Diagnosis, Therapy and Follow-up Care of Vulvar Cancer and its Precursors. Guideline of the DGGG and DKG (S2k-Level, AWMF Registry Number 015/059, November 2015.

Purpose: This is an official guideline, published and coordinated by the Arbeitsgemeinschaft Gynäkologische Onkologie (AGO, Study Group for Gynecologic Oncology) of the Deutsche Krebsgesellschaft (DKG, German Cancer Society) and the Deutsche Gesellschaft für Gynäkologie und Geburtshilfe (DGGG, German Society for Gynecology and Obstetrics). The number of cases with vulvar cancer is on the rise, but because of the former rarity of this condition and the resulting lack of literature with a high level of evidence, in many areas knowledge of the optimal clinical management still lags behind what would be required. This updated guideline aims to disseminate the most recent recommendations, which are much clearer and more individualized, and is intended to create a basis for the assessment and improvement of quality care in hospitals. Methods: This S2k guideline was drafted by members of the AGO Committee on Vulvar and Vaginal Tumors; it was developed and formally completed in accordance with the structured consensus process of the Association of Scientific Medical Societies in Germany (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften, AWMF). Recommendations: 1. The incidence of disease must be taken into consideration. 2. The diagnostic pathway, which is determined by the initial findings, must be followed. 3. The clinical and therapeutic management of vulvar cancer must be done on an individual basis and depends on the stage of disease. 4. The indications for sentinel lymph node biopsy must be evaluated very carefully. 5. Follow-up and treatment for recurrence must be adapted to the individual case.

Prognostic Factors for Local, Loco-regional and Systemic Recurrence in Early-stage Breast Cancer.

Aim: The risk of recurrence in breast cancer depends on factors such as treatment but also on the intrinsic subtype. We analyzed the risk factors for local, loco-regional and systemic recurrence, evaluated the differences and analyzed the risk of recurrence for different molecular subtypes. Material and Methods: A total of 3054 breast cancer patients who underwent surgery followed by adjuvant treatment at HSK hospital or Essen Mitte Hospital between 1998 and 2011 were analyzed. Based on immunohistochemical parameters, cancers were divided into the following subgroups: luminal A, luminal B (HER2-), luminal B (HER2+), HER2+ and TNBC (triple negative breast cancer). Results: 67 % of tumors were classified as luminal A, 13 % as luminal B (HER2-), 6 % as luminal B (HER2+), 3 % as HER2+ and 11 % as TNBC. After a median follow-up time of 6.6 years there were 100 local (3.3 %), 32 loco-regional (1 %) and 248 distant recurrences (8 %). Five-year recurrence-free survival for the overall patient collective was 92 %. On multivariate analysis, positive nodal status, TNBC subtype and absence of radiation therapy were found to be independent risk factors for all forms of recurrence. Age < 50 years, tumor size, luminal B (HER2-) subtype and breast-conserving therapy were additional risk factors for local recurrence. Compared to the luminal A subtype, the risk of systemic recurrence was higher for all other subtypes; additional risk factors for systemic recurrence were lymphatic invasion, absence of systemic therapy and mastectomy. Conclusion: Overall, the risk of local and loco-regional recurrence was low. In addition to nodal status, subgroup classification was found to be an important factor affecting the risk of recurrence.

Additional prognostic value of lymph node ratio over pN staging in different breast cancer subtypes based on the results of 1,656 patients.

PURPOSE: Although the impact of lymph node ratio (LNR: ratio of metastatic to resected LNs) in breast cancer (BC) has been investigated, its prognostic value in molecular subtypes remains unclear. Our aim was to evaluate the impact of LNR compared to pN-stage in BC subtypes. PATIENTS/METHODS: We analyzed the impact of LNR and pN-stage on disease-free (DFS) and overall survival (OS) in 1,656 patients with primary BC who underwent primary axillary surgery (removal of ≥10 LNs) between 1998 and 2011. The cut-off points for LNR were previously published. Using immunohistochemical parameters tumors were grouped in luminalA, luminalB/HER2-, luminalB/HER2+, HER2+ and triple negative (TNBC). RESULTS: For the entire cohort 5/10-year DFS and OS rates were 88/77% and 88/75%, respectively. LNR and pN-stage were independent prognostic parameters for DFS/OS in multivariate analysis in the entire cohort and each molecular subgroup (p < 0.001). However, increasing LNR seemed to discriminated 10-year DFS slightly better than pN-stage in luminalA (intermediate/high LNR 65/44% versus pN2/pN3 71/53%), luminalB/HER2- (intermediate/high LNR 48/24% versus pN2/pN3 41/42%), and TNBC patients (intermediate/high LNR 49/24% versus pN2/pN3 56/33%). CONCLUSIONS: LNR is an important prognostic parameter for DFS/OS and might provide potentially more information than pN-stage in different molecular subtypes.

Influence of diabetes mellitus and nodal distribution in endometrial cancer and correlation to clinico-pathological prognostic factors.

OBJECTIVE: The aim of this study was to describe the relationships between the distribution of nodal disease, clinico-pathological patterns and recurrence and survival in surgically staged cases of endometrial cancer. METHODS: Charts were abstracted from patients with endometrial carcinoma from 1985 to 1995. Data on clinicopathologic variables, adjuvant treatment, site of recurrence and survival were collected. The chi square test was used to test associations between variables. The Kaplan-Meier method was used for survival analysis and Cox's proportional hazards model for multiple regression analysis. RESULTS: Sixty-nine out of 181 patients underwent lymph node dissection. Twenty-three had pelvic lymph node dissection, 23 underwent pelvic and paraaortic lymph node dissection and 20 patients had lymph node sampling. The median count of removed lymph nodes was 22.4. Fifty-four lymph node dissections showed negative lymph nodes and in 15 cases there was a minimum of one positive lymph node. Overall survival was in correlation to nodal involvement with a p value of 0.0017. Patients with lymph node involvement showed significantly more recurrence than patients with negative lymph nodes (p = 0.003). The depth of myometrial invasion correlated with lymph node metastasis (p = 0.01) and patients with additional diabetes mellitus showed significantly more nodal involvement (p = 0.02). CONCLUSION: Endometrial cancer showed pelvic lymph node (PLN) and paraaortic lymph node (PALN) involvement. Under-diagnosis of the disease might result if there was only a PLN, but with or without PALN involvement there was no significant difference in overall survival or recurrence. There was an univariate correlation between lymph node involvement and diabetes.

[Plastic reconstructive procedures of vulvar carcinoma: results and complications]. / Plastisch-rekonstruktive Vulvachirurgie -- Ergebnisse und Komplikationen.

PURPOSE: This study describes the results of the plastic reconstructive measures in 207 patients with a primary or a recurrent vulvar cancer. These procedures were analysed in sight of surgical excision, previous therapy, and detailed postoperative results. METHODS: All procedures and clinical parameters were recorded standardized in a data bank and analysed using statistical methods. RESULTS: In 123 local (cutaneous or fasciocutaneous) and 84 regional (myocutaneous) flaps we found a primary healing in about 2/3 of the cases. Local flaps exhibited secondary healing in 31 %, regional flaps in 20 %. This often involved the donor sites and generally did not present any permanent problems. Pronounced healing disturbances (necrosis of more than 10 %) was not achieved in local flaps, in regional flaps it aroused in 5.9 %. Gluteal femoral flaps were used most frequently and showing the best results of all myocutaneous flaps. They were comparable with the local reconstructions by a high degree of reliability and healing. In 15 cases a tissue-loss was observed. In these patients, elevated risk factors, certain oncological characteristics and technical problems could be demonstrated. CONCLUSION: Plastic surgery enlarges the spectrum of operative therapy of vulvar cancer, especially in extensive or recurrent tumors, leading to a favourable oncological outcome and good cosmetic results. Severe healing disturbances are rare and can be controlled.

Reconstructive surgery following resection of primary vulvar cancers.

OBJECTIVE: This study describes the surgical treatment and follow-up of 213 patients with primary vulvar cancer; particular attention is given to reconstructive surgical procedures. METHODS: The clinical and pathological parameters of the patients were recorded according to standardized procedures, and the data concerning type of operation, surgical reconstruction and postoperative course of disease (recurrence-free and overall survival) were analyzed. RESULTS: In about one-third of the cases, plastic surgery reconstruction involving skin-flaps was performed. In the present group of patients, plastic surgery procedures led to an elevated degree of operability as well as to more satisfactory results in terms of wound healing. For minor cosmetic defects, local (fasciocutaneous) skin-flaps resulted in excellent wound healing and short periods of in-patient treatment, even in patients with larger tumors. In cases exhibiting more severe wounds extending over larger areas of the vulva and its surrounding regions, similarly encouraging results were achieved using regional (myocutaneous) skin-flaps. CONCLUSION: The present study shows that reconstructive surgery of the vulva leads to good results in patients with vulvar cancer. Plastic surgery enlarges the spectrum of available operative therapy in vulvar cancer, especially in large tumors, and its application leads to a favorable oncological outcome as well as excellent cosmetic results in patients with vulvar cancer.

[Stereotactic vacuum-assisted breast biopsy - analysis of 166 cases]. / Stereotaktische Vakuumbiopsie der Brust - Eine Analyse von 166 Fällen.

OBJECTIVE: Screening mammography (as planned in Germany) will lead to an increasing number of breast biopsies. The purpose of this study was to determine the promise of directional large core biopsy as a patient-protecting therapeutic method. MATERIAL AND METHODS: 166 vacuum assisted, X-ray-guided biopsy procedures were analysed. RESULTS: Histopathologic examination resulted in 75.8 % benign lesions. Atypical proliferation and noninvasive neoplasia was found in 18.6 %, invasive carcinoma in 5.4 % of the biopsies. Complications were few. Neither skin- or chestwall injuries, nor pain or intraoperative bleeding caused an abortion. Postoperative we found four cases of bleeding, further on in 28.3 % a superficial, in 3 % a larger and deep hematoma, but in total without any operative revision. No infection was diagnosed. In the average 17.2 (8-31) specimens were removed. After excision of 18 probes the definitive histopathologic diagnosis was clear in all cases, also, the microcalcifications were found. The underestimation rate amounted to 3 of 35 cases. CONCLUSIONS: This clinical study proves stereotactic vacuum-assisted biopsy as a relieable method for analysing indeterminate mammographically detected breast lesions, which shows lower rates of complications than conventional surgical procedures.

p53 expression and resistance against paclitaxel in patients with metastatic breast cancer.

PURPOSE: Paclitaxel is an important agent in the pharmacological treatment of metastatic breast cancer. Despite its efficacy in selected patients, the majority of patients have a resistance against paclitaxel. The aim of this study was to identify the responding patients and hence prevent the other patients from ineffective treatment. Identifying these patients could spare them an ineffective treatment and could in turn characterize a subgroup of patients with a higher response rate. MATERIAL AND METHODS: Thirty-three patients with metastatic breast cancer received paclitaxel 175 mg/m(2 )either as first- (15 patients) or as second-line (18 patients) treatment. Immunohistochemistry was performed on the blocks of the primary tumors with monoclonal antibodies against p53, HER-2/ neu, P-glycoprotein, Glutathione-S-Transferase-pi, and beta-tubulin II. The expression of those factors was then correlated with the objective response to paclitaxel. RESULTS: Ten of 33 patients had an objective response to treatment. A significant correlation with the objective response was found for the expression of p53. None of the tumors with p53 expression ( n=11) responded to paclitaxel. In contrast, 10 of the 22 patients without p53 expression showed an objective response ( P=0.013). Expression of HER-2/ neu, P-glycoprotein, Glutathione-S-Transferase-pi, and beta-tubulin II did not show a correlation with the response to paclitaxel. CONCLUSION: The immunohistochemical detection of p53 characterizes patients with metastatic breast cancer unlikely to respond to paclitaxel.

[Valence of immunohistochemical analysis of endometrial carcinoma biopsy specimen]. / Wertigkeit der Abradathistologie von Endometriumkarzinomen.

OBJECTIVE: We compared immunohistological examination of endometrium biopsy specimen with the results of the immunohistological examination of tumor specimen to analyse the valence of this preoperative examination according to the clinico-pathological findings and overall-survival. MATERIAL AND METHOD: Between 1985 and 1995 193 women were treated of an endometrial carcinoma at the University hospital Mainz. In this group we evaluated 41 patients with enough preoperative endometrial biopsy material for a retrospective immunohistochemical analysis and complete follow-up data. The materials from diagnostic curettage were stained and analysed for oestrogen and progesterone receptor status and for MiB-1. The results were statistically analysed using Logrank-test for overall survival. RESULTS: The mean follow-up time was 49 months. We found a significant correlation between staining results of oestrogen (p-value = 0.0005) and progesterone (p-value=0.0003) receptor status with overall survival as well as for MiB-1 (p-value=0.05). The correlation of staining results between biopsy specimen results and tumor material from hysterectomy was 84-85 %. CONCLUSION: These well known prognostic factors are measurable on biopsy specimen material in same quality and high valence as on hysterectomy material.

Characterization of a human carcinosarcoma cell line of the ovary established after in vivo change of histologic differentiation.

OBJECTIVES: Cell lines are valuable in vitro models for clinical and basic research. Most ovarian cancer cell lines described are serous cystadenocarcinomas or poorly differentiated adenocarcinomas. The establishment of ovarian cancer cell lines with rare histologic differentiation is especially of interest. We describe the establishment of a carcinosarcoma cell line of the ovary after in vivo selection. METHODS: The cell line OV-MZ-22 was established from a solid tumor mass in the upper abdomen. At the time of establishment, the patient underwent secondary debulking and was pretreated with six cycles of cis-platinum/epirubicin/cyclophosphamide. Features of the cell line studied included morphology, ultrastructure, heterotransplantation, chromosome analysis, and analysis of intermediate filament proteins and actins by immunocytochemistry. RESULTS: The first histologic report of the patient described a papillary cystadenocarcinoma, which changed to a carcinosarcoma with predominantly sarcomatous differentiation at secondary debulking. This cell line is aneuploid and shows no expression of the tumor-associated antigens CA-125 and CEA, but an overexpression of MDR-1, lung resistance protein, p53, and topoisomerase I and II, but not of multidrug-resistance-associated protein. The cell line did not give rise to transplant tumors in nude mice. The histologic and immunocytochemical comparison of the primary and the relapsed tumor proved evidence of an in vivo change of differentiation from predominantly papillary cystadenocarcinoma to carcinosarcoma. Morphological characteristics and intermediate filament pattern underlined the sarcomatous differentiation and origin of this cell line. The differentiation phenotype of OV-MZ-22 cells is that of smooth-muscle cells. CONCLUSION: The change of histologic differentiation was apparently due to a selection process caused by platinum-containing chemotherapy. The origin of the cell line and its rarity make this new line an appropriate tool for further investigation.

Release of non-neuronal acetylcholine from the human placenta: difference to neuronal acetylcholine.

The synthesis and release of non-neuronal acetylcholine, a widely expressed signaling molecule, were investigated in the human placenta. This tissue is free of cholinergic neurons, i.e. a contamination of neuronal acetylcholine can be excluded. The villus showed a choline acetyltransferase (ChAT) activity of 0.65 nmol/mg protein per h and contained 500 nmol acetylcholine/g dry weight. In the absence of cholinesterase inhibitors the release of acetylcholine from isolated villus pieces amounted to 1.3 nmol/g wet weight per 10 min corresponding to a fractional release rate of 0.13% per min. The following substances did not significantly modify the release of acetylcholine: oxotremorine (1 microM), scopolamine (1 microM), (+)-tubocurarine (30 microM), forskolin (30 microM), ouabain (10 microM), 4alpha-phorbol 12,13-didecanoate (1 microM) and tetrodotoxin (1 microM). Removal of extracellular calcium, phorbol 12,13-dibutyrate (1 microM) and colchicine (100 microM) reduced the acetylcholine release between 30% and 50%. High potassium chloride (54 mM and 108 mM) increased the acetylcholine release slightly (by about 30%). A concentration of 10 microM nicotine was ineffective, but 100 microM nicotine enhanced acetylcholine release gradually over a 50-min period without desensitization of the response. The facilitatory effect of nicotine was prevented by 30 microM (+)-tubocurarine. Inhibitors of cholinesterase (physostigmine, neostigmine; 3 microM) facilitated the efflux of acetylcholine about sixfold, and a combination of both (+)-tubocurarine (30 microM) and scopolamine (1 microM) halved the enhancing effect. In conclusion, release mechanisms differ between non-neuronal and neuronal acetylcholine. Facilitatory nicotine receptors are present which are activated by applied nicotine or by blocking cholinesterase. Thus, cholinesterase inhibitors increase assayed acetylcholine by two mechanisms, protection of hydrolysis and stimulation of facilitatory nicotine receptors.

Perineal excision of a large angiomyxoma in a young woman following magnetic resonance and angiographic imaging.

BACKGROUND: Aggressive angiomyxomas are rare, arise from connective tissue of the perineum or the lower pelvis, and affect predominantly young women. CASE: We describe an unusual case of aggressive angiomyxoma in which the perineal approach was possible owing to MRI scanning and selective angiography indications. CONCLUSION: In cases of large aggressive angiomyxomas these diagnostic procedures should make it possible to decide which operative route might be best for the patient.

[Endometrial carcinoma in patients with diabetes mellitus]. / Prognostische Bedeutung einer Diabeteserkrankung beim Endometriumkarzinom.

OBJECTIVE: The purposes of this study were to analyze the relationship between clinical and pathological risk factors in endometrial cancer and additional diabetes mellitus and to clarify the correlation between additional diabetes mellitus and survival of patients with this disease. - MATERIAL AND METHODS: This analyze included 181 patients with endometrial carcinoma who were treated between 1985 and 1995 at the University hospital Mainz. Patients with sarcoma were excluded. For statistical analysis a chi(2)-test was performed for univariat analysis. A Kaplan-Meier procedure was performed for over all survival and disease free interval and COX-Regression for multivariate analysis of independence. - RESULTS: The mean follow-up period was 49 months. The mean age was 65 years. 21.8 % of the patients had an additional diabetes mellitus. These patients had a significantly deeper infiltration of the Myometrium (p-value = 0.004) and were more likely to have lymphonode metastasis (p-value = 0.02). - CONCLUSION: Our results show a correlation between Diabetes mellitus and adverse prognostic factors witch affects by the rate of lymphonode spread and overall survival.

[P53-status in primary ovarian carcinomas, ovarian metastases of neoplasms in other sites and benign ovarian tumors: predictive value in comparison to histopathological parameters]. / P53-Status in primären Ovarialkarzinomen, Ovarialmetastasen von Fremdtumoren und benignen Ovarialtumoren: Wertigkeit als Prognosefaktor im Vergleich zu histopathologischen Parametern.

OBJECTIVE: The purpose of this study was to determine whether the tumor suppressor gene p53 can be used as a prognosis factor to assess individual patient risk in primary ovarian carcinoma. MATERIALS AND METHODS: The concentration of the mutated, as well as the wild type p53 was examined in 98 cases of ovarian carcinoma. Among 98 ovarian tumors examined, 77 were primary carcinomas, 14 tumors were metastasis of foreign tumors, and 7 were benign ovarian tumors. The pan-53 ELISA from Fa. Dianova was used to test for the p53 protein. RESULTS: The p53 protein concentration exhibited a wide range in the different tissue samples. Benign tumors contained significantly lower p53 concentrations than malignant tumors. After the data was analyzed using Kaplan-Meier, a p53 concentration of 507.1 pg/ml was established as cut-off point for assessing cancer prognosis as good or poor. Patients exhibiting p53 concentrations over 507.1 pg/ml had a median life expectancy of 20 months, and patients exhibiting lower tumor concentrations of p53 had a life expectancy of over 70 months. A significant relationship between patient life expectancy could also be shown for tumor stage and type, whereas not for tumor grading. CONCLUSIONS: Based on the results of this study, the routine measurement of p53 may allow for a better prognostic assessment of life expectancy of patients with primary ovarian carcinoma.

[Value of p53, urokinase plasminogen activator, PAI-1 and Ki-67 in vulvar carcinoma]. / Untersuchungen zu p53, UPA, PAI-1 und Ki-67 beim Vulvakarzinom.

OBJECTIVE: The present study was to measure new prognostic factors including the plasminogen activator urokinase and the plasminogen inhibitor PAI-1, as well as p53 and Ki-67, a marker of proliferation and to compare the clinical value of these in relation to the classic histopathological prognostic factors. MATERIAL AND METHODS: The patient collective included 45 patients with vulvar carcinoma, both primary tumors and recurrences. RESULTS: Highly significant correlations were found for tumor diameter and thickness. According to Kaplan-Meier estimations, the influence of thickness on the prognosis had a p-value of 0.048, while the influence of diameter had a p-value of 0.029. The variable grading was also significantly associated to the probability of survival (p = 0.01). There was no statistically significant correlation between p53 and the parameters grading, degree of keratinization and Ki-67 color index. The correlation between p53 and PAI-1 as well as between UPA and PAI-1 was highly significant. According to the Kaplan-Meier estimations, Ki-67, UPA and PAI-1 had no influence on survival in our group of patients. CONCLUSIONS: For p53, the median value could be used as a divider with the median survival of patients with a p53 below 122 pg/mg protein being 151 months and with a p53 above 122 pg/mg being only 61 months. The corresponding p-value was significant at 0.0201.

Intron variants of the p53 gene are associated with increased risk for ovarian cancer but not in carriers of BRCA1 or BRCA2 germline mutations.

Two biallelic polymorphisms in introns 3 and 6 of the p53 gene were analysed for a possible risk-modifying effect for ovarian cancer. Germline DNA was genotyped from 310 German Caucasian ovarian cancer patients and 364 healthy controls. We also typed 124 affected and 276 unaffected female carriers with known deleterious BRCA1 or BRCA2 germline mutation from high-risk breast-ovarian cancer families. Genotyping was based on PCR and high-resolution gel electrophoresis. German ovarian cancer patients who carried the rare allele of the MspI restriction fragment length polymorphism (RELP) in intron 6 were found to have an overall 1.93-fold increased risk (95% confidence internal (CI) 1.27-2.91) which further increased with the age at diagnosis of 41-60 years (odds ratio (OR) 2.71, 95% CI 1.10-6.71 for 41-50 and OR 2.44, 95% CI 1.12-5.28 for 51-60). The 16 bp duplication polymorphism in intron 3 was in a strong linkage to the MspI RFLP. In BRCA1 or BRCA2 mutation carriers, no difference in allele frequency was observed for carriers affected or unaffected with ovarian cancer. Our data suggest that intronic polymorphisms of the p53 gene modify the risk for ovarian cancer patients but not in carriers with BRCA1 or BRCA2 mutations.

[Value of clinically established MRI procedures concerning the pretherapeutic evaluation of maximal tumor diameter in primary or recurrent cervix cancer in relation to palpation findings and histopathologic whole mount specimens]. / Wertigkeit klinisch etablierter MRT-Verfahren hinsichtlich der prätherapeutischen Bestimmung des maximalen Tumordurchmessers beim primären und rezidivierten Zervixkarzinom im Vergleich zum Palpationsbefund und dem histopathologischen Grossflächenschnitt.

OBJECTIVE: The maximal tumor diameter of cervical cancer is one of the most important prognosis factors concerning patients' survival. The purpose of this study was to investigate the efficiency of different MRI-procedures in relation to clinical palpation concerning pretherapeutic tumor diameter assessment. MATERIAL AND METHODS: Thirty-one patients with biopsy proven primary cervical cancer and its recurrence (n = 10), respectively, underwent dynamic and conventional MRI before further treatment. The results of maximal tumor diameters were compared to palpatory findings and then correlated to the whole mount specimen as gold standard. RESULTS: The contrast-enhanced dynamic and T2-weighted MRI allows a significantly better (p < 0.05) assessment of maximal tumor diameter of cervical cancer than the conventional T1-weighted MRI. The T2-weighted MRI showed the highest correlation (r = 0.83) in respect to the whole mount specimen up to FIGO-IIB disease. The contrast-enhanced dynamic MRI and the palpation were characterized by the highest correlation coefficients of r = 0.77, r = 0.70 respectively, in advanced cervical cancer > FIGO-IIB disease. CONCLUSIONS: The MRI procedures offer no evident advantage in relation to clinical palpation to determine the maximal tumor diameter of cervical cancer or its recurrency and seems not to be indicated generally.

Urokinase and plasminogen activator-inhibitor (PAI-1) status in primary ovarian carcinomas and ovarian metastases compared to benign ovarian tumors as a function of histopathological parameters.

Ninety-eight patients with histologically confirmed ovarian tumors (77 primary ovarian carcinomas of stages T1 to T3 according to the postoperative histopathological classification pTNM classification, 14 ovarian metastases of various origins and seven benign ovarian tumors) were investigated with regard to the concentration of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor (PAI-1) in membrane extracts of tumors. The results were correlated with the clinical course and with histopathological findings. With more advanced stage of primary ovarian carcinomas, there was a highly significant rise in the membrane concentrations of both uPA and PAI-1. However, increasing dedifferentiation of the tumors correlated only with uPA, but not with PAI-1. There was no correlation between the number of steroid receptors for estradiol and progesterone and the content of uPA or PAI-1 in the primary ovarian carcinomas. In the 14 ovarian metastases of different origins incluced in the study, the contents of uPA and PAI-1 were comparable to those of primary ovarian carcinomas. Compared with the malignant ovarian tumors, the median uPA and PAI-1 concentrations in the membrane fraction were 2.5-6 fold lower (highly significant) in the group of seven benign tumors. A cut-off value of 4.8ng/mg pellet protein for a prognostically favorable (< 4.8) or unfavorable course (> 4.8) could be determined for uPA (p = 0.0392) but not for PAI-1 on the basis of the Kaplan and Meier survival curves in the malignant primary ovarian carcinomas.

[Detection of angiogenesis-dependent parameters by functional MRI: correlation with histomorphology and evaluation of clinical relevance as prognostic factor using cervix carcinoma as an example]. / Erfassung angiogeneseabhängiger Parameter mittels funktioneller MRT: Korrelation mit der Histomorphologie sowie Abklärung der klinischen Relevanz als Prognosefaktor am Beispiel des Zervixkarzinomes.

PURPOSE: Purpose of this study is to compare functional MRI parameters with histomorphological markers of tumor microvessel density (MVD) and permeability (vascular endothelial growth factor) and to determine the ultimate value of both approaches by correlation with disease outcome in patients with primary cancer of the uterine cervix. METHOD: Pharmacokinetic parameters were calculated from contrast-enhanced dynamic MR imaging series in 37 patients with biopsy-proven primary cervical cancer. On the operative whole mount specimens, histomorphological markers of tumor angiogenesis (MVD, VEGF) were compared with the MRI-derived parameters. For MRI and histomorphological data, Kaplan-Meier survival curves were calculated and compared using logrank statistics. RESULTS: Significant (p < 0.05-0.01) associations were found between MVD and dynamic MRI parameters. No significant relationships were observed between VEGF expression and dynamic MRI parameters. Disease outcome was better assessed with dynamic MRI parameters than with the histomorphological approach. CONCLUSIONS: It is concluded that 1) the pathophysiological basis for the amplitude A in dynamic MRI is MVD but not VEGF expression; and 2) a functional, dynamic MRI approach may be more suited to assess angiogenic activity in terms of patient survival than current histomorphological-based markers of tumor angiogenesis.

Angiogenic activity of cervical carcinoma: assessment by functional magnetic resonance imaging-based parameters and a histomorphological approach in correlation with disease outcome.

Angiogenesis plays a fundamental role in tumor growth and metastasis. What is needed is a quantitative, noninvasive, and repeatable assay to estimate functional angiogenic activity of the entire tumor. The aims of the present study were to: (a) examine the relationship between functional magnetic resonance imaging (MRI)-based parameters with established histomorphological markers of tumor angiogenesis [histological microvessel density (HMVD) and vascular endothelial growth factor expression (VEGF)]; and (b) determine the ultimate value of both approaches to assess functional angiogenic active hotspots as markers of disease outcome in patients with cancer of the uterine cervix. Pharmacokinetic parameters (amplitude A, tissue exchange rate constant k21) were calculated from contrast-enhanced dynamic MRI series in 57 patients (mean age, 49 +/- 14 years) with biopsy proven uterine cervical cancer. Both pharmacokinetic parameters were correlated to histomorphologically determined areas of high HMVD and VEGF expression obtained from the operative specimens after radical surgery. In addition, the functional MRI and histomorphological data were used to assess disease outcome. A significant association was found between HMVD and the amplitude A (P < 0.001) and a less pronounced association with k21, (P < 0.05), respectively. No significant associations were found between the pharmacokinetic parameters (A, k21) and VEGF expression. When stratified into high and low median k21 groups, median k21 values >5.4 min(-1) were the only significant (P < 0.05) factors in predicting poor patient survival. None of the histomorphological markers of angiogenesis (HMVD or VEGF expression) showed any predictive power. We have found that: (a) focal hotspots of HMVD are the pathophysiological basis for differences in functional MRI; (b) areas of high microvessel density and microvessel permeability do not necessarily coincide, as demonstrated by the histomorphological and functional MRI findings; (c) the functional angiogenic activity of a tumor may not be sufficiently characterized by a histomorphological approach but rather by a functional MRI-based approach; and (d) functional MRI-based analysis may assess tumor angiogenic activity in terms of disease outcome more comprehensively than the histomorphological approach.