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M Nagel

Publications and source records attributed to M Nagel.

At least 37 records · Page 2Linked to original sources
PubMed2000

Clinical consequences of molecular diagnosis in families with mismatch repair gene germline mutations.

Hereditary nonpolyposis colorectal cancer (HNPCC), clinically defined by the Amsterdam criteria, is associated with mismatch repair gene germline mutations. This study was performed to evaluate the efficiency of combined clinical and molecular diagnostics in identifying carriers of a mutated gene in families meeting criteria of the Bethesda guidelines and to examine the influence of molecular diagnosis on clinical decision-making in carriers and noncarriers. Seventy-two patients meeting criteria of the Bethesda guidelines were tested for microsatellite instabilities (MSI). MSI-H tumors were found in 38 (52.8%) index patients. Complete sequencing of hMLH1 and hMSH2 in 38 MSI-H patients and of hMSH6 in one of these patients revealed 15 pathogenic germline mutations, including three novel mutations, and three novel unclassified germline variants. Twelve of the 15 pathogenic mutations were found in patients fulfilling the Amsterdam I/II criteria. Surgical and genetic counseling was offered to the affected families; as a result of molecular diagnosis in the 15 families, 26 index patients and affected carriers and 8 asymptomatic carriers of a mutated mismatch repair gene were included in the surveillance program, and 26 noncarriers were excluded from this program. Although germline mutations are detected in only 20.8% of patients fulfilling criteria of the Bethesda guidelines, family history and MSI-H tumor classification are both strong indicators for germline mutations in hMSH2, hMLH1, and hMSH6 genes, resulting in a 51.9% mutation detection rate. Identification of individual mutation status allows clear-cut decisions on whether or not inclusion in surveillance programs is indicated.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Use of phage display for the generation of human antibodies that neutralize factor IXa function.

The use of libraries of phage-displayed human single-chain antibody fragments (scFv) has become a new, powerful tool in rapidly obtaining therapeutically useful antibodies. Here, we describe the generation of human scFv and F(ab')2 directed against the gamma-carboxyglutamic acid (Gla) domain of coagulation factor IX. A large library of human scFv, displayed either on M13 phage or expressed as soluble proteins, was screened for binding to human Gla-domain peptide (Tyr1-Lys43). Among a panel of scFv that bound to the factor IX-Gla domain, six scFv clones recognized full-length factor IX and exhibited strong inhibitory activity of factor IX in vitro. After reformatting as F(ab')2, the affinity for factor IX of three selected clones was determined: 10C12 Kd = 1.6 nmol/l, 13D1 Kd = 2.9 nmol/l, and 13H6 Kd = 0.46 nmol/l. The antibodies specifically bound to factor IX and not to other coagulation factors, as assessed by enzyme-linked immunosorbent-type and human plasma clotting assays. The complementarity determining region amino acid sequences of clones 10C12 and 13D1 only differed at a single residue, whereas 13H6 showed little homology, suggesting that 13H6 binds to a different epitope within the factor IX-Gla domain. Despite the slightly lower affinity of 10C12 F(ab')2 versus 13H6 F(ab')2, 10C12 was consistently more potent than 13H6 in prolonging the activated partial thromboplastin time (APTT), in inhibiting platelet-mediated plasma clotting, and in inhibiting factor X activation by the intrinsic Xase complex. Finally, 10C12 F(ab')2 also recognized and neutralized factor IX/factor IXa of different species, as demonstrated by the specific APTT prolongation of dog, mouse, baboon and rabbit plasma. In summary, the results validate the usefulness of scFv phage-displayed libraries to rapidly generate fully human antibodies as potential new therapeutics for thrombotic disorders.

Amino Acid Sequence↗
PubMed2000

[Surgery of hereditary colorectal carcinoma].

Hereditary colorectal cancer syndromes account for about 7% of all colorectal carcinomas. The most frequent form is Hereditary Nonpolyposis Colorectal Cancer (HNPCC). Identification, cloning and sequence analysis of the predisposing genes enables identification of mutation carriers and non-mutation carriers, respectively. These genetic informations can be used in an individually tailored clinical surveillance program and may ultimately result in standard preventive surgical treatment. In classical FAP the surgical standard is performing a restorative proctocolectomy. It is still unclear now, if this procedure should be modified in attenuated forms (colectomy with ileorectostomy). Due to a high rate of synchronous and metachronous carcinomas a subtotal colectomy in the case of first colon cancer seems to be indicated in HNPCC patients. A proctocolectomy or a restorative proctocolectomy should be weighed in case of carcinomas in the lower rectum. These procedures should be performed under the precondition of identification of the pathogenic germline mutation in the patient, only. In addition, a synchronous prophylactic hysterectomy with oophorectomy should be recommended postmenopausal gene carriers. Intensive counseling of the patient should proceed these preventive procedures involving surgeons, gastroenterologists, geneticists, molecular biologists, gynecologists, physicians and psychologists. It is recommended to have patients treated exclusively in specialized centers. Currently, six interdisciplinary centers for cancer surveillance and early diagnosis in hereditary colorectal cancer are being sponsored in Germany by the Deutsche Krebshilfe since 1999. In the future clinical studies have to be conducted to evaluate the efficacy of extended colorectal resections versus efficacy of surveillance and conventional resections according to general oncological principles.

