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C Wittekind

Publications and source records attributed to C Wittekind.

At least 73 records · Page 4Linked to original sources
PubMed2000

Frequency of p16(INK4A) alterations and K-ras mutations in intrahepatic cholangiocarcinoma of the liver.

BACKGROUND: Inactivation of the tumour suppressor gene p16 (CDKN2/MTS-1/INK4A) and K-ras mutations are among the most frequent genetic alterations in human malignancies. AIMS: To investigate the tumour suppressor gene p16 and its possible association with K-ras mutations in intrahepatic cholangiocarcinomas of the liver. METHODS: The status of p16 was evaluated in 41 cholangiocarcinomas by methylation specific polymerase chain reaction, microsatellite analysis, DNA sequencing, and immunohistochemical staining. K-ras mutations were determined by direct DNA sequencing analyses after microdissection. The results obtained were correlated with histopathological variables and patient survival. RESULTS: Hypermethylation of the 5' CpG island of the p16 gene was found in 34 of 41 (83%) carcinomas. Homozygous deletion at the p16 region was present in two (5%), and loss of heterozygosity (LOH) in eight cases (20%). We failed to detect p16 gene missense mutations. K-ras mutations were found in 22 of 41 (54%) cholangiocarcinomas and in two cases of tumour surrounding non-neoplastic liver tissue. All 22 cancers with K-ras mutations also exhibited methylated p16. We failed to observe a correlation between K-ras or p16 status and histopathological factors or prognosis of patients. CONCLUSION: These data suggest that inactivation of the p16 gene is a frequent event in cholangiocarcinoma. The most common somatic alteration is promotor methylation of the p16 gene which is closely associated with K-ras mutations. We failed to establish p16 or K-ras status as independent prognostic factors in these tumours.

Bile Duct Neoplasms↗
PubMed2000

[Current concepts of metastasis classification].

New findings of molecular pathology provide better insight in the process of metastasis. Single findings in few patients are, however, useful in being taken as parameters which signalize the individual risk of a metastasis not detectable by clinical methods. In addition they cannot be used as prognostic factors. On the other hand, there are important data which indicate a prognostic significance of so called isolated tumour cells, which can be detected by cytological or molecular methods. Current and proposed classifications of metastasis reflect the necessity, to better describe the situation of an individual patient to design an optimal therapy. Such more exact classifications will form the basis of a more differentiated therapy and will give more exact data to estimate prognosis.

Humans↗
PubMed2000

[Pathology of liver tumors].

Neoplasms of the liver may arise from any cell type within the liver parenchyma. Hepatocellular carcinoma is by far the most common primary malignant tumour of the liver in adults. Indeed, it is one of the most common tumours in the world with striking geographic differences. These incidence rates can be explained by differences in Hepatitis-Virus carrier rates which they closely reflect. Nearly 10% of malignant liver tumors are represented by cholangiocarcinoma which originates from small intrahepatic bile ducts. Hepatoblastoma accounts for approximately 5% of malignancies in childhood. Most hepatoblastomas fall into epithelial or mixed epithelial and mesenchymal categories. Fetal-type cells and embryonal-type cells represent the epithelial components. Rare primary malignant non-epithelial tumours are angiosarcomas, leiomyosarcomas or fibrosarcomas, arising from vascular or mesenchymal components of the liver respectively. All types of Hodgkin and Non-Hodgkin Lymphomas may secondarily involve the liver. Most primary hepatic lymphomas are of diffuse large B-cell type and are extremely rare.

Adult↗
PubMed2000

[Prognostic significance of proliferation markers in hepatocellular carcinoma (HCC)].

BACKGROUND: The prognosis of patients with curatively resectable hepatocellular carcinoma depends mainly on anatomic extent of the tumour and on the general condition of the patient. Given the growing evidence that proliferation indices may be of prognostic significance in hepatocellular carcinomas, identification and quantitation of proliferative capacity may be of prognostic importance. METHODS: We have compared four different methods to assess proliferation in a series of 193 curatively (R0-) resected hepatocellular carcinomas: Mitotic count, immunohistochemical assessment of the MIB-1- (Ki-67-), Antigen Proliferating Cell Nuclear Antigen (PCNA) and silverstained nucleolar organiser regions (AgNOR). The results obtained were compared with pathohistological stage (according to UICC), Edmondson Grade and with survival rate. RESULTS: In each carcinoma, we could demonstrate mitotic figures, MIB-1, PCNA and AgNOR dots in variable proportions. Significant statistical correlations were seen between Mitotic Index, the rate of nuclear positivity for MIB-1 and PCNA and the number of AgNOR dots. In univariate survival analysis tumour stage and Edmondson Grade, Mitotic Index, MIB-1 and PCNA Index and mean AgNOR-number were significant patients' survival influencing factors. Performing multivariate Cox survival analysis, Mitotic Index, concomitant cirrhosis, Edmondson Grade and patient age were the only significant independent prognostic factors. CONCLUSION: These results indicated that Mitotic Index is an additional prognostic parameter which could provide auxiliary information for patients' outcome.

