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C Wittekind

Publications and source records attributed to C Wittekind.

At least 19 recordsLinked to original sources
PubMed2001

INK4a-ARF alterations and p53 mutations in hepatocellular carcinomas.

The INK4a-ARF (CDKN2A)- locus on chromosome 9p21 encodes for two tumour suppressor proteins, p16(INK4a) and p14(ARF), that act as upstream regulators of the Rb-CDK4 and p53 pathways. To study the contribution of each pathway in tumorigenesis of hepatocellular carcinoma (HCC), we analysed the alterations of p14(ARF), p16(INC4a) and p53. After microdissection, DNA of 71 hepatocellular carcinomas was analysed for INK4-ARF inactivation and p53 mutation by DNA sequence analysis, methylation-specific PCR (MSP), restriction-enzyme related polymerase chain reaction (RE-PCR), mRNA expression and immunohistochemistry. In addition, microdeletion of p14(ARF) and p16(INC4a) were assessed by differential PCR. Inactivation of p14(ARF) was found in 11/71 cases (15%), alterations of p16(INK4a) occurred in 47/71 carcinomas (66%), which correlated with loss of mRNA transcription. Five tumours (7%) had homozygous deletions of the INK4a-ARF locus. We failed to detect specific mutations of both exons. P16(INK4a) methylation with an unmethylated p14(ARF) promotor appeared in 39 cases. Mutations of p53 were found in 30 of 71 HCC (42%), and only one of them harboured p14(ARF) inactivation. We failed to establish alterations of the INK4a-ARF locus or p53 status as independent prognostic factor in these tumours. Our data indicate, that p14(ARF) methylation occurs independently of p16(INK4a) alterations in a subset of HCC together with wild type p53. The INK4a-ARF-/p53-pathway was disrupted in 86% of HCC, either by p53 mutations or by INK4a-ARF inactivation, and may have co-operative effects in hepatocarcinogenesis.

Adult↗
PubMed2001

Frequent k- ras -2 mutations and p16(INK4A)methylation in hepatocellular carcinomas in workers exposed to vinyl chloride.

Vinyl chloride (VC) is a know animal and human carcinogen associated with liver angiosarcomas (LAS) and hepatocellular carcinomas (HCC). In VC-associated LAS mutations of the K- ras -2 gene have been reported; however, no data about the prevalence of such mutations in VC associated HCCs are available. Recent data indicate K- ras -2 mutations induce P16 methylation accompanied by inactivation of the p16 gene. The presence of K- ras -2 mutations was analysed in tissue from 18 patients with VC associated HCCs. As a control group, 20 patients with hepatocellular carcinoma due to hepatitis B (n = 7), hepatitis C (n = 5) and alcoholic liver cirrhosis (n = 8) was used. The specific mutations were determined by direct sequencing of codon 12 and 13 of the K- ras -2 gene in carcinomatous and adjacent non-neoplastic liver tissue after microdissection. The status of p16 was evaluated by methylation-specific PCR (MSP), microsatellite analysis, DNA sequencing and immunohistochemical staining. All patients had a documented chronic quantitated exposure to VC (average 8883 ppmy, average duration: 245 months). K- ras -2 mutations were found in 6 of 18 (33%) examined VC-associated HCCs and in 3 cases of adjacent non-neoplastic liver tissue. There were 3 G --> A point mutations in the tumour tissue. All 3 mutations found in non-neoplastic liver from VC-exposed patients were also G --> A point mutations (codon 12- and codon 13-aspartate mutations). Hypermethylation of the 5' CpG island of the p16 gene was found in 13 of 18 examined carcinomas (72%). Of 6 cancers with K- ras -2 mutations, 5 specimens also showed methylated p16. Within the control group, K- ras -2 mutation were found in 3 of 20 (15%) examined HCC. p16 methylation occurred in 11 out of 20 (55%) patients. K- ras -2 mutations and p16 methylation are frequent events in VC associated HCCs. We observed a K- ras -2 mutation pattern characteristic of chloroethylene oxide, a carcinogenic metabolite of VC. Our results strongly suggest that K- ras -2 mutations play an important role in the pathogenesis of VC-associated HCC.

Adult↗
PubMed2001

Expression of the p53 homologues p63 and p73 in multiple simultaneous gastric cancer.

The tumour-suppressor protein p53 has recently been shown to belong to a family that includes two structurally related proteins, p63 and p73. This study investigated the status of p53 and its two homologues in multiple simultaneous gastric carcinomas. Expression and mutation of p53, p73 and p63 including the two major isotypes TAp63 and black triangleNp63, were examined by direct DNA-sequencing, in situ hybridization, western blotting and immunohistochemistry in 68 gastric carcinomas of 32 patients. The results obtained were correlated with pathohistological stage (according to UICC(16)) and several other histopathological factors and finally with patient survival. p53 mutations were detected in 23/68 carcinomas (34%) from 18 patients with a discordant mutation pattern. Independently of p53 mutation status, p73 transcripts and protein expression were found in 33/68 carcinomas from 24 patients. p63 positivity was found in 21 patients; 25 out of 68 tumours expressed p63. The number of cells containing p63 and their distribution depend on the degree of tumour differentiation. High grade carcinomas of the diffuse type exhibited a significantly higher p63 expression. In intestinal metaplasia and atrophic gastritis, an increase of TAp63 and black triangleNp63 staining was also observed. Specific mutations of p73 or p63 causing amino acid substitutions were not identified. Neither p53, p73 nor p63 were related to prognosis. p73 and p63 have rarely been found to be mutated in gastric carcinomas, but both proteins were expressed in only a subset of tumours. The status of these p53 homologues was discordant in all patients with multiple simultaneous gastric carcinomas. The increased expression of p63 (TAp63 and black triangleNp63) in less well differentiated gastric carcinomas may indicate that p63 can act to promote neoplastic growth in the gastric epithelium.

DNA Mutational Analysis↗
PubMed2001

Adjuvant versus neoadjuvant radiochemotherapy for locally advanced rectal cancer. A progress report of a phase-III randomized trial (protocol CAO/ARO/AIO-94).

AIM: The standard treatment for patients with clinically resectable rectal cancer is surgery. Postoperative radiochemotherapy is recommended for patients with advanced disease (pT3/4 or pN+). In recent years, encouraging results of preoperative radiotherapy have been reported. This prospective randomized phase-III trial (CAO/ARO/AIO-94) compares the efficacy of neoadjuvant radiochemotherapy to standard postoperative radiochemotherapy. We report on the design of the study and first results with regard to toxicity of radiochemotherapy and postoperative morbidity. PATIENTS AND METHODS: Patients with locally advanced operable rectal cancer (uT3/4 or uN+, Mason CS III/IV) were randomly assigned to pre- or postoperative radiochemotherapy: A total dose of 50.4 Gy (single dose 1.8 Gy) was applied to the tumor and the pelvic lymph nodes. 5-FU (1,000 mg/m2/d) was administered concomitantly in the first and fifth week of radiation as 120-h continuous infusion. Four additional cycles of 5-FU chemotherapy (500 mg/m2/d, i.v. bolus) were applied. Radiochemotherapy was identical in both arms except for a small-volume boost of 5.4 Gy in the postoperative setting. Time interval between radiochemotherapy and surgery was 4-6 weeks in both arms. Techniques of surgery were standardized and included total mesorectal excision. In addition, stratification according to surgeons involved has been provided for. Primary endpoints of the study are 5-year overall-survival, local and distant control, secondary endpoints include rate of curative (R0) resections and sphincter saving procedures, toxicity of radiochemotherapy, surgical complications and quality of life. RESULTS: As of 15th November 2000, 628 patients were randomized from 26 participating institutions: 310 patients were randomized to postoperative radiochemotherapy, 318 patients to preoperative radiochemotherapy. Acute toxicity (WHO) of radiochemotherapy was low, with less than 15% of patients experiencing Grade 3 or higher toxicity: The principal toxicity was diarrhea, with 12% in the postoperative radiochemotherapy arm and 10% in the preoperative radiochemotherapy arm having Grade-3, and 1% in either arm having Grade-4 diarrhea. Erythema, nausea and leukopenia were the next common toxicities, with less than 3% of patients in either arm suffering Grade 3 or greater leukopenia or nausea. Postoperative complication rates were similar in both arms, with 12% (postoperative radiochemotherapy) and 13% (preoperative radiochemotherapy) of patients, respectively, suffering from anastomotic leakage, 4% (postoperative radiochemotherapy) and 3% (preoperative radiochemotherapy) from postoperative bleeding, and 6% (postoperative radiochemotherapy) and 5% (preoperative radiochemotherapy) from delayed wound healing. CONCLUSION: The patient accrual of our trial is satisfactory, neoadjuvant radiochemotherapy is well tolerated and bears no higher risk for postoperative morbidity.

Adult↗
PubMed2001

[Anatomy and pathology of intrahepatic and extrahepatic bile duct tumors].