Adenomatous Polyposis Coli↗
PubMed1999

[Multi-modal therapy concepts in gastrointestinal tumors].

A large variety of adjuvant and neoadjuvant treatment concepts were developed during the recent years to improve the results of gastrointestinal tumors. There exist generally accepted guidelines for adjuvant treatment of colon and rectal cancer, while for the tumors of the upper gastrointestinal tract convincing results of randomized studies are still missing. Therefore ongoing and future studies have to find out, which patients could have a benefit from multimodal therapy.

Combined Modality Therapy↗
PubMed1999

[An unusual picture of insulinoma in type-2 diabetes mellitus and morbid obesity].

HISTORY AND CLINICAL FINDINGS: Marked hyperinsulinism was demonstrated in the course of an oral glucose tolerance test (oGTT) in a 63-year-old woman with severe obesity (height 1.59 m, body weight 123 kg, body-mass index 46.4 kg/m2). The diabetic metabolic state, first diagnosed 12 years ago, had been replaced by a low plasma glucose level: she often had attacks of ravenous hunger. A reducing diet of 800 kcal had not been tolerated. She had not had any syncopes. She had continually gained weight since puberty, but her weight had remained relatively constant for the past 5 years during which she had been treated with L-thyroxine for a diffuse goitre (stage II). INVESTIGATIONS: In the course of an oGTT (75 g glucose) the basal insulin concentration (146 pmol/l) had risen to 1663 pmol/l at 30 min. The basal proinsulin level was 50 times normal (66 pmol/l vs. 1.418 pmol/l), while the initial plasma glucose level had fallen from 4.3 mmol/l to 3.8 mmol/l. Spiral computed tomography of the pancreas showed a 3 x 2.5 cm mass in the region of the tail of the pancreas. TREATMENT AND COURSE: At laparoscopy a 4 cm tumor was palpated in the region of the pancreatic tail. Left resection of the pancreas was performed. Histopathological examination of the surgical specimen confirmed an insulinoma. A repeat of oGTT 6 months postoperatively demonstrated a markedly diminished insulin level compared with the preoperative results, as well as a diabetic metabolic state. CONCLUSION: In case of dramatic improvement of diabetes mellitus in an obese patient without drug treatment or weight reduction an insulin-producing tumour should be considered in the differential diagnosis. There may be no typical hypoglycaemic symptoms because of insulin resistance associated with the obesity.

Combined Modality Therapy↗
PubMed1999

[Postoperative radiotherapy in endometrial carcinoma. A retrospective analysis of 541 cases].

PURPOSE: This retrospective study was designed to evaluate the role of adjuvant radiotherapy for surgically treated endometrial carcinoma. PATIENTS AND METHODS: From 1980 through 1988, 541 patients were treated with either intravaginal cuff irradiation with a high-dose-rate (HDR) Iridium-192 remote afterloading technique (n = 294) or with combined HDR-brachytherapy and additional external pelvic irradiation to 54 Gy (n = 247) after surgery for endometrial cancer. Afterloading irradiation was administered in 4 fractions 4 to 6 weeks after surgery. A dose of 30 Gy was delivered at a depth of 0.5 cm from the vaginal mucosa. RESULTS: Patients with HDR-brachytherapy alone showed a 5-year survival of 94.3% for Stage I and 73.6% for Stage II (p = 0.0007). Patients who received both brachytherapy and additional external pelvic irradiation had a 5-year survival of 94.1% for Stage I, 81.1% for Stage II, 70.4% for Stage III and 46.9% for Stage IV (p = 0.0001). The main predictors for survival in a multivariate analysis were stage and grading. Patients with combined radiotherapy had a local recurrence rate of 3.2%, whereas patients with brachytherapy alone who were better selected and had more favorable prognostic factors showed a recurrence rate of 2%. Low-risk patients (Stage I, Grade 1, low infiltration) in the HDR-brachytherapy group had 6 relapses, mainly caused by insufficient treatment on the basis of papillary histology. High-risk patients with poorly differentiated tumors, which infiltrate more than half the myometrial wall might benefit from additional external radiotherapy in terms of reduction of local recurrence and better survival. Five-year actuarial survival rate was 93.6% after combined radiotherapy vs 86.7% after brachytherapy alone. Complications were graded according to the RTOG scoring system. Severe late complications were fistulas of bladder and/or bowel, which occurred in 2.8% in the combined radiotherapy group, and 0.7% in the HDR brachytherapy group. CONCLUSIONS: Low-risk patients should be generally treated postoperative with HDR-brachytherapy alone. Combined radiotherapy decreased pelvic relapses for high-risk patients with overall low complication rates. We conclude that an individually adjusted postoperative radiotherapy allows a well tolerated treatment with excellent results.

