Biomedical subjects

Hans-Detlev Saeger

Publications and source records attributed to Hans-Detlev Saeger.

15 recordsLinked to original sources

PubMed2006

N-Acetyltransferase (NAT) 2 acetylator status and age of tumour onset in patients with sporadic and familial, microsatellite stable (MSS) colorectal cancer.

INTRODUCTION: N-Acetyltransferase (NAT) 2 is an important enzyme involved in the metabolism of different xenobiotics, including potential carcinogens. Allelic variants of the NAT2 gene are determined by a pattern of single nucleotide polymorphisms (SNPs) resulting in slow (SA), intermediate (IA) or rapid acetylator (RA) phenotypes and causing the individual differences in the NAT2 metabolic capacity. To clarify the potential modifying role of the NAT2 acetylator status in microsatellite stable (MSS) colorectal cancer (CRC), we studied 140 patients with sporadic CRC (group 1) and 69 patients with CRC who met at least one criterion of the revised Bethesda guidelines (group 2). OBSERVATIONS: We did not observe any significant difference in the NAT2 acetylator status frequency between patients in both groups and 100 healthy controls (P=0.486). Regardless of a younger median age of tumour onset (AO) of 41 years in group 2 patients compared to 64 years in group 1 patients, no significant difference in AO was found between RA and SA status patients in both groups. The median AO in group 1 was 65 years in patients with RA and 63 years with SA status (P=0.065). The median AO in group 2 was 40 years in patients with RA and 42 years with SA status (P=0.814). Multivariate Cox regression analysis revealed that neither the NAT2 acetylator status (P=0.064 and 0.810, respectively) nor the gender (P=0.165 and 0.918, respectively) was a risk factor for the AO in both groups. These data do not support the hypothesis that the NAT2 acetylatorship acts as a modifying factor on the AO in sporadic and familial, microsatellite stable CRC.

Acetylation↗

PubMed2006

Genomic rearrangements in MSH2, MLH1 or MSH6 are rare in HNPCC patients carrying point mutations.

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant disease with high penetrance, caused by germline mutations in the mismatch repair (MMR) genes MLH1, MSH2, MSH6, PMS2 and MLH3. Most reported pathogenic mutations are point mutations, comprising single base substitutions, small insertions and deletions. In addition, genomic rearrangements, such as large deletions and duplications not detectable by PCR and Sanger sequencing, have been identified in a significant proportion of HNPCC families, which do not carry a pathogenic MMR gene point mutation. To clarify whether genomic rearrangements in MLH1, MSH2 or MSH6 also occur in patients carrying a point mutation, we subjected normal tissue DNA of 137 colorectal cancer (CRC) patients to multiplex ligation-dependent probe amplification (MLPA) analysis. Patients fulfilled the following pre-requisites: all patients met at least one criterion of the Bethesda guidelines and their tumors exhibited high microsatellite instability (MSI-H) and/or showed loss of expression of MLH1, MSH2 or MSH6 proteins. PCR amplification and Sanger sequencing of all exons of at least one MMR gene, whose protein expression had been lost in the tumor tissue, identified 52 index patients without a point mutation (Group 1), 71 index patients with a pathogenic point mutation in MLH1 (n=38) or MSH2 (n=22) or MSH6 (n=11) (Group 2) and 14 patients with an unclassified variant in MLH1 (n=9) or MSH2 (n=3) or MSH6 (n=2) (Group 3). In 13 of 52 patients of group 1 deletions of at least one exon were identified. In addition, in group 3 one EX1_15del in MLH1 was found. No genomic rearrangement was identified in group 2 patients. Genomic rearrangements represent a significant proportion of pathogenic mutations of MMR genes in HNPCC patients. However, genomic rearrangements are rare in patients carrying point mutations in MMR genes. These findings suggest the use of genomic rearrangement tests in addition to Sanger sequencing in HNPCC patients.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Synergy of glucose and growth hormone signalling in islet cells through ICA512 and STAT5.

