Establishment of a Mucin Secreting Cell Line Cx-03 from an Uterine Carcino Sarcoma.

PURPOSE: The identification of novel cell lines which combine the most important properties of mucosal membranes in terms of drug absorption, transmembrane transport and mucus secretion can help to establish improved and meaningful test systems for pharmacological and infectiological studies. METHODS: We have established a novel mucus secreting tumor cell line (Cx-03) derived from a female patient who underwent radical hysterectomy after diagnosis of a large malignant carcino sarcoma (Muellerian mixed tumor). Via xenotransplantation in SCID beige mice, recultivation and subcloning a stable cell line was established from primary tumor cells. RESULTS: Human origin and novelty of the cell line was determined by karyotype analysis and STR fingerprint. During growth cells produce considerable amounts of a PAS positive viscoelastic mucus. Immunostaining revealed expression of mucins and the mucin modifier CLCA1. We demonstrate in initial electrophysiological experiments that confluent, polarized monolayers of Cx-03 are formed (on PCF-filter supports) that exhibit stable electrical resistance (> 600 Ω cm2). Confluent Cx-03 monolayers express barrier-forming tight junction proteins claudin-1 and -4 which co-localize with zonula occludens protein-1 (ZO-1) at cell-cell contacts. CONCLUSIONS: Mucus secretion is a rare property among mammalian cell lines. In combination with its ability to form polarized monolayers Cx-03 might contribute as a novel cell based model for drug absorption, transport and barrier studies.

[Ichthyosis uteri (psoriasis uteri) : A very rare disorder]. / Ichthyosis uteri (Psoriasis uteri) : Ein äußerst seltener Befund.

In ichthyosis uteri, the entire endometrium is replaced by squamous, sometimes even keratotic epithelium. The etiology is discussed controversially and not fully understood. However, in most cases a chronic inflammatory stimulus is identified. An association with malignancy is possible. Therefore, adequate consecutive diagnostic procedures, as well as exact macro- and micromorphologic evaluation is mandatory. In this case report we describe this currently rare disorder and review the main literature on this topic.

Progression-free survival as surrogate end point for overall survival in clinical trials of HER2-targeted agents in HER2-positive metastatic breast cancer.

BACKGROUND: The gold standard end point in randomized clinical trials in metastatic breast cancer (MBC) is overall survival (OS). Although therapeutics have been approved based on progression-free survival (PFS), its use as a primary end point is controversial. We aimed to assess to what extent PFS may be used as a surrogate for OS in randomized trials of anti-HER2 agents in HER2+ MBC. METHODS: Eligible trials accrued HER2+ MBC patients in 1992-2008. A correlation approach was used: at the individual level, to estimate the association between investigator-assessed PFS and OS using a bivariate model and at the trial level, to estimate the association between treatment effects on PFS and OS. Correlation values close to 1.0 would indicate strong surrogacy. RESULTS: We identified 2545 eligible patients in 13 randomized trials testing trastuzumab or lapatinib. We collected individual patient data from 1963 patients and retained 1839 patients from 9 trials for analysis (7 first-line trials). During follow-up, 1072 deaths and 1462 progression or deaths occurred. The median survival time was 22 months [95% confidence interval (CI) 21-23 months] and the median PFS was 5.7 months (95% CI 5.5-6.1 months). At the individual level, the Spearman correlation was equal to ρ = 0.67 (95% CI 0.66-0.67) corresponding to a squared correlation value of 0.45. At the trial level, the squared correlation between treatment effects (log hazard ratios) on PFS and OS was provided by R(2) = 0.51 (95% CI 0.22-0.81). CONCLUSIONS: In trials of HER2-targeted agents in HER2+ MBC, PFS moderately correlates with OS at the individual level and treatment effects on PFS correlate moderately with those on overall mortality, providing only modest support for considering PFS as a surrogate. PFS does not completely substitute for OS in this setting.

Ki67 levels as predictive and prognostic parameters in pretherapeutic breast cancer core biopsies: a translational investigation in the neoadjuvant GeparTrio trial.

BACKGROUND: The proliferation marker Ki67 has been suggested as a promising cancer biomarker. As Ki67 needs an exact quantification, this marker is a prototype of a new generation of tissue-based biomarkers. In this study, we have systematically evaluated different cut points for Ki67 using three different clinical end points in a large neoadjuvant study cohort. PATIENTS AND METHODS: We have evaluated pretherapeutic Ki67 levels by immunohistochemistry in 1166 breast cancer core biopsies from the neoadjuvant GeparTrio trial. We used the standardized cutoff-finder algorithm for three end points [response to neoadjuvant chemotherapy (pCR), disease-free (DFS) and overall-survival (OS)]. The analyses were stratified for hormone receptor (HR) and HER2 status by molecular subtype radar diagrams (MSRDs). RESULTS: A wide range of Ki67 cut points between 3%-94% (for pCR), 6%-46% (for DFS) and 4%-58% (for OS) were significant. The three groups of Ki67 ≤ 15% versus 15.1%-35% versus >35% had pCR-rates of 4.2%, 12.8%, and 29.0% (P < 0.0005), this effect was also present in six of eight molecular subtypes. In MSRD, Ki67 was significantly linked to prognosis in uni- and multivariate analysis in the complete cohort and in HR-positive, but not triple-negative tumors. CONCLUSIONS: Ki67 is a significant predictive and prognostic marker over a wide range of cut points suggesting that data-derived cut point optimization might not be possible. Ki67 could be used as a continuous marker; in addition, the scientific community could define standardized cut points for Ki67. Our analysis explains the variability observed for Ki67 cut points in previous studies; however, this should not be seen as weakness, but as strength of this marker. MSRDs are an easy new approach for visualization of biomarker effects on outcome across molecular subtypes in breast cancer. The experience with Ki67 could provide important information regarding the development and implementation of other quantitative biomarkers.

Cerebral metastases in metastatic breast cancer: disease-specific risk factors and survival.

BACKGROUND: Survival of patients suffering from cerebral metastases (CM) is limited. Identification of patients with a high risk for CM is warranted to adjust follow-up care and to evaluate preventive strategies. PATIENTS AND METHODS: Exploratory analysis of disease-specific parameter in patients with metastatic breast cancer (MBC) treated between 1998 and 2008 using cumulative incidences and Fine and Grays' multivariable regression analyses. RESULTS: After a median follow-up of 4.0 years, 66 patients (10.5%) developed CM. The estimated probability for CM was 5%, 12% and 15% at 1, 5 and 10 years; in contrast, the probability of death without CM was 21%, 61% and 76%, respectively. A small tumor size, ER status, ductal histology, lung and lymph node metastases, human epidermal growth factor receptor 2 positive (HER2+) tumors, younger age and M0 were associated with CM in univariate analyses, the latter three being risk factors in the multivariable model. Survival was shortened in patient developing CM (24.0 months) compared with patients with no CM (33.6 months) in the course of MBC. CONCLUSION: Young patients, primary with non-metastatic disease and HER2+ tumors, have a high risk to develop CM in MBC. Survival of patients developing CM in the course of MBC is impaired compared with patients without CM.

Prognostic impact of additional extended surgical procedures in advanced-stage primary ovarian cancer.

BACKGROUND: Treatment of advanced-stage ovarian carcinoma includes radical cytoreductive surgery, which aims at removing all visible tumor tissue followed by platinum and paclitaxel chemotherapy. Complete tumor resection may require extended surgical procedures. This paper reports on the prognostic impact of extensive surgery and surgical morbidity in patients with advanced-stage ovarian carcinoma. METHODS: Patients with ovarