Margarete Mitze

Intratumoral pO2 predicts survival in advanced cancer of the uterine cervix.

Experimental evidence suggests that the hypoxic fraction in a solid tumor may increase its malignant potential and reduce its sensitivity towards non-surgical treatment modalities (e.g. standard irradiation, certain anticancer agents). However, the clinical importance of tumor hypoxia remains uncertain since valid methods for the routine measurement of intratumoral O2-tensions in patients have so far been lacking. A clinically applicable standardized procedure has been established which enables the determination of intratumoral oxygen tensions in advanced cervical cancers by use of a computerized polarographic needle electrode histography system. Tumor oxygenation as measured by this method represents a novel tumor feature which can be individually determined for each tumor and which is independent from other known oncological parameters. The results of an interim analysis of an open prospective clinical trial to evaluate the prognostic significance of tumor oxygenation based on the survival data of the first 31 patients are presented. Fifteen patients have been treated by primary radiation, 11 patients received multimodality therapy including irradiation. After a median follow-up of 19 months (range 5-31 months), Kaplan-Meier-life table analysis showed significantly lower survival and recurrence-free survival for patients with a median pO2 of < or = 10 mmHg compared to those with better oxygenated tumors (median pO2 > 10 mmHg). The Cox proportional hazards model revealed that the median pO2 and the clinical stage according to the FIGO are independent, highly significant predictors of survival and recurrence-free survival. We conclude from these preliminary results that tumor oxygenation as determined with this standardized procedure appears to be a new independent prognostic factor influencing survival in advanced cancer of the uterine cervix.

Hypoxia and radiation response in human tumors

This study demonstrates by an updated analysis of an ongoing prospective study that tumor oxygenation, as measured with a validated standardized polarographic needle electrode method before treatment, powerfully predicts the prognosis of patients receiving radiotherapy for intermediate and advanced stage cancer of the uterine cervix. First evidence for a host component in tumor oxygenation based on a significant correlation between median pO(2) values determined in normal subcutaneous fatty tissue and in cervical cancer is also presented. Further investigations are necessary to clarify whether tumor hypoxia is just a marker of intrinsic tumor aggressiveness or whether the negative impact of tumor hypoxia on survival is related to radiobiological mechanisms caused by hypoxia per se, which may include (1) the reduced oxygen enhancement effect, (2) increased radioresistance due to expression of genes for cell cycle delay and stress proteins, and/or (3) accelerated tumor progression to more radioresistant and metastatic variants by increased genetic heterogeneity.

Biological and prognostic significance of stratified epithelial cytokeratins in infiltrating ductal breast carcinomas.

Abstract The biological significance of the differential expression of cytokeratin (CK) polypeptides in breast carcinomas is unclear. We examined the CK profiles of 101 primary infiltrating ductal breast carcinomas using monoclonal antibodies directed against 11 different CKs and against vimentin. Two major CK phenotypes were distinguished: first, a phenotype expressing only the simple-epithelial CKs 7 (variably), 8, 18 and 19, and secondly, a bimodal phenotype co-expressing significant amounts of one or more of the stratified-epithelial CKs 4, 14 and 17. The vast majority of G1 and G2 carcinomas had the simple-epithelium phenotype, as did a subgroup of G3 carcinomas. Interestingly, the majority (62%) of G3 carcinomas exhibited the bimodal phenotype, with the expression of CKs 4, 14 and 17 being statistically correlated with poor histological differentiation and absence of steroid hormone receptors. The distribution of vimentin only partially overlapped with that of these stratified-epithelial CKs. Prognostic analyses suggested that the presence of CKs 4, 14 and/or 17 was associated with short overall and disease-free survival in subgroups comprising G3, oestrogen-receptor-negative and vimentin-negative tumours. In node-positive tumours the correlation between these CKs and a shorter disease-free interval attained statistical significance (log rank, 0.0096). Thus, abnormal CK profiles in ductal breast carcinomas appear to reflect disturbed regulation of differentiation-related gene expression programmes and may prove to be of clinical value.