Brachytherapy↗
PubMed1999

[Crohn disease of the esophagus].

INTRODUCTION: Since the landmark report by Crohn, Ginzburg and Oppenheimer in 1932, the spectrum of involvement of Crohn's disease has expanded to include the entire digestive tract from mouth to anus. The involvement of the esophagus by Crohn's disease is very rare. METHODS: We report a 41-year-old male patient with severe Crohn's disease of the distal esophagus with a fistula to the right bronchial system. RESULTS: After a long period of nutritional support we performed a transthoracic esophagectomy and a Nissen fundoplication. Postoperatively his course was complicated by pneumonia and withdrawal symptoms. CONCLUSIONS: Esophagectomy is indicated in Crohn's disease of the esophagus with severe stricture or fistula formations.

Adult↗
PubMed1999

[Early results and complications of surgery of liver metastases].

Following resection of liver metastases the overall prognosis still remains limited because of the lack of adjuvant therapy. The number of explorative laparotomies, non-radical resections and complications needs to be reduced. One hundred and ten laparotomies in 97 patients with liver metastases were performed with the intention to cure between October 1993 and February 1998. In a prospective analysis we reviewed: patient characteristics, characteristics of primary tumors and metastases, part and extent of liver resection, radicality, complications and mortality. Additionally, a prospective study about the value of ultrasonography and CT scan concerning the evaluation of preoperative liver findings was undertaken between January 1995 and February 1998. Altogether, resection of liver metastases was achieved in 75 cases (68.2%). Nineteen patients (25.3%) had postoperative complications. Two patients (2.7%) died following liver resection. Thirty-five operations (31.8%) had to be finished as only an explorative laparotomy. The major reason for these restricted operations was in 15 patients (42.9%) regional recurrence or peritoneal metastases. Preoperative determination of the liver finding (quantity, localization and size) by ultrasonography and CT scan achieved an accuracy of 68.9% each. The results of this analysis show that resection of liver metastases can be accomplished with minor morbidity and mortality. The high number of explorative laparotomies still remains a central problem in the surgery of liver metastases. By the introduction of duplex sonography and contrast-medium-enhanced helical CT scan, liver pathology can be defined more precisely in the preoperative evaluation. However, preoperative detection of regional recurrence or peritoneal metastases remains difficult.

Adult↗
PubMed1999

Reduction of the nitrogen and carbon content in swine waste with algae and bacteria.

Animal waste causes environmental problems like eutrophication of ground and surface water or the pollution of the atmosphere because of its high NH4+ content. The aim of our study was to fix the nitrogen of swine waste as biomass. Therefore, an isolated alga, Chlorella sp., and bacteria naturally living in liquid manure were grown in batch cultures (containing diluted swine waste supplied with a nutrient solution) and continuous cultures (undiluted liquid manure) to achieve reduction of NH4+ and total organic carbon (TOC) contents. For continuous cultivation, a photobioreactor of our own design was used. The batch cultivation of Chlorella sp. and bacteria in swine waste resulted in good growth of both groups of organisms and in a reduction of 25% NH4+ and 80% TOC. In the continuous cultivation a steady state was not achieved owing to a change in the composition of the bacterial population. NH4+ was totally removed, but NO2- (up to 100 mM) was transiently released. NO3- was not detected. These effects might be explained by the presence of heterotrophic nitrifiers, which are able to oxidize NH4+ to NO2- and to reduce NO2- to gaseous compounds.

Animal Husbandry↗
PubMed1999

Establishment of substratum polarity in the blastocoel roof of the Xenopus embryo.