Adenocarcinomas of the intra- and extrahepatic bile ducts are rare tumors that begin with malignant transformation of the bile duct epithelia. Intrahepatic cholangiocarcinomas derive from the small bile ducts located proximally to the right and left hepatic ducts. Extrahepatic bile duct carcinomas originate in the right or left hepatic duct, the cystic duct, or the choledochal duct. Tumors located at the bifurcation are called Klatskin tumors. The intrahepatic cholangiocarcinomas are classified according to the TNM classification of liver tumors, while the extrahepatic bile duct tumors have their own TNM classification. Several factors, accompanied by a chronic inflammatory reaction, have been discussed in the etiopathogenesis of these tumors: schistosomiasis, ulcerative colitis with primary sclerosing cholangitis, and inborn bile duct cysts of the liver as a consequence of a disturbance of the ductal plate formation. Over 95% of bile duct tumors are adenocarcinomas. In the nomenclature of precursor lesions a two-grade classification of dysplasia (low-grade versus high-grade) has been found to be more reproducible.

Adenocarcinoma↗
PubMed2001

[Pathology and pathomorphologic diagnosis of germ cell tumors of the testis].

Testicular germ cell tumors are rare and comprise about 90% of all testis tumors. Genetic factors may play a role in the pathogenesis as can be deduced by a higher family-linked incidence and the p53 gene seems to be important in the development of these tumors which derive from a malignant transformed germ cell. Testicular intraepithelial neoplasia (TIN) may differentiate in two directions, namely into seminomas which comprise nearly 50% of all testicular germ cell tumors and non-seminomas. Since the term "differentiated teratoma" may be misleading, we propose the use of the term "teratoma" only. A preoperative diagnosis by biopsy is not indicated. An exact postoperative diagnosis including all necessary classifications, particularly the WHO and the TNM classifications, requires a very careful preparation of the resected specimen. The histological diagnosis should list all the different types of the WHO classification and the percentage of the tumor should be indicated, at least for embryonal carcinomas. For T categorisation in the TNM classification, the presence of invasion of veins or lymph vessels is important. Documentation, preferably in the form of a standard checklist, is strongly recommended.

Diagnosis, Differential↗
PubMed2001

Adenoma of the papilla and ampulla--premalignant lesions?

Ampullary adenomas arising in the papilla or the ampulla Vateri, are rare, benign, neoplastic lesions. No specific aetiological factors, such as diet, chemical or environmental causes, have been identified yet. An established risk factor which is accompanied by the development of adenoma is the presence of genetically inherited polyposis syndromes, e.g. familial adenomatosis coli (FAP). Adenomas assume tubular, tubulovillous, or villous architecture and are not different from adenomas arising elsewhere in the gastrointestinal tract. The full neoplastic spectrum, ranging from mild to high grade dysplasia, up to invasive carcinoma, resembles the adenoma-carcinoma sequence of the large bowels.

Adenoma↗
PubMed2001

C282Y and H63D mutation of the hemochromatosis gene in German porphyria cutanea tarda patients.

BACKGROUND AND AIMS: Patients with porphyria cutanea tarda (PCT) have a susceptibility to reversible inactivation of hepatocyte uroporphyrinogen decarboxylase, which can be triggered by alcohol, hepatitis C virus, and other agents. Inherited factors that may predispose to PCT include the C282Y mutation in the hemochromatosis (HFE) gene. METHODS: We analyzed the hemochromatosis mutations C282Y and H63D in liver biopsies and serum samples of 190 German patients (mean age 48+/-12.5 years) with sporadic PCT. The hepatic iron concentration was determined within the liver tissue. Age-matched healthy blood donors (115 donors) served as controls. RESULTS: The C282Y and H63D mutations were found in 75 (39%) and 85 (45%) of 190 patients with PCT, respectively. Twenty-two patients (12%) were homozygous for the C282Y mutation, and eighteen patients (9%) were compound heterozygotes, displaying both the C282Y and the H63D mutation. Within the control group, 3 of 115 patients were heterozygous for C282Y (3%) and 12 for H63D (10%). Serum and hepatic iron, ferritin, transferrin saturation, or liver enzymes did not differ significantly between patients with or without HFE mutations. CONCLUSIONS: The high frequency of homo- and heterozygosity for the C282Y and H63D alleles strongly suggests that these mutations are important predisposing factors for PCT in German patients.

DNA↗
PubMed2001

p16INK4A-alterations in primary angiosarcoma of the liver.

