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H Denk

Publications and source records attributed to H Denk.

At least 37 records · Page 2Linked to original sources
PubMed1999

Gastric neuroendocrine neoplasms: tumour clonality and malignancy-associated large X-chromosomal deletions.

Type I gastric carcinoid tumours associated with corporal (body of stomach) atrophic gastritis (CAG) are benign tumours developing as the final step of a hyperplastic precursor sequence. The neoplastic nature of these tumours has been assumed but never proved. Type III gastric carcinoid tumours and neuroendocrine carcinomas are malignant neoplasms without known precursor lesions. To assess the neoplastic nature of type I carcinoids, the clonal status of 35 tumours from 23 female patients was investigated using the human androgen receptor (HUMARA) gene test, which is based on the pattern of X-chromosome inactivation. For comparison, the same test was also performed on four type III carcinoids and two neuroendocrine carcinomas. DNA extracted from paraffin sections was digested with Hha I restriction enzyme and then amplified by polymerase chain reaction (PCR) using established HUMARA primers. The PCR products were analysed in an automated DNA sequencer. In a complementary analysis of the same tumours, loss of heterozygosity (LOH) on the X chromosome was studied using three polymorphic markers (DXS989, DXS1003, DXS1192) in a PCR-microsatellite-based technique. After exclusion of non-informative cases, 14 of 16 type I carcinoids were found to be monoclonal on the basis of the pattern of X-chromosome inactivation. Monoclonality was also documented in one of three type III carcinoids and in the single neuroendocrine carcinoma, on the basis of LOH at the HUMARA locus, which per se can be regarded as evidence for clonality. Extensive LOH of the X chromosome involving at least two markers, was found in all metastasizing tumours (two type III carcinoids and two neuroendocrine carcinomas), but in none of the 27 benign carcinoids of types I and III. These results indicate that most type I carcinoids are true monoclonal neoplasms and that malignant evolution in gastric neuroendocrine tumours is associated with extensive allelic deletion of one X chromosome.

Adult↗
PubMed1999

Altered microtubule-associated tau messenger RNA isoform expression in livers of griseofulvin- and 3,5-diethoxycarbonyl-1, 4-dihydrocollidine-treated mice.

Tau proteins belong to the family of microtubule-associated proteins (MAPs), which so far have been mostly detected in neuronal cells. Different domains on the protein serve different functions. By alternative splicing, several mRNAs and tau isoforms are created from one gene, which contain these functionally important domains to various degrees, and thus differ in their microtubule-related properties. In the present article, several novel observations are reported. Tau mRNA and proteins have been identified and further characterized in mouse liver. It is shown on the basis of mRNA determinations that at least three tau isoforms differing particularly with respect to their amino-terminal domains are present in mouse liver. The major and predominant isoform (isoform 1) lacks portions encoded by exons 2 and 3, which are responsible for cross-talk of microtubules with their environment ("projection domain"). Moreover, mRNA encoding tau protein with four repeats of the microtubule binding domain predominate in embryonal as well as adult mouse liver in contrast to brain, in which a shift from the predominant three-repeat isoform to the four-repeat isoform characterizes the transition from the embryonic to the adult stage. Intoxication with griseofulvin (GF) or 3,5-diethoxycarbonyl-1, 4-dihydrocollidine (DDC) significantly affects in a reversible manner the levels of tau mRNA as well as isoform ratios in mouse liver, but not in mouse brain. Tau mRNAs are significantly increased in intoxicated mouse livers. Moreover, a shift to isoform 1 lacking exons 2 and 3 occurs. However, the increase in liver tau protein was less than expected from increased mRNA levels, which could be the result of translational or posttranslational regulation. The consequences on microtubular function are as yet unclear, but impairment can be expected because the overexpressed tau mRNA isoform lacks the domain that mediates interaction of microtubules with their environment. On the other hand, the ratio of polymerized (microtubules) to nonpolymerized tubulin remained unaffected.

Animals↗
PubMed1999

Analysis of intracytoplasmic hyaline bodies in a hepatocellular carcinoma. Demonstration of p62 as major constituent.

Intracytoplasmic hyaline bodies (IHBs) resemble inclusions in hepatocellular carcinoma cells, which so far have escaped further characterization. A relationship to Mallory bodies was suggested on the basis of light microscopy and filamentous ultrastructure. A hepatocellular carcinoma containing numerous IHBs was studied. Our studies revealed immunoreactivity of IHBs with the monoclonal antibodies SMI 31 and MPM-2, which recognize hyperphosphorylated epitopes present on paired helical filaments in Alzheimer's disease brains (SMI 31) or on diverse proteins hyperphosphorylated by mitotic kinases in the M-phase of the cell cycle (MPM-2). One- and two-dimensional gel electrophoresis of tumor extracts followed by immunoblotting with SMI 31 and MPM-2 antibodies revealed a major immunoreactive protein with an apparent molecular weight between 62 and 65 kd, which was resolved into several highly acidic (pH 4.5) protein components in two-dimensional gels. This protein was undetectable in non-neoplastic liver tissue. Sequence analysis identified the SMI 31 and MPM-2 immunoreactive material as p62, indicating that p62 is a major constituent of IHBs. p62 is an only recently discovered protein that is a phosphotyrosine-independent ligand of the SH2 domain of p56(lck), a member of the c-src family of cytoplasmic kinases. Moreover, p62 binds ubiquitin and may act as an adapter linking ubiquitinated species to other proteins. These features suggest a role of p62 in signal transduction and possibly also carcinogenesis. IHBs observed in the hepatocellular carcinoma cells presented are the first indications of a role of p62 in disease.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Long-term results of radical surgery for rectal cancer: multivariate analysis of prognostic factors influencing survival and local recurrence.

AIMS: To evaluate consistent radical surgery performed over a 13-year period for rectal cancer in terms of local tumour control and long-term survival. METHODS: Radical surgical procedure principally using total mesorectal excision (TME) for middle and lower rectal tumours, high ligation of the inferior mesenteric artery and sphincter-saving resections (SSR) whenever possible, has been performed prospectively since January 1984. RESULTS: Tumour resection was possible in 98.8% (636/644), potentially curative resections (UICC/AJCC R0 resection) in 85.7% (552/644) and sphincter preservation in 71.7% (462/644). Five- and 10-year observed survival rates, surgical mortality not excluded, for all patients were 49.2% and 37.4%. Tumour-adjusted 5- and 10-year survival rates were 60.5% and 55.3%. For curatively operated patients (UICC/AJCC R0) 5- and 10-year observed survival rates were 56.3% and 42.6% and tumour-adjusted survival rates were 68.6% and 62.7%. The 5- and 10-year local recurrence rates for R0 resected patients were 12.0% and 12.6%. Post-operative hospital mortality was 3.1%. CONCLUSIONS: Multivariate analysis using Cox's model identified increasing pT category and pN category, old age and low tumour location as detrimental factors having independent influence on survival. For local tumour failure only pT and pN category as well as adjuvant radiation therapy were identified in the Cox model as having an independent detrimental influence.

Adult↗
PubMed1999

Atypical ductular proliferation and its inhibition by transforming growth factor beta1 in the 3,5-diethoxycarbonyl-1,4-dihydrocollidine mouse model for chronic alcoholic liver disease.

Many acute and chronic liver diseases are often associated with atypical ductular proliferation (ADP). These ADPs have gained increasing interest since a number of recent observations suggest that ADPs may represent progenies of the putative liver stem cell compartment. In this study, we show that feeding mice with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) results in persistent proliferation of primitive ductules with poorly defined lumens. Similar to oval cell proliferation in other rodent models as well as in various human liver diseases, DDC-induced ADP originated from the portal tract, spread into the hepatic lobule, and was associated closely with appearance of hepatocytes harboring an antigen (A6), which normally is expressed in biliary epithelium. Furthermore, DDC treatment severely inhibited the regenerative capacity of mice after partial hepatectomy. The development of ADP was selectively blocked in DDC-fed TGF-beta1 transgenic mice producing active TGF-beta1 in the liver and no accumulation of new hepatocytes expressing the A6 antigen was observed. Moreover, the transforming growth factor beta1 (TGF-beta1) transgenic mice did not survive beyond 3 weeks from starting the DDC-containing diet. The results suggest that persistent activation of the hepatic stem cell compartment is essential for liver regeneration in the DDC model and that active TGF-beta1 may negatively control activation of stem cells in the liver. These data further emphasize the relevance of the DDC model as an experimental tool for studying chronic liver diseases.

Animals↗
PubMed1999

[Stomach carcinoma. Optimizing therapy by extended lymph node dissection].