The fibronectin fibril matrix on the blastocoel roof of the Xenopus gastrula contains guidance cues that determine the direction of mesoderm cell migration. The underlying guidance-related polarity of the blastocoel roof is established in the late blastula under the influence of an instructive signal from the vegetal half of the embryo, in particular from the mesoderm. Formation of an oriented substratum depends on functional activin and FGF signaling pathways in the blastocoel roof. Besides being involved in tissue polarization, activin and FGF also affect fibronectin matrix assembly. Activin treatment of the blastocoel roof inhibits fibril formation, whereas FGF modulates the structure of the fibril network. The presence of intact fibronectin fibrils is permissive for directional mesoderm migration on the blastocoel roof extracellular matrix.

Activins↗
PubMed1999

[Therapy of deep leg vein thrombosis. When is surgical therapy indicated?].

In spite of quite a few clinical trials the benefit of venous thrombectomy is seen controversially. The primary objectives of treating venous thrombosis are survival rate, prevention of pulmonary embolism and of postthrombotic syndrome. We report our experience with 47 patients who underwent venous thrombectomy. The mortality rate was 0%. We did not observe clinically relevant pulmonary embolism. After two years 90% of thrombectomised veins were patent. The mortality rates given in the literature of conservative treatment with heparin and following oral anticoagulation are 0.4 to 1.6%. Fibrinolysis shows mortality rates of 1 to 2.4, and thrombectomy of 3.8%, respectively. Venous thrombectomy is an effective treatment to prevent pulmonary embolism. In our own experience we saw no clinically significant pulmonary event. The danger of embolism rises with the proximity of the venous thrombus. Therefore those patients may have the greatest potential benefit from thrombectomy who present with a mobile inguinal thrombus or a thrombus in the iliac vein. So far there are no statistically sufficient data to support the indication of thrombectomy to prevent a postthrombotic syndrome.

Adult↗
PubMed1999

[Management of esophageal perforation].

The majority of esophageal perforations is caused by endoscopic procedures, while the spontaneous rupture, also known as Boerhaave's syndrome, is rare. Regardless of the cause the esophageal perforation is an urgent surgical problem. The main diagnostic method is a water-soluble contrast study of the esophagus, probably supplemented by a CT-scan. In case of uncertain diagnosis or localisation eosophagoscopy should be performed. We believe that esophageal perforation should be operated, the factor "time" seems to be important for prognosis. In case of early surgical treatment (within 24 hours) a primary suture is sufficient and safe. Only after a delay in diagnosis with extended mediastinal spillage and necrosis of the esophageal wall the use of autogenous tissue to buttress the esophageal repair may be necessary. Esophagectomy should only be performed for perforated carcinomas. We treated 10 patients in a 4-years-period by primary surgical repair combined with drainage. Nine of them survived, only a 82-years old patient died because of an unresectable perforated esophageal carcinoma.

Adult↗
PubMed1999

[Hierarchy and research].

Surgical research needs structural and organizational conditions. These have to ensure, that the young surgeon finds the opportunity for scientific activities and development in a highly professional environment.

Curriculum↗
PubMed1999

[Smoking behavior in Germany].

In a representative sample, 7,124 men and women in the age of 18 to 79 years were interviewed regarding their smoking habits. In 1998, one third of the participants, 37% of the men and 28% of the women, were smokers. The highest proportion of smokers was found in the youngest age group of 18 to 24 years--49% males and 44% females. The mean cigarette consumption of male smokers was 20 cigarettes per day, that for female smokers was 16. About one third of the smokers have tried to stop smoking at least once during the past year. 86% of the men and 80% of the women started their habit under the age of 20. Compared to a previous survey in 1990/92, the proportion of male smokers dropped by 3% in West Germany, whereas in East Germany the figure remained the same. The proportion of female smokers rose by 1% in West Germany and by 8% in East Germany (from 21% to 29%). The latter change means an increase of the smoking prevalence by 42% in East German women during the short period of only 7 years.

Adolescent↗
PubMed1998

[Color Doppler sonography in liver surgery. Status of perioperative monitoring].

AIM: Resection of liver tumours is not always successful despite detailed diagnostic work-up preoperatively. In our study we compared the predictive value of colour Doppler imaging of the liver with other radiological examinations for tumour staging, surgical decision making and postoperative complications. METHODS: From 1/95 to 6/1997 we investigated 76 patients with liver tumours; 60 patients with liver metastases, 13 with primary liver carcinomas and 3 with benign lesions. Resectability was defined in colour Doppler imaging by tumour localisation, distance of the tumour to the central vessels and blood flow in the portal vein. CT-scan in all patients and angiography in patients with central tumour localisation was performed. The preoperative results were compared to intraoperative ultrasound and surgical examination. RESULTS: 108 out of 118 intrahepatic lesions were found preoperatively using high-resolution ultrasound. Ultrasound and CT-scan achieve comparable results in delineating pathologic changes in the liver. Considering only the liver findings and local resectability in 76 patients, the sensitivity achieved for B-mode-ultrasound was 77.6% (59/76); for CT-scan 78.9% (61/76) and for colour Doppler imaging 86.4% (66/76). 31 out of 76 laparotomies were terminated after exploration. Resectability was correctly predicted by ultrasound in 55 (72.4%) and by CT-scan in 57 (73.7%) patients. Colour Doppler imaging improved the ultrasound results in up to 62 (81.6%) patients. Unsuspected not resectable tumour growth was found in 9 patients with local/regional recurrences, in 4 patients with peritoneal spread and in one patient with multiple bilateral liver metastases. CONCLUSIONS: Using high-resolution ultrasound systems the preoperative detection of lesions in the liver achieves the results of CT-scan. Little isoechogenic lesions, peritoneal spread and locoregional recurrences can be missed by ultrasound examination. Colour Doppler imaging shows compared with B-mode and CT-scan a higher sensitivity for the detection of the infiltration of hilar structures and can take place of more invasive methods in preoperative liver investigations. Considering functional and morphological aspects colour Doppler imaging makes an essential contribution to the planning of liver surgery. Using lung passing contrast media the determination of tumour vascularisation and perioperative quantification of liver perfusion is possible. The use of the intraoperative ultrasound is justified to determine resection limits, detection of smallest non-palpable lesions and to control perfusion after vascular reconstruction. In experienced hands colour Doppler imaging gives valuable preoperative information with excellent cost-benefit ratio.

Equipment Design↗
PubMed1998

[Surgical procedure in primary and metastatic breast carcinoma].

We know that breast cancer is already a systemic disease in the majority of patients at the time it is first diagnosed, requiring an interdisciplinary treatment concept. This fact has changed the surgical treatment approach of primary breast cancer which currently follows the principle: "As much as necessary, as little as possible". Improved early detection of breast carcinomas allows the treatment of a majority of early stage breast cancer patients with breast-conservation surgery, followed by irradiation except for a few contraindications. Although survival is not significantly different for patients who undergo breast conservation surgery plus irradiation than for those having modified radical mastectomy, the pattern and prognostic value of locoregional failure are different. Locoregional failure after breast conservation requires mastectomy, thoracic wall recurrence will be treated by (en-bloc) resection and irradiation. Following rigorous selection criteria and indications, surgical resection of distant metastases to the liver, lung or brain can improve the quality of life and prolong survival, it should therefore be taken into consideration in individual cases. Since the two breast cancer susceptibility genes, BRCA1 and BRCA2, have been detected, high-risk patients should be offered the possibility of genetic counseling and genetic testing. Based on our present knowledge, the surgical approaches for BRCA1 or BRCA2 mutation carriers with breast cancer remain unchanged. There are some indications that molecular tumor parameters can be used to identify a subgroup of primary breast cancer patients who are characterized by a poorer prognosis. The results achieved in our own patients add further evidence in favor of this theory.

Biomarkers, Tumor↗
PubMed1998

[Molecular diagnosis and clinical consequences in families with HNPCC syndrome].

Thirteen families were included in our HNPCC surveillance program, eight of which met strict and three incomplete Amsterdam criteria. Two index patients were younger than 35 years of age. Tumors of all index persons showed microsatellite instabilities in at least 50% of the ten markers studied. Immunohistochemical analysis of tumor sections was performed using antibodies against hMLH1 and hMSH2 proteins in order to identify the mutated gene, which is not expressed in the tumor. Coding regions of hMLH1 and hMSH2 genes were amplified by PCR from genomic DNA and sequenced. In nine families pathogenetic mutations all resulting in a truncated protein, could be identified. Furthermore, 21 intron and exon polymorphisms were found. Since July 1997 we have offered surgical and genetic counseling to families with hereditary cancer syndromes in a special outpatient clinic. In addition to 13 index patients three asymptomatic gene carriers were included and eight noncarriers were excluded from the HNPCC surveillance program, as recommended by the HNPCC study group of Germany. Molecular diagnosis has considerable clinical implication in hereditary nonpolyposis colorectal cancer (HNPCC) families with respect to family members who actually have the disease as well as gene carriers and noncarriers.

Adaptor Proteins, Signal Transducing↗