BACKGROUND/AIMS: Alterations in the p16 (CDKN2/MTS-1/INK4A) gene have been implicated in the tumorigenesis of different human cancers. Recent evidence shows that transcriptional silencing as a consequence of hypermethylation of CpG islands is the predominant mechanism of p16INK4a gene inactivation in malignant epithelial tumors. This study was performed to determine whether alterations of p16 are involved in the development of angiosarcoma of the liver. METHODS: The status of p16 was evaluated in 17 angiosarcomas of the liver by methylation-specific PCR (MSP), microsatellite analysis, DNA sequencing and immunohistochemical staining. The results obtained were correlated with histopathological variables and with patient survival. RESULTS: Hypermethylation of the 5' CpG island of the p16 gene was found in 12 out of 17 (71%) angiosarcomas examined. Homozygous deletion at the p16 region was present in one case (6%), and loss of heterozygosity was present in two cases (12%). We failed to detect p16 gene missense mutations. The status of p16 correlated with neither histopathological factors nor with the prognosis of the patients with angiosarcomas. CONCLUSIONS: These data suggest that inactivation of the p16 gene is a frequent event in angiosarcomas of the liver. The most common somatic alteration is promotor methylation of the p16 gene. We failed to establish p16 as independent prognostic factors in these tumors.

Aged↗
PubMed2000

Author reply

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Journal Article↗
PubMed2000

Decreased expression of p27 protein is associated with advanced tumor stage in hepatocellular carcinoma.

Reduced expression of the cyclin-dependent kinase inhibitor p27 has previously been correlated with fatal clinical outcome in some tumors, including gastric, breast, and prostate cancers. For hepatocellular carcinoma, the findings are equivocal. In situ hybridization and immunohistochemistry were performed on a series of 203 curatively (R0) resected hepatocellular carcinomas and in corresponding non-cancerous liver tissue to detect p27. Patients receiving liver transplantation were excluded. The results were correlated with histopathological stage according to the UICC system, Edmondson grade, several other histopathological factors of possible prognostic significance, and finally patient survival. Whereas p27 mRNA was expressed homogeneously in all carcinomas examined, the p27 protein was found in various amounts. The labeling index of p27 protein was significantly lower in advanced stages of the disease (P < 0.001, chi(2) = 28.1). We observed decreased p27 protein in higher pT categories (P < 0.001, chi(2) = 24.7) and in multiple tumor nodules (P < 0.001, chi(2) = 9.3). Multivariate Cox survival analysis identified age, co-existing cirrhosis, and Edmondson grade as independent prognostic factors. We conclude that evaluation of p27 in hepatocellular carcinoma is useful to predict stage of disease and may have clinical significance, e.g., in predicting optimal therapeutic regimes.

Adult↗
PubMed2000

p53 mutation pattern in hepatocellular carcinoma in workers exposed to vinyl chloride.

BACKGROUND: Vinyl chloride (VC) is a known animal and human carcinogen that is associated with liver angiosarcoma and most likely also with hepatocellular carcinoma (HCC) in humans. METHODS: The authors examined the presence of p53 gene mutations in 18 HCC specimens from patients with known exposure to VC (median, 8883 parts per million-years; median duration, 245 months). In all cases, other risk factors for the development of HCC (hepatitis B virus and hepatitis C virus infections, alcohol consumption, and metabolic or autoimmune disorders) were excluded. Three patients had concomitant cirrhosis. The p53 gene was examined by direct sequencing of exons 5-9. RESULTS: Mutations of the p53 gene were found in 11 of 18 HCCs examined. The point mutations detected were comprised of five transversions and five transitions. Five of 11 mutations (codons 175, 245, 248, 273, and 282) occurred at CpG sites. Histopathologic liver alterations (mild sinusoidal dilatation, [portal] fibrosis, and centrilobular siderosis) in tumor surrounding nonneoplastic liver confirmed exposure to VC. CONCLUSIONS: The results of the current study indicated a relation between VC exposure and the development of HCC. The mutation pattern of p53 with a nearly equal rate of incidence of transitions and transversions and a high rate of incidence of mutations at CpG sites may reflect endogenous mechanisms (e.g., deamination of 5-methylcytosine) rather than exogenous carcinogens.

Aged↗
PubMed2000

Photodynamic therapy for advanced bile duct cancer: evidence for improved palliation and extended survival.