Adult↗
PubMed2000

[Isolated tumor cells in primary malignant liver tumors].

The failure to reduce the mortality of patients with malignant liver tumors (hepatocellular carcinoma, cholangiocarcinoma) is probably a result of the early dissemination of cancer cells to secondary sites, which is usually missed by conventional diagnostic procedures used for tumor staging. Recent developments in the field of molecular biology enable us to detect tumor cells at a submicroscopic level. Therefore, over the past 10 years, sensitive assays have been developed to detect individual carcinoma cells disseminated to regional lymph nodes or distant organs. In contrast to colorectal and also breast cancer where disseminated tumor cells may be of additional prognostic value, few data exist for hepatocellular carcinomas. Until now, no relevant studies have been reported for cholangiocarcinoma. Alpha-fetoprotein and also albumin mRNA have been used for the detection of circulating micrometastatic tumor foci of hepatocellular carcinoma (HCC); however, the interpretation of the results has been equivocal. If hepatocyte-specific mRNAs are detected in the circulation, it is possible to infer the presence of circulating, presumably malignant, liver cells. The literature about the incidence of "micrometastases" and specificity of different assays for hepatocellular carcinomas varies tremendously. This clearly indicates the need for uniformity in protocols. For hepatocellular carcinoma, mRNA for alpha-fetoprotein and albumin is not a specific marker of circulating micrometastases, but may serve for treatment monitoring. Nevertheless, PCR-based techniques are a powerful tool in the therapeutical monitoring of hepatocellular carcinoma and will find their way into the daily practice of diagnostic histopathologists in the near future.

Bile Duct Neoplasms↗
PubMed1999

International Union Against Cancer. Classification of isolated tumor cells and micrometastasis.

BACKGROUND: Findings of isolated (disseminated or circulating) tumor cells (ITC) by immunocytochemistry and molecular pathology methods have led to varied interpretations and different applications of the TNM system. METHODS: An analysis of the relevant literature was undertaken. In addition, optional proposals for the classification of ITC, micrometastasis, and cytologic results in pleural and peritoneal washings are presented. RESULTS: Immunocytochemistry has a lower false-positive rate than nonmorphologic methods such as flow cytometry or the polymerase chain reaction; therefore the method(s) used always should be recorded. At the current time, the independent prognostic significance of ITC in regional lymph nodes and in the general circulation (blood, bone marrow, and other distant sites) is difficult to assess. To enable comparisons of treatment results and to avoid variation in staging, a finding of ITC should not be considered in the TNM and residual tumor (R) classifications, at least not at the current time. However, for future evaluation of their prognostic significance, the respective findings should be documented according to uniform criteria. CONCLUSIONS: ITC should be distinguished from micrometastasis. To investigate the independent prognostic significance of ITC and of positive lavage cytology, uniform data collection according to the proposed coding schema is recommended.

Ascitic Fluid↗
PubMed1999

Risk factors for relapse in stage I non-seminomatous germ-cell tumors: preliminary results of the German Multicenter Trial. German Testicular Cancer Study Group.

Risk factor analysis to identify low-risk patients for occult metastatic disease (vascular invasion, percentage embryonal carcinoma, MIB-I proliferation rate) yields reliable results if performed by experts. A correct prediction is possible at the 90% level. Similar accuracy, however, may be achieved if the computed tomography (CT) staging is optimized and the evaluation performed by an experienced investigator. The combination of both methods (biological risk factor analysis and CT staging) may virtually exclude the risk of relapse in a limited number of patients. However, so far, no risk factor that is able to reliably predict occult metastatic disease or relapse in clinical state I patients has been identified in prospective trials. The preliminary results of the current German Multicenter Trial suggest an inferior value of prediction for low-risk patients if risk factor analysis and/or CT staging is performed in non-specialized centers.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1999

Expression of p73 and its relation to histopathology and prognosis in hepatocellular carcinoma.