Nutrients and growth hormones promote insulin production and the proliferation of pancreatic beta-cells. An imbalance between ever-increasing metabolic demands and insulin output causes diabetes. Recent evidence indicates that beta-cells enhance insulin gene expression depending on their secretory activity. This signalling pathway involves a catalytically inactive receptor tyrosine phosphatase, ICA512, whose cytoplasmic tail is cleaved on glucose-stimulated exocytosis of insulin secretory granules and then moves into the nucleus, where it upregulates insulin transcription. Here, we show that the cleaved cytosolic fragment of ICA512 enhances the transcription of secretory granule genes (including its own gene) by binding to tyrosine phosphorylated signal transducers and activators of transcription (STAT) 5 and preventing its dephosphorylation. Sumoylation of ICA512 by the E3 SUMO ligase PIASy, in turn, may reverse this process by decreasing the binding of ICA512 to STAT5. These findings illustrate how the exocytosis of secretory granules, through a retrograde pathway that sustains STAT activity, converges with growth hormone signalling to induce adaptive changes in beta-cells in response to metabolic demands.

Animals↗

PubMed2006

Michael Trede.

Explore the source record for details and available documents.

General Surgery↗

PubMed2006

Occult endometrial cancer and decision making for prophylactic hysterectomy in hereditary nonpolyposis colorectal cancer patients.

BACKGROUND AND OBJECTIVE: Hereditary nonpolyposis colorectal cancer (HNPCC) is the most frequent form of hereditary colorectal cancer. In addition to the high lifetime risk for colorectal cancer in mutation carriers, there is also a remarkably increased risk for endometrial cancer (EC). METHODS: In this retrospective study, clinical and molecular approach to the individual decision making as to whether or not to perform a prophylactic hysterectomy in a subset of HNPCC patients is discussed. 147 female patients meeting at least one criterion of the Bethesda guidelines were included in this analysis between 1995 and 2003. After clinical and genetic counseling, patients gave informed written consent and microsatellite analysis, immunohistochemistry and sequencing of the mismatch repair genes MLH1, MSH2 and MSH6 was performed. RESULTS: 11 of the analyzed patients had a personal history of EC and had undergone previous hysterectomy at ages 26 to 62 years. Prophylactic hysterectomy with oophorectomy was considered in postmenopausal women meeting the Amsterdam criteria and/or carrying a disease causing mismatch repair gene mutation who were operated on because of diagnosed colorectal cancer in our center for hereditary cancer. This procedure was performed in 4 patients. None of them had shown any symptoms of a gynecologic malignancy. Preoperative gynecological examination showed no evidence for EC or ovarian cancer in these patients. Postoperative histological examination showed EC stage T1b N0 M0 in 2 patients. CONCLUSIONS: Since the efficiency of gynecological surveillance is uncertain, prophylactic hysterectomy could be an option for a subset of HNPCC patients and mutation carriers.

Adult↗

PubMed2006

cAMP-dependent phosphorylation of PTB1 promotes the expression of insulin secretory granule proteins in beta cells.

Glucose stimulates the exocytosis of insulin secretory granules of pancreatic beta cells. Granule stores are quickly refilled by activation of posttranscriptional mechanisms that enhance the biosynthesis of granule components. Rapid replacement of granules is important to sustain insulin secretion, since new granules appear to be preferentially released. Posttranscriptional regulation of granule biogenesis includes the glucose-induced nucleocytoplasmic translocation of polypyrimidine tract binding protein 1 (PTB1), which binds mRNAs encoding granule proteins, and thus promotes their stabilization and translation. Glucagon-like peptide 1 (GLP-1) potentiates glucose-stimulated insulin gene expression and secretion by increasing cAMP levels in beta cells. Here, we show that elevation of cAMP levels causes the protein kinase A-dependent phosphorylation and nucleocytoplasmic translocation of PTB1, thereby preventing the rapid degradation of insulin mRNA and enhancing the expression of various granule proteins. Taken together, these findings identify PTB1 as a common downstream target of glucose and GLP-1 for the posttranscriptional upregulation of granule biogenesis.