Median survival time of nonresectable hilar bile duct cancer is only 4 to 6 months owing to tumor spread in the biliary tree, refractory cholestasis, and sepsis or liver failure. We explored whether local photodynamic therapy of nonresectable bile duct cancer could improve survival. A sample size of 23 patients is required to detect an increase in 6-month survival rate from less than 50% to greater than 70% in a single-arm phase-II trial with a statistical power of 80% (Fleming's single step procedure; alpha = 0.05). Twenty-three consecutive patients (8 women, 15 men; 67 +/- 14 years) with nonresectable bile duct cancer (Bismuth type III n = 2, type IV n = 21) were treated with photodynamic therapy and biliary endoprosthesis. Photofrin (QLT Pharmaceuticals, Vancouver, Canada) (2 mg/kg body weight intravenously) was photoactivated after 1 to 4 days with laser light (630 nm; 242 J/cm(2)) via endoscopic retrograde access. The 6-month survival rate was 91% after diagnosis and 74% after start of photodynamic therapy (30-day mortality rate was 4%) at a median follow-up time of 10.3 months after diagnosis. Causes of death were tumor progression (n = 9) and bacterial infections (n = 4). The median rate of local tumor response was 74%, 54%, 29%, and 67% after the first, second, third, fourth, and fifth photodynamic therapy. Time to progression ranged from 3 to 8 months. All patients, except 1 with diffuse liver metastases, improved in cholestasis, performance, and quality of life. Photodynamic therapy can prevent tumor occlusion of hilar bile ducts. The apparent benefit in survival time should be confirmed in a controlled trial versus palliation by endoprosthesis only.

Adenocarcinoma↗
PubMed2000

Diagnosis and staging of lymph node metastasis.

The process of lymph node metastasis is not completely understood. Although we know some basic molecular mechanisms of metastasis, the exact procedure from the initiation of a primary tumour to overt lymph node metastasis remains obscure. A few morphological features of different primary tumours are known to correlate with the probability of lymph node metastasis, e.g., tumour histology (carcinoma vs. sarcoma), tumour size, T category, poor grade of differentiation and invasion of lymph vessels. Few attempts have been made to use markers of molecular differentiation such as nm23 as an additional indicator of lymph node metastasis. A drawback is the lack of an exact definition of lymph node metastasis or micrometastasis and how to include new findings such as the demonstration of cytokeratin-positive cells in "tumourfree" lymph nodes. Some of these aspects will be discussed within this review and proposals for classifications presented.

Classification↗
PubMed2000

Laparoscopic abdominoperineal resection: early postoperative results of a prospective study involving 116 patients. The Laparoscopic Colorectal Surgery Study Group.

PURPOSE: Although laparoscopic colorectal surgery is attracting ever more attention, its use for curative treatment of colorectal carcinoma in particular continues to be controversial. The present study was an attempt to analyze the results of the perioperative course, oncologic quality, and preliminary long-term results. METHOD: The data considered here were collected within the framework of a prospective, observational study initiated on August 1, 1995, and involving a total of 18 institutions in Germany and Austria. At the end of three years, the results are now being presented selectively, i.e., focusing only on abdominoperineal resection. RESULTS: A total of 116 patients underwent laparoscopic abdominoperineal resections, 98 (84.5 percent) of which were performed with curative intent. The mean operating time was 226 (confidence interval, 140-365) minutes. Seven patients (6 percent) experienced an intraoperative complication, which in more than one-half of the cases was a vascular injury involving the presacral venous plexus; the conversion rate was 3.4 percent. Postoperatively, 40 patients developed 97 complications--including those of a very minor nature--giving an overall morbidity rate of 34.4 percent. Reoperation in six patients (5.2 percent) had to be performed for an afterbleed in one-half of the cases and ileus in the other one-half. Postoperative mortality was a low 1.7 percent. In most of the curative resections, an oncologically radical operation with high transection of the inferior mesenteric artery and a complete dissection of the pelvis down to the floor was performed. The median number of lymph nodes investigated was 11.5, and there was wide fluctuation in the numbers among the individual institutions. Tumor cell dissemination occurred intraoperatively in five patients. In the meantime, 79 patients (81 percent) underwent at least one follow-up examination, the mean follow-up period being 491 days. Seven patients developed a local recurrence, and a further six patients developed distant metastases. For recurrence-free survival rate, the Kaplan-Meier estimation calculated a probability of 71 percent. CONCLUSION: Not all of the reservations about laparoscopic abdominoperineal resection, in particular with regard to resection with curative intent, have yet been eliminated. The present study does, however, show that a laparoscopic approach can in principle meet oncologic requirements of radicality and, with regard to the postoperative course, is associated with considerable benefits to the patient.

Abdomen↗