Immunohistochemical evaluation of growth fractions in human breast cancers using monoclonal antibody Ki-67

SummaryWe performed immunohistochemical analyses of 568 breast/cancer specimens using Ki-67, a monoclonal antibody specific for a nuclear antigen present in proliferating cells. The specimens were divided into three groups (I–III) according to the proportion of Ki-positive cells detected. These findings were compared with features of tumor extension as well as with certain prognostic variables.There was no detectable correlation between Ki-67 reactivity and either tumor size or node involvement. In contrast, a statistically significant correlation was found between Ki-67 reactivity and tumor grading, in that G-I tumors had small growth fractions, while a high proportion of G-III tumors exhibited strong (group III) Ki-67 positivity. When growth fractions were compared with biochemical receptor status, a significant difference was detected between tumors with negative and positive findings for receptors. The same co-variation was observed with respect to the overexpression ofneu-protein P185, with mostneu-positive carcinomas being strongly positive for Ki-67 (group III).In the relapse cases examined, there was a close correspondence between Ki-67 reactivity and the duration of the disease-free period. Long-term observation of patients with primary breast carcinoma revealed that, with regard to overall survival, the less reactive groups I and II differed significantly from group III. With respect to disease-free survival, no difference was detectable between Ki-groups II and III, but when these two groups together were compared with group I, a significant trend emerged. Similar results for both overall and disease-free survival were obtained for subgroups of pT2 and G-II carcinomas as well as for receptor expression. Node-negative tumors in the highly reactive group III exhibited a strong trend indicating unfavorable overall survival rates, whereas no such difference was demonstrable with respect to disease-free survival. Node-positive tumors could not be differentiated on the basis of overall survival, but the correlation with growth fraction was significant for disease-free survival.In conclusion, Ki-67 offers a simple and effective method for defining the proliferating cell compartment of breast carcinoma, and may facilitate the assessment of individual tumors as well as efforts to predict the course of disease.

Peanut lectin histochemistry of 120 mammary carcinomas and its relation to tumor type, grading, staging, and receptor status

Peanut lectin (PNL) is known to bindβ-d-galactosyl-(1-3)-N-acetyl-d-galactosamine, which provides antigenetic determination of the Thomsen-Friedenreich antigen (TFAg). The aim of this study was to analyse the expression of peanut lectin binding sites in mammary carcinomas and to correlate these with tumor type, histological grading, staging and biochemical receptor status. The series comprised 120 invasive mammary carcinomas and 14 cases with normal breast tissue or benign epithelial proliferations as controls. In controls mainly luminal or apical PNL-binding was discovered, however, in all except three carcinomas a cytoplasmatic localisation of TFAg with three major patterns was found: diffuse, granular-globular and vacuolar reactions. The quantitative-qualitative evaluation of the PNL-staining revealed a statistically significant correlation between globular-vacuolar PNL-reaction and tumor type with a higher percentage of this type of reaction in invasive lobular carcinomas as opposed to tubular and invasive ductal carcinomas. Furthermore a statistically significant relationship was disclosed between PNL-histopositivity and estrogen positive - progesterone positive cases. However, the findings of contradictory PNL-status and hormone-receptor status illustrates clearly the difficulty of predicting the biochemical receptor status. No correlation was found between PNL-histochemistry, histological grading, and pathological staging. The practical implications of PNL-histochemistry of mammary carcinomas are discussed.

Imunohistochemical Demonstration of Carcinoembryonic Antigen (CEA) in 120 Mammary Carcinomas and its Correlation with Tumor Type, Grading, Staging Plasma-CEA, and Biochemical Receptor Status

Antisera to CEA were used for the immunohistochemical localization and quantification of this antigen in 120 Bouin-fixed, paraffin embedded mammary carcinomas. These results were compared to tumor type, grading, staging, biochemical receptor status, cytosolic CEA-levels of the same tumors, and preoperative plasma CEA-levels. Mammary carcinomas were usually characterized by a low percentage of CEA-positive tumor cells: 50.9% of the cases contained more than 5% CEA-positive tumor cells and were therefore defined as being CEA-histopositive in this study. A relation could be shown between CEA-histopositivity and the histologic tumor type. The majority of invasive lobular carcinomas, tubular, and cribriform carcinomas was CEA-negative (72%). Conversely, 70% of invasive ductal carcinomas were CEA-positive. There was a significantly higher percentage of CEA-histopositivity in grade III tumors than in grade I/II carcinomas. The results obtained by quantification of the immunohistochemical staining of CEA were positively correlated with the results obtained by cytosolic CEA-assay. The overall concordance between tissue and plasma determinations of CEA was found to be 57.1%. A positive trend could be found between CEA-positivity and staging. However, no correlation was observed between CEA-positivity and estrogen receptor status.

Value of routine abdominal and lymph node sonography in the follow-up of breast cancer patients

OBJECTIVE The aim of this study was to review usefulness and intervals for abdominal sonography during the follow-up of breast cancer patients. Additionally, we assessed the value of regional lymph node sonography in patients with possible locoregional recurrence. SUBJECTS Retrospectively, 2657 abdominal ultrasound examinations of 414 patients and 299 sonographic examinations of the regional lymph nodes in 227 patients after surgical treatment for breast cancer were evaluated. RESULTS Follow-up abdominal sonography revealed metastases in 6.8% of patients, and in 1% of examinations. There was no dependence on the initial T- or N-stage. At sonography of the regional lymph nodes in patients with suspicious palpatory findings metastatic nodes were found in 15.9% of patients, and in 12% of examinations. CONCLUSION Risk-adapted follow-up intervals for abdominal sonography cannot be proposed, regular examinations are not recommended. Lymph node sonography is useful and promising in the evaluation of suspicious palpatory findings.

C-erbB-2-oncogene expression in breast carcinoma: Analysis by S1 nuclease protection assay and immunohistochemistry in relation to clinical parameters

The c-erbB-2 mRNA was detected by the S1 nuclease protection assay and Northern blotting in breast cancer tissues. In contrast to the Northern blot analysis which has been used in all recent publications concerning c-erbB-2 expression on the level of RNA, the S1-nuclease protection assay has distinct advantages with respect to sensitivity, reproducibility, and handling of radioactive probes. We compared the expression of c-erbB-2 in 120 breast carcinomas which were operated in the years 1989-1990 on the level of the mRNA (S1 nuclease protection assay) and the protein (immunohistochemistry), respectively. In general, results obtained with both methods were in good agreement. Only minor differences in classification were observed with 18 samples, all of them belonging to either the moderate or the weak c-erbB-2 expression phenotype. In addition, the level of c-erbB-2-protein was investigated by immunohistochemistry in 271 breast carcinomas which were operated in the years 1984-1987. Comparison of the level of c-erbB-2 expression with the patient history indicates that patients whose tumors had already metastasized to the axillary nodes showed a reduced overall and disease-free survival in the group with pronounced expression of the c-erbB-2 protein. Thus the strong expression of c-erbB-2 oncogene in primary breast cancers appears to be an additional and particular prognostic factor in lymph node positive patients.

Tumor Oxygenation and Tumor Vascularity: Evidence for Their Clinical Relevance in Cancer of the Uterine Cervix and Considerations on Their Potential Biological Role in Tumor Progression

Most solid malignancies are thought to be derived from a single neoplastic precursor cell having lost proliferation control and gained the ability to penetrate basement membranes and to invade into the stroma. During the disease course tumors increase their overall cell number by local expansion and the development of regional and distant metastases. Along with the increase in cell number the tumors loose hormonal or other external signal dependencies and acquire resistances towards radio— and chemotherapy. The progressing disease causes symptoms through impaired tissue/organ functions and complications, and finally kills the individual (unless other causes leading to death become manifest earlier).