Animals↗

PubMed2005

N-acetyltransferase (NAT) 2 acetylator status and age of onset in patients with hereditary nonpolyposis colorectal cancer (HNPCC).

N-acetyltransferase (NAT) 2 is an essential polymorphic enzyme involved in the metabolism of various xenobiotics, including potential carcinogens. The individual differences in the NAT2 metabolic capacity are caused by allelic variants of the NAT2 gene which are determined by a pattern of single nucleotide polymorphisms (SNPs) resulting in slow (SA), intermediate (IA) or rapid acetylator (RA) phenotypes. Highly penetrant germline mutations in mismatch repair (MMR) genes are the cause of the disease in hereditary nonpolyposis colorectal cancer (HNPCC). There is no strict correlation between the type of germline mutation in MMR genes and the HNPCC phenotype, but age of tumor onset (AO) in HNPCC has been associated at least in part with different variants in apoptosis-related genes. To clarify the potential modifying role of the NAT2 acetylator status in HNPCC, we performed a multicenter study in 226 individuals with colorectal cancer carrying exclusively pathogenic germline mutations in MSH2 or MLH1. We did not observe any significant difference in the NAT2 acetylator status frequency between HNPCC patients and 107 healthy controls (P=0.156), and between MLH1 and MSH2 mutation carriers (P=0.198). Multivariate Cox regression analysis revealed that male patients had a significantly increased risk to develop CRC compared to females during any interval (P=0.043), while the NAT2 acetylator status (P=0.447) and the mutated gene (MLH1 or MSH2) (P=0.236) were not risk factors for AO. The median AO in HNPCC patients was 39 years in patients with RA as well as with SA status (P=0.347). In MLH1 mutation carriers, the median AO was 38 years in RA and 36 years in SA status patients (P=0.901), whereas in MSH2 mutation carriers, the median AO was 39 years in RA and 42 years in SA status patients (P=0.163). Log-rank test revealed a significantly lower age of CRC onset in male compared to female HNPCC patients (P=0.0442). These data do not support the hypothesis that the NAT2 acetylatorship acts as a modifying factor on AO in HNPCC-associated CRC.

Acetylation↗

PubMed2005

Gene expression analysis of pancreatic cell lines reveals genes overexpressed in pancreatic cancer.

BACKGROUND: Pancreatic cancer is one of the leading causes of cancer-related death. Using DNA gene expression analysis based on a custom made Affymetrix cancer array, we investigated the expression pattern of both primary and established pancreatic carcinoma cell lines. METHODS: We analyzed the gene expression of 5 established pancreatic cancer cell lines (AsPC-1, BxPC-3, Capan-1, Capan-2 and HPAF II) and 5 primary isolates, 1 of them derived from benign pancreatic duct cells. RESULTS: Out of 1,540 genes which were expressed in at least 3 experiments, we found 122 genes upregulated and 18 downregulated in tumor cell lines compared to benign cells with a fold change >3. Several of the upregulated genes (like Prefoldin 5, ADAM9 and E-cadherin) have been associated with pancreatic cancer before. The other differentially regulated genes, however, play a so far unknown role in the course of human pancreatic carcinoma. By means of immunohistochemistry we could show that thymosin beta-10 (TMSB10), upregulated in tumor cell lines, is expressed in human pancreatic carcinoma, but not in non-neoplastic pancreatic tissue, suggesting a role for TMSB10 in the carcinogenesis of pancreatic carcinoma. CONCLUSION: Using gene expression profiling of pancreatic cell lines we were able to identify genes differentially expressed in pancreatic adenocarcinoma, which might contribute to pancreatic cancer development.

Adult↗

PubMed2005

Current practice patterns in pancreatic surgery: results of a multi-institutional analysis of seven large surgical departments in Germany with 1454 pancreatic head resections, 1999 to 2004 (German Advanced Surgical Treatment study group).