BACKGROUND: The prognosis for surgically treated gastric cancer patients remains poor in most Western countries compared with reports of Japanese investigators over the last three decades. The aim of the study was to prove whether D2, D3 lymphadenectomy is able to improve long-term survival in a Western gastric cancer patients collective as well. METHODS: A radical surgical procedure using D2, D3 lymphadenectomy on principle as defined by the Japanese Research Society for Gastric Cancer was done prospectively since January 1984. Out of 626 patients with gastric cancer, 433 were surgically treated for potential cure between January 1st, 1984 and December 31st, 1996. Postoperative complications and long-term survival were evaluated. RESULTS: For curatively operated patients five- and ten-year tumor specific survival rates were 57.7% and 44.3%, the median survival time was 96 months. Postoperative hospital mortality was 4.8% for R0 resected patients and 10.4% for palliative procedures. CONCLUSION: Radical D2, D3 lymphadenectomy yielded survival rates similar to those in Japanese investigations without negative effect on low postoperative mortality. These results reaffirm the value of radical lymph node dissection with wide resection margins.

Adult↗
PubMed1999

Combined restorative proctocolectomy and pancreaticoduodenectomy for familial adenomatous polyposis.

This is a case report on FAP in a 41-year-old woman in which preoperative examination showed a giant tubulovillous adenoma of the descending duodenum surrounding the papilla of Vater, in addition to pancolon adenomatous polyposis, and isolated adenomas in the gastric antrum and corpus. As it was impossible to remove the giant villous adenoma in the duodenum endoscopically, prophylactic surgical treatment was chosen consisting of restorative proctocolectomy and additional pancreaticoduodenectomy. Flat tubulovillous adenomas in the gastric corpus were successfully removed by total snare biopsies before operation. FAP coli patients treated by prophylactic surgery are now known to be at risk of developing adenomas anywhere in the intestine and many affected patients later die from upper gastrointestinal tumors. In this single case report, the simultaneous occurrence of FAP coli and giant villous adenoma of the duodenum indicates the frequent outcome of this genetic alteration requiring lifelong surveillance. This rare case report includes a short survey of the relevant literature.

Adenomatous Polyposis Coli↗
PubMed1999

Identification of p62, a phosphotyrosine independent ligand of p56lck kinase, as a major component of intracytoplasmic hyaline bodies in hepatocellular carcinoma.

Intracytoplasmic hyaline bodies (IHBs) resemble a peculiar type of cytoplasmic inclusions in cells of hepatocellular carcinoma (HCC) which so far have escaped further characterization. In order to determine protein composition of IHBs we investigated tissue of a HCC containing numerous IHBs by immunohistochemistry and Western blot analysis using a large panel of different antibodies. Our studies revealed immunoreactivity of IHBs with the monoclonal antibodies SMI 31 and MPM-2 which recognize hyperphosphorylated epitopes present on paired helical filaments in Alzheimer's disease brains (SMI 31) and on proteins hyperphosphorylated by mitotic kinases (MPM-2), respectively. In two-dimensional Western blots of HCC extracts SMI 31 and MPM-2 antibodies detected a 62 to 65 kD protein with an isoelectric point around 4.5. Microsequencing identified this protein as p62, a recently identified phosphotyrosine-independent ligand of the SH2 domain of tyrosine kinase p56lck. Immunoreactivity of p62 protein spots with antibodies to phosphorylated epitopes (i.e. SMI 31 and MPM-2) suggest that p62 is highly phosphorylated in IHBs. This is the first report on accumulation of p62 as cellular inclusions and its association with human disease.

Adaptor Proteins, Signal Transducing↗
PubMed1997

[Intestinal schistosomiasis, a facultative precancerous condition? Review of the literature with reference to Schistosoma japonicum associated rectum carcinoma].

After a latency period of 20 years, in a 39-year-old Austrian citizen of Chinese origin, a surgically removed rectal carcinoma, as well as the neighboring chronic inflammatory rectal mucosa with various degrees of dysplasia and one positive neighboring lymph node, showed helminthiasis in the histopathological examination, convincing us of a link between carcinoma and chronic helminthiasis. Whereas the etiological context between chronic infection by Schistosoma haematobium and endemic frequent urinary bladder carcinoma is considered a matter of fact, whether of not the incidence of intestinal carcinoma is increased in connection with chronic intestinal schistosomiasis is controversial. The etiological and pathogenetic link between helminthiasis and carcinoma should be considered in the same way as for other related inflammatory large-bowel diseases. In the sequence chronic inflammation-severe dysplasia, the formation of carcinoma could possibly occur. Besides a survey of trematodes parasitology and pathology, the link between rectal carcinoma and Schistosomiasis japonicum is pointed out by means of appropriate literature investigations.

Adult↗
PubMed1997

A first report of familial visceral myopathy with additional chylous ascites in two siblings.

BACKGROUND: Familial visceral myopathy in two siblings, involving the intestine with concurrent chylous ascites and chylous pleural effusion, is reported. In this connection a review of the recent gastroenterologic literature was performed. PATIENTS: In two siblings, admitted between 1992 and 1995 with increasing ascites, loss of weight, and attacks of subileus, the diagnosis of familial visceral myopathy was established. CASE ONE: During the initial preoperative examination hepatogenous ascites was diagnosed. Visceral myopathy and chylous ascites were subsequently established by means of an explorative laparotomy in conjunction with histologic examination of specimens taken from the small-bowel wall. CASE TWO: The patient's brother was admitted 3 years later with similar symptoms. Complaints of chylous ascites and chylous pleural effusion in connection with attacks of subileus are still present. OUTCOME: The female sibling was discharged from hospital with unchanged complaints and died only a few months later; the male sibling is still alive, but with unchanged complaints. CONCLUSIONS: Rare cases of familial and sporadic myopathy have been reported in the recent literature, but to our knowledge these are the first cases with concurrent chylous ascites and chylous pleural effusion in this uncommon disorder.

Aged↗
PubMed1997

Long-term survival analysis of gastric cancer limited to the subserosa.

Long-term survival following surgery for gastric cancer limited to the subserosa was analyzed. Between 01.01.1984 and 30.06.1995. 265 patients were operated for gastric cancer that did not invade beyond the subserosa. Extended lymphadenectomy was performed in all cases and was constant as all patients were operated by only two surgeons. The survival outcome was analyzed with particular regard to the exact depth of tumor infiltration and lymph node involvement. The percentage of patients with positive lymph nodes increased drastically from 1.7% for mucosal invasion to 22.7% for submucosal tumor involvement. A further substantial increase was observed from 34.3% for involvement of the muscularis propria to 66.1% for subserosal involvement. The 10-year tumor specific survival rate for tumors limited to the mucosa was 100%, for submucosa and muscularis propria invasion 79.3% and 72.9% respectively, for subserosal involvement 10-year survival was 54.6%. In multivariate analysis of pathohistological variables only pT- and pN-categories according to the UICC were found to have independent prognostic influence on survival. Long-term survival indicates that gastric cancer limited to the mucosa may well be treated with a less radical approach. Gastric cancer of the submucosa and muscularis propria both have a similar good long-term prognosis with radical surgery alone whereas cancer of the subserosa probably requires some form of adjuvant therapy.

Aged↗
PubMed1996

Experimental Mallory body formation is accompanied by modulation of the expression of multidrug-resistance genes and their products.

Mallory bodies (MBs) are characteristic morphological features of alcoholic hepatitis and are also found in other chronic liver disorders and hepatocellular neoplasms. MBs can be produced in mouse liver by chronic administration of the porphyrinogenic drugs griseofulvin (GF) and 3,5-diethoxy-carbonyl-1,4-dihydrocollidine (DDC). The mechanisms causing the formation of MBs are poorly understood, and the significance of MB formation during the course of liver disease remains unclear. We investigated the relationship between the mechanisms underlying the formation of MBs and the regulation of multidrug resistance (mdr) genes and their products, the P-glycoproteins (Pgp). Immunofluorescence microscopy using the monoclonal antibody C219 revealed an increase of Pgp expression in almost all hepatocytes after 3 to 8 days of feeding mice DDC- and GF-containing diets. However, after approximately 4 weeks of DDC and approximately 8 weeks of GF feeding, when the first small MBs appeared and loosening and diminution of keratin intermediate filament (KIF) cytoskeleton occurred in some hepatocytes, a decrease or loss of Pgp staining in affected hepatocytes was observed. After feeding mice DDC for 6 weeks and GF for 12 weeks, many hepatocytes contained MBs and displayed a disruption of the immunohistochemically demonstrable KIF meshwork. Double immunofluorescence microscopy with the keratin polyclonal antibody and the mab C219 at this time point revealed a complete loss of Pgp staining in affected cells, although remaining hepatocytes with unaltered KIF meshwork showed a strong reaction with the C219 antibody. Northern blot analyses revealed a significant increase of mdr2 mRNA and, to a lesser extent, of mdr1a mRNA in the livers of DDC- and GF-fed animals.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Triple therapy with sucralfate, amoxycillin and metronidazole for healing duodenal ulcer and eradicating Helicobacter pylori infection.

METHODS: Seventy-seven chronic duodenal ulcer patients (50 male) were entered into this study. Treatment was started with sucralfate suspension (2 g b.d.) for 8 weeks. After 2 weeks the patients also received 750 mg amoxycillin t.d.s. plus 500 mg metronidazole t.d.s. for 12 days. Endoscopy with six antral biopsies (urease test, Gram staining, culture and histology) was performed before commencement of sucralfate therapy, 4 weeks after the end of antibiotic therapy, and during the follow-up examinations at 6 and 12 months. RESULTS: Seven patients were excluded prematurely from the study. Helicobacter pylori in five patients had primary resistance to metronidazole and these patients were also excluded. The ulcer healing rate 4 weeks after the end of antibiotic therapy was 92% and the H. pylori eradication rate was 82% (all per protocol). In all patients who were still H. pylori-positive, the bacterium became resistant to metronidazole and histologically the inflammatory state of the mucosa was the same as before treatment. All H. pylori-eradicated patients (n = 53) were re-examined after 6 and 12 months; no ulcer recurrence was observed and each time only one reinfection was found. CONCLUSIONS: In an open study, sucralfate with amoxycillin and metronidazole appeared to act together to eradicate H. pylori infection and to speed duodenal ulcer healing.

Adult↗
PubMed1995

A 10-year experience with Japanese-type radical lymph node dissection for gastric cancer outside of Japan.

BACKGROUND: The prognosis for surgically treated gastric cancer remains poor in most Western countries compared with reports from Japanese investigators during the past 3 decades. METHODS: A radical surgical procedure principally to extended lymphadenectomy as defined by the Japanese Research Society for Gastric Cancer was performed prospectively from January 1984 to June 30, 1994 for 512 patients with gastric cancer, 345 of whom were treated with potentially curative surgery. Clinical, histopathologic, and surgical factors were examined for their influence on long term survival by univariate and multivariate analyses. RESULTS: Five- and 10-year survival rates for all patients were 40.5% and 34.3%, respectively, and for patients who underwent tumor resection were 45.7% and 38.6%, respectively. For patients who underwent curative surgery, 5- and 10-year adjusted survival rates were 57.7% and 44.3%, respectively, with a median survival of 96 months. Postoperative hospital mortality was 6.8%:4.9% for R-0 resected patients, 9% for R-1 and R-2 resected patients, and 13.4% for those with palliative procedures. Multivariate analysis using the Cox model identified age older than 65 years, prior total gastrectomy, an increasing number of positive lymph nodes, a high pathologic N classification, male sex, a high pT classification, and low preoperative hemoglobin level as detrimental factors with an independent influence on survival. CONCLUSION: Radical lymphadenectomy in this 10-year Austrian study yielded survival rates similar to those in Japanese investigations without sacrificing low postoperative mortality. In particular, the relatively high overall survival rates seemed to reaffirm the value of radical lymph node dissection with wide resection margins.

Aged↗
PubMed1995

[Chronic hepatitis].

Chronic hepatitis is defined as primary necroinflammatory liver disease with a duration of at least 6 months. It is etiologically heterogeneous and may be caused by hepatitis viruses (B, C, D, others?), autoimmune processes, drug reactions and metabolic disorders. A certain percentage of chronic hepatitides is etiologically still uncertain (cryptogenic). Nomenclature and classification of chronic hepatitis proposed in 1968 on the basis of morphologic appearance is still widely used. However, in view of the recent advances in our knowledge of etiology, pathogenesis, course of the disease, and, particularly, progress in therapy a classification based on morphology alone is unsatisfactory. A modern classification of chronic hepatitis should be easy to apply and reproducible, and based on etiology, grading of necro-inflammation and staging of the disease. Grading should consider portal, periportal and lobular inflammation and type and extent of liver cell alterations and necrosis. Fibrosis and cirrhosis are histological features of staging. Alterations may be semi-quantified particularly to facilitate comparison of results in clinical trials.

Autoimmune Diseases↗
PubMed1995

Alcoholic liver disease: molecular-pathologic aspects.

Mallory bodies (MBs) are characteristic morphologic features of alcoholic hepatitis but are also associated with non-alcoholic liver diseases including long lasting cholestasis, metabolic and neoplastic disorders. MBs contain in addition to keratins non-keratin components, including microtubule-associated (tau protein) and other not yet characterized proteins in an aggregated form. Aggregation of these components in the cell is promoted by posttranslational modifications, such as partial proteolysis, phosphorylation and cross-linking, and may result in functional and structural disturbances of the cell depending on the physiologic function of the components involved. Several enzymes responsible for these modifications are Ca(++)-dependent. Thus, disturbance of Ca(++)-homeostasis may play an essential role in the pathogenesis of MBs. In some structural aspects MBs closely resemble inclusions associated with degenerative disorders of the central nervous system, including Alzheimer's and Parkinson's disease. Studies on the pathogenesis of MBs, therefore, not only shed light on a peculiar type of liver cell injury but may also assist in the understanding of other chronic degenerative diseases, particularly those of the central nervous system.

Alzheimer Disease↗