many molecular and oncogenic markers show promise to supplement or modify the current staging systems eventually, to the authors' knowledge none have yet been evaluated sufficiently to recommend their inclusion in the TNM system.

Microsatellite instability is uncommon in intestinal mucosa of patients with Crohn's disease.

Patients with long-standing inflammatory bowel disease have an increased risk for colorectal carcinoma. Microsatellite instability occurs in colonic neoplasms and has been reported in colonic tissues from patients with ulcerative colitis. Patients with Crohn's disease also have an increased risk for colorectal cancer, although it is lower than that associated with ulcerative colitis. This study was designed to determine whether microsatellite instability occurs in Crohn's disease, and whether it occurs with similar frequency to that observed in ulcerative colitis. In all, 177 tissue samples from 33 patients with Crohn's disease were evaluated for microsatellite alterations. Microsatellite instability occurred in five different tissue samples from one of 33 Crohn's disease patients. Four of the five tissue samples showed microsatellite instability at more than one locus. We conclude that microsatellite instability is less common in Crohn's disease than ulcerative colitis and may reflect differences in cancer risk between these two forms of inflammatory bowel disease.

Esophageal squamous cell carcinomas arising in patients from a high-risk area of North China lack an association with Epstein-Barr virus.

The aim of this study was to determine whether EBV associates with esophageal squamous cell carcinoma (ESCC), the most common malignancy in some parts of northern China, because these tumors frequently have an intense lymphocyte infiltrate. Fifty-one paraffin-embedded samples of ESCC from a high-risk area of North China were studied. The tumors included 9 well-differentiated, 31 moderately differentiated, and 11 poorly differentiated tumors. The cancer tissues and their nonmalignant adjacent mucosa (16 dysplastic and 42 normal) were evaluated by in situ hybridization using an antisense EBV-encoded RNA-1 probe and PCR amplification for EBV BamHI W fragment. In all cases, EBV was negative by both in situ hybridization and PCR. Our study suggests that EBV does not play a role in the carcinogenesis of ESCC in the geographic region.

Carboxyl ester lipase activity in milk prevents fat-derived intestinal injury in neonatal mice.

Carboxyl ester lipase (bile salt-stimulated lipase) is a pancreatic enzyme capable of hydrolyzing esters of cholesterol and fat-soluble vitamins. It also efficiently digests triglycerides (TG) into free fatty acids and glycerol and is abundant in the milk of humans and several other species. We used the mouse as a model to test the hypothesis that milk-derived carboxyl ester lipase (CEL) digests milk TG and that without its activity milk lipids and their digestion intermediates can disrupt the intestinal epithelium of neonates. CEL protein and enzymatic activity were shown to be abundant in mouse milk. After 24-h administration of the CEL-specific inhibitor, WAY-121,751-5, the small intestines of treated and control neonates were analyzed histologically for signs of fat malabsorption and injury to their villus epithelium. In vehicle-fed controls, TG were digested and absorbed in the duodenum and jejunum, whereas, in inhibitor-fed littermates, large intracellular neutral lipid droplets accumulated in enterocytes of the ileum, resulting in damage to the villus epithelium. Similar results were observed in neonates nursed by CEL knockout females compared with heterozygous controls. The results suggest that lack of CEL activity causes incomplete digestion of milk fat and lipid accumulation by enterocytes in the ileum of neonatal mice.

The relation of p53 gene mutations to gastric cancer subsite and phenotype.

OBJECTIVES: We investigated p53 gene mutations in advanced gastric cancers by direct DNA sequencing, in order to determine the frequency of mutations in gastric cancers having different epidemiological backgrounds, tumors of the cardia were compared with those arising in the antrum or corpus. Intestinal type cancers were compared with diffuse or other histologic types. We have chosen to assess the frequency of mutations solely based on DNA sequencing. METHODS: Paraffin embedded tissues from 100 gastric cancers were evaluated. The mutational status of the p53 gene in exons 5 through 9 were determined by direct sequencing of PCR products. RESULTS: Mutations in exons 5, 6, 7 and 8 were found in 35 of 100(35%)stomach cancers. One tumor had mutations in both exons 5 and 8. No mutations were detected in exon 9. p53 gene mutations were significantly more frequent in cancers of the cardia (19/35; 54%) than the antrum and corpus (16/65 (25%)) (p < or = 0.005). p53 mutations were more frequent in intestinal type cancers (28/67; 42%) than diffuse cancers or other histologic types of cancer (7/33; 21%), but the difference was not statistically significant. CONCLUSIONS: Cancers of the cardia more frequently contain p53 mutations than do antral and corpus cancers, suggesting that cancers in the proximal and distal stomach evolve through different molecular pathways.