Despite decreasing mortality rates, morbidity is still high after pancreatic head resection. Comparative data in the United States and Europe show a relationship between hospital volume and mortality. Treatment strategies vary frequently, partially because of the lack of evidence-based data. We performed a multi-institutional analysis in Germany evaluating current numbers, indications, techniques, and complication rates of pancreatic head resection. Questionnaires were completed by seven high-volume surgical departments regarding quantitative and qualitative aspects of pancreatic head resections in the period from 1999 to 2004 (five prospective and two retrospective institutional databases). A total of 1454 pancreatic head resections (944 for malignancy) were reported. Mean annual hospital volume ranged from 14 to 52 (10 to 43 in malignancy). Mortality was between 1.1% and 4.8%, morbidity was between 24% and 46%, and pancreatic leakage was between 9% and 20%. In malignant disease, all centers perform standard lymphadenectomy and regard arterial infiltration as a contraindication for resection. However, the rate of portal vein resection varied from 0% to 28%. No consensus is seen on the type of surgery for malignancy and chronic pancreatitis. After resection for pancreatic cancer less than one fourth of the patients receive adjuvant therapy. The results of our analysis in Germany confirm that pancreatic head resection can be performed with low mortality in specialized units. Variations in indications, operative technique, and perioperative care may demonstrate the lack of evidence-based data and/or personal and institutional experience. The low number of patients receiving adjuvant therapy after resection of pancreatic cancer suggests that more efforts must be made to establish novel adjuvant therapies under randomized study conditions.

Digestive System Surgical Procedures↗

PubMed2004

Polypyrimidine tract-binding protein promotes insulin secretory granule biogenesis.

Pancreatic beta-cells store insulin in secretory granules that undergo exocytosis upon glucose stimulation. Sustained stimulation depletes beta-cells of their granule pool, which must be quickly restored. However, the factors promoting rapid granule biogenesis are unknown. Here we show that beta-cell stimulation induces the nucleocytoplasmic translocation of polypyrimidine tract-binding protein (PTB). Activated cytosolic PTB binds and stabilizes mRNAs encoding proteins of secretory granules, thus increasing their translation, whereas knockdown of PTB expression by RNA interference (RNAi) results in the depletion of secretory granules. These findings may provide insight for the understanding and treatment of diabetes, in which insulin secretion is typically impaired.

Animals↗

PubMed2004

Gastrointestinal stromal tumor presenting as a scrotal mass.

We describe a huge abdominal gastrointestinal stromal tumor (GIST) extending through the right inguinal canal. The reported case illustrates that the scrotum might be a place of initial presentation of a GIST growing along preformed anatomical structures. Urologists should be aware of this condition that might be mistaken for a primarily testicular malignancy.

Diagnosis, Differential↗

PubMed2003

Preventive surgery for colon cancer in familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer syndrome.

BACKGROUND: A better understanding of the molecular basis of hereditary colorectal cancer syndromes such as hereditary nonpolyposis colorectal cancer syndrome (HNPCC) and familial adenomatous polyposis (FAP) has profound consequences for both the diagnosis and (prophylactic) treatment of (pre)malignant neoplastic lesions. DISCUSSION: Sequence analysis of the underlying genes for these conditions and the detection of disease-causing genetic alterations in an index patient enable predictive testing for individuals at risk within an affected family. However, the clinical implications of predictive molecular testing depend on the overall penetrance and variability in the expression of pathogenic mutations. The extent of these parameters differs considerably among the various known hereditary colorectal cancer syndromes. Hence the integration of genetic information into the daily surgical practice remains challenging. CONCLUSIONS: This review provides an update on the indications for family assessment, purpose and limitations of the genetic testing and resulting recommendations for prophylactic surgery in FAP and HNPCC.

Adenomatous Polyposis Coli↗

PubMed2003

Systematic isolation of genes differentially expressed in normal and cancerous tissue of the pancreas.

BACKGROUND: There is increasing knowledge about the genetic basis of pancreatic cancer (PaCa). Tumor suppressor genes (TSGs; e.g. p53 and DPC4) and oncogenes (e.g. K-ras) have been shown to be involved in the development of PaCa. However, the extent of chromosomal changes (gains and losses) implicates that many more genes may be involved in the multistep progression of PaCa. Identification of these genes is essential for understanding the molecular events in the development of PaCa. METHODS: We assembled public and proprietary libraries of more than 4 million expressed sequence tags using newly developed software tools. RESULTS: We identified a total of 249 genes with specific expression patterns in normal and cancerous tissue of the pancreas. Of these, 27 genes were found to be preferentially expressed in normal tissue of the pancreas, while 222 genes showed significant upregulation of expression in PaCa. Of the 249 genes, 232 (93.2%) were found to represent known human genes or putative human homologues of genes characterized previously in other species, while 17 (6.8%) represent putative new genes. CONCLUSION: These genes may represent a valuable source to identify novel TSGs and oncogenes involved in the carcinogenesis of PaCa.

DNA, Complementary↗

PubMed2002

Value of a protective stoma in low anterior resections for rectal cancer.

INTRODUCTION: Anastomotic leakage is a major problem in colorectal surgery and in particular in operations for low rectal cancer. The present study investigates the question whether a protective stoma can reduce the (clinical and radiologic) anastomotic leakage rate and/or the rate of leakage requiring surgery. METHODS: The investigation took the form of a prospective multicenter study involving 75 German hospitals and was performed between January 1, 1999, and December 31, 1999. A comparison was made of the postoperative results of procedures performed with and those performed without a protective stoma in patients undergoing low anterior rectal resection. In addition, logistic regression using the target criteria, overall anastomotic leakage and anastomotic leakage requiring surgery, was applied. RESULTS: Among the 3,695 operations performed for carcinoma of the rectum or colon, 482 were low anterior resections. In 334 patients (69.3 percent) no protective stoma was constructed, whereas 148 (30.7 percent) received such protection. Age, American Society of Anesthesiologists physical status, and body mass index were identical in both groups. In the group receiving a protective stoma, however, neoadjuvant radiochemotherapy was more common, the tumors were lower-and thus the total mesorectal excision rate higher, the intraoperative complication rate was higher, and the duration of the operation was longer. The differences were all significant. The major criterion (overall anastomotic leakage rate) was identical in the two groups, but the rate of leakage requiring surgery was significantly lower in patients receiving a protective stoma (p = 0.028). The logistic regression revealed that use of a protective stoma is a predictor of protection against anastomotic leakage requiring surgery. The distance of the tumor from the anal verge and the duration of the operation are further predictors. CONCLUSION: The particular benefit of a covering stoma is reduction in the rate of leaks requiring surgery and thus in the severe consequences of an anastomotic leakage.

Adult↗

PubMedDate not supplied

Retroperitoneal soft tissue sarcomas: prognosis and treatment of primary and recurrent disease in 117 patients.

BACKGROUND: The objective of this study was to define prognostic factors for patients with primary soft tissue sarcomas (STS) arising from the retroperitoneum. PATIENTS AND METHODS: One hundred and seventeen consecutive patients, resected in our institutions between July 1972 and November 2002, were reviewed. RESULTS: The prognostic factors predicting survival were incomplete resection, a tumor of high grade (G3), metastases to lymph nodes and distant metastasis. Patients with a malignant fibrous histiocytoma (MFH) or a malignant peripheral nerve sheath tumor (MPNST) had a worse prognosis than those patients with other tumors. The prognostic factors predicting local recurrence were incomplete resection and high grade (G3). The prognostic factors predicting metastasis were incomplete resection, lymph node metastasis at the time of the resection of the primary tumor and tumor histology. CONCLUSION: Since only complete tumor resection offers a chance for cure, it is mandatory, and local control remains the most significant challenge in the management of retroperitoneal sarcomas. Other therapies can support surgical treatment, depending on the tumor localization and histological entity. The management of patients with a STS should be provided by a specialized team of surgeons, oncologists and radiotherapists, and patients should be enrolled in a treatment study whenever possible.

Chemotherapy, Adjuvant↗