BACKGROUND: The protein p73, the first identified homologue of the tumor suppressor gene p53 (also known as TP53), has been shown to induce apoptosis (programmed cell death), but its function in tumor development has not been established. This study was undertaken to investigate the expression of p73 in liver tissue of patients with hepatocellular carcinoma (HCC) and to determine whether this expression has any impact on prognosis. METHODS: In situ hybridization and immunohistochemistry for the detection of p73 RNA transcripts and protein, respectively, were performed in tissues from 193 patients with curatively (R0-) resected HCC. Patients receiving liver transplantation were excluded. The results obtained were analyzed with respect to their association with pathohistologic stage, Edmondson grade, p53 expression status and several histopathologic factors of possible prognostic value, and, finally, with patient survival. RESULTS: RNA transcripts encoding p73 were detected by in situ hybridization in tumor cells but not in stromal, endothelial, or inflammatory cells or in cholangiocytes. Transcripts were also found occasionally in non-neoplastic hepatocytes. By immunohistochemistry, we detected p73 protein in 61 (32%) of the 193 carcinomas examined. Positive immunohistochemical staining was confined to the cell nucleus. Univariate survival analysis showed that p73 expression status was statistically significantly related to prognosis (two-sided P<.0001). Patients with p73-positive tumors had a poorer prognosis than those with p73-negative carcinomas. Multivariate Cox survival analysis identified the age of the patient, p73 expression status, co-existing cirrhosis, and Edmondson grade as independent prognostic factors. CONCLUSION: The protein p73 is overexpressed by a subset of HCCs and could serve as a useful indicator of prognosis in patients with this disease.

Apoptosis↗
PubMed1999

Apoptosis and the expression of Fas and Fas ligand (FasL) antigen in rejection and reinfection in liver allograft specimens.

BACKGROUND AND METHODS: To investigate the frequency of apoptosis and the expression of Fas/Fas ligand (FasL) in liver allografts, we examined 97 biopsy specimens from 62 patients after orthotopic liver transplantation. The results of the biopsies were as follows: acute allograft rejection (n=32); hepatitis C virus (HCV) reinfection (n=18); cytomegalovirus infection (n=5); acute rejection plus HCV reinfection (n=3); and stable graft function (n=30); and after treatment of acute rejection (n=9). RESULTS: Apoptotic cells were found in all cases examined, and their frequency increased significantly during acute rejection (0.17 vs. 9.0; P<0.05). The immunoreactivity of Fas and FasL antigen was higher in specimens with acute rejection than in those with stable graft function. Increased apoptosis, Fas, and FasL expression, however, were also seen in HCV reinfection. CONCLUSION: We conclude that apoptosis plays an important role in the hepatocellular damage observed in acute rejection and also in HCV reinfection. However, these parameters are, taken by themselves, not useful as indicators of acute rejection or HCV reinfection.

Apoptosis↗
PubMed1999

Apoptosis and proliferation in relation to histopathological variables and prognosis in hepatocellular carcinoma.

The prognosis of patients with resectable hepatocellular carcinoma depends mainly on the anatomical extent of the tumour and on the general condition of the patient. Given the growing evidence that proliferation indices may be of prognostic significance in hepatocellular carcinomas and that parameters of cell loss (usually, but not exclusively, due to programmed cell death) are biologically relevant, the identification and quantitation of proliferative capacity and apoptosis may be of prognostic importance. In this study four different methods have been used to assess proliferation in a series of 193 curatively (R0) resected hepatocellular carcinomas: mitotic count, immunohistochemical assessment of MIB-1 (Ki-67), proliferating cell nuclear antigen (PCNA), and silver-stained nucleolar organizer regions (AgNORs). Apoptosis was assessed using the in situ-end labelling (ISEL) technique in combination with morphological criteria. Patients who received liver transplantation were excluded. The results obtained were compared with histopathological stage (according to UICC), Edmondson grade, several other histopathological factors, and survival rate. Significant statistical correlations were seen between the mitotic index, the rate of nuclear positivity for MIB-1 and PCNA, and the number of AgNOR dots. In univariate survival analysis, tumour stage and Edmondson grade, mitotic index, MIB-1 and PCNA index, and mean AgNOR number were significant factors influencing patients' survival. On multivariate Cox survival analysis, mitotix index, concomitant cirrhosis, Edmondson grade, and patient age were the only significant independent prognostic factors. Apoptosis was not related to prognosis or to other parameters examined. These results indicated that mitotic index is an additional prognostic parameter which could provide auxiliary information for patients' outcome. MIB-1 and PCNA immunostaining and AgNORs showed a good correlation among themselves. Apoptosis did not predict prognosis in hepatocellular carcinoma.

Apoptosis↗
PubMed1999

[Neoadjuvant radiochemotherapy in soft tissue sarcomas. Optimization of local functional tumor control].

BACKGROUND: Adequate local control rates > 90% and acceptable functional results are the paramount goals in the treatment of soft-tissue sarcoma. Purpose of this paper is to evaluate response, long-term control, functional outcome and toxicity following neoadjuvant radiochemotherapy (RCT) in advanced and recurrent soft tissue sarcoma. PATIENTS AND METHODS: Between 1992 and 1998, a total of 23 patients in whom primary curative limb and function sparing surgery seemed impossible entered the study. Sixteen patients had primary and 7 patients recurrent sarcoma. The stages according to AJCC/UICC 1997 were as follows: rIA (2), rIIA (5) IIA (4), IIB (2), III (7), IV (3). RCT consisted of an accelerated split-course radiation (1.5 to 1.6 Gy twice daily, median total dose 60 Gy, range 60 to 64 Gy, break of 1 week after 30 Gy) with concomitant chemotherapy using adriamycin (50 mg/m2/d on days 2 and 30) and ifosfamide (1.5 g/m2/d on days 1 to 5, 29 to 33). Median follow-up was 26 months (range 2 to 92 months). RESULTS: Twenty-two patients underwent surgery with a curative (R0) resection being achieved in 20/22 (91%) patients and gross residual (R2) tumor or unclear tumor margins (RX) in 1 patient, respectively. Effective tumor-downstaging was documented in 4/22 (18%) patients (ypT0: 3 patients, ypT1: 1 patient). Long-term local tumor control after R0/RX resection remained 100%. Without prognostic impact on tumor response and local control have been the variables primary vs. recurrent tumor, grading, stage and gender. Delayed wound healing was only noted in 1/22 (5%) patients. Four patients developed distant metastases. Overall-, NED- and distant-metastases-free survival rates were 83%, 64% and 68%, respectively, at 3 years. Grade 3/4 neutropenia (WHO) was seen after 21/46 (46%) cycles of chemotherapy with 1 patient dying of septicemia. The functional results were good to excellent in 18/22 (82%) patients. CONCLUSION: Accelerated split-course radiation with 60 to 64 Gy and concurrent chemotherapy using adriamycin/ifosfamide is a safe and effective treatment for soft tissue sarcoma. This regimen may be considered in all cases with recurrent and advanced disease not amenable to primary curative or limb sparing surgery.

Adult↗
PubMed1999

Chondromatosis of the ankle joint (Reichel syndrome).

A case of chondromatosis of the upper ankle joint in childhood is described. It is a monoarticular disease with a good prognosis, frequently without known prior trauma or inflammation, although often free fragments of cartilage are seen in the joint cavities. It originates from the synovium of the joint, and is known in the literature as Reichel syndrome.

Acute Disease↗
PubMed1999

Expression of p73, a novel protein related to the p53 tumour suppressor p53, and apoptosis in cholangiocellular carcinoma of the liver.

p73, the first homologue of the tumour suppressor protein p53, was recently discovered on chromosome 1p36 and has been shown to induce apoptosis in a p53-like manner. The present study was performed with the aim of investigating the expression of p53, its new homologue p73 and the occurrence of apoptosis in cholangiocellular carcinoma. Protein levels of p73 were examined in 41 patients with curatively (R0-) resected cholangiocellular carcinomas with an antiserum, raised against a peptide in the N-terminal domain of p73. The incidence of mutations in the p53 gene was analysed by direct sequencing and also immunohistochemically. Apoptotic cell death was assessed using in-situ end-labelling (ISEL) technique in combination with morphological criteria. The results obtained were correlated with patient survival. Immunostaining of p73 protein was detected in 17/41 carcinomas examined (41%). The immunoreactivity was confined to the cell nucleus. In 15/41 patients (37%), mutations of the p53 gene were observed. Eleven out of these 15 patients stained also positive for p73. In contrast, out of 26 patients without any detectable p53 mutation, only six exhibited p73 immunostaining. We failed to observe a correlation between p73 expression or p53 and apoptosis within a given tumour. Survival analysis including the parameters stage and grade of disease, p73 and p53, and also apoptosis, showed that tumour stage and grade as well as p53 and p73 were significantly related to prognosis. In Cox regression survival analysis, however, only extent of primary tumour and lymph node status had an independent prognostic impact. Our results with a high prevalence of p73 within tumours harbouring mutated p53 gene suggest that p73 could compensate for p53 function. We failed to establish p73 or p53 as independent prognostic factors in cholangiocellular carcinoma of the liver.

Apoptosis↗
PubMed1999

Comparison of different double immunostaining protocols for paraffin embedded liver tissue.

Most of the double immunostaining protocols that have been introduced so far have been developed for application on fresh frozen material or based on different species antibodies. In liver tissue, general problems of double immunostaining techniques are further complicated by tissue-specific difficulties, such as necrosis or high intracellular protein content. To assess a reliable double immunostaining protocol for archived, paraffin embedded liver tissue, different protocols based on the use of same species primary antibodies were evaluated in terms of sensitivity, specificity and non-specific background staining in pathological liver specimens. We compared peroxidase-anti-peroxidase, alkaline phosphatase-anti-alkaline phosphatase (PAP/APAP), labelled-avidin-biotin (LAB/LAB) and digoxigenin-anti-digoxigenin (dig-a-dig/PAP) techniques using different cytokeratin antibodies and an antibody against PCNA. Comparison of the double immunostaining techniques revealed a high sensitivity and specificity in all procedures. Sections, which were stained employing PAP/APAP-technique, displayed a higher background staining compared to sections which were treated with the LAB/LAB or dig-a-dig/PAP protocol. In contrast to the dig-a-dig/PAP protocol, the LAB/LAB technique provides a better time/cost relationship. Therefore, we would like to recommend a modified LAB/LAB protocol for simultaneous detection of different antigens in archived liver tissue.

Animals↗
PubMed1998

Apoptosis, proliferation, bax, bcl-2 and p53 status prior to and after preoperative radiochemotherapy for locally advanced rectal cancer.

PURPOSE: To investigate the relationship between apoptotic cell death, proliferative activity, and the expression of apoptosis regulating proteins in rectal cancer prior to and after radiochemotherapy. MATERIALS AND METHODS: In 32 patients dispositioned to receive preoperative radiochemotherapy for locally advanced rectal carcinoma, pretherapy biopsies and the final resected specimen after radiochemotherapy were available for analyses. Apoptotic cells were identified and quantified using in situ end labeling (ISEL) technique. The expression of the bax protein was assessed immunohistochemically. Additionally, double immunostaining was performed for apoptotic cells and bax expression. The proliferative activity was determined by immunohistochemical assessment of the Ki67 (MIB-1) and the proliferating cell nuclear antigen (PCNA). p53- and bcl-2 expression was analyzed immunohistochemically. A clinical-to-pathologic downstaging after radiochemotherapy was achieved in 25 of 32 patients (78%). During follow-up, tumor recurrence was observed in six cases. In one case, no residual tumor was detected after radiochemotherapy. RESULTS: After radiochemotherapy, the apoptotic index increased significantly in almost every case examined. In contrast, the proliferative activity was significantly decreased in resected specimens as compared to biopsies. Bax immunostaining was detected in 12/31 (39%) biopsies and in 26/31 (84%) resected specimens. In the resected specimen, significantly more apoptotic cells that were bax-positive were found than in biopsies. Bcl-2 immunostaining occurred in 15/31 biopsies and 12/31 resected specimens, respectively. Tumors that were immunohistochemically negative for p53 (20/31 [65%]) generally exhibited a higher apoptotic index and a high expression level of bax than p53-positive tumors (11/31 [35%]). However, we did not find any correlation between the (pre- and post-therapeutic) rate of apoptosis or the level of bax expression and the degree of clinical-to-pathologic downstaging or the frequency of tumor recurrence. CONCLUSION: Our results indicate that radiochemotherapy is associated with an increase in bax expression and also in apoptotic cell death. The observation of higher rates of apoptosis and bax in p53-negative tumors suggests that p53 might be a possible regulating factor of apoptosis in rectal cancer.

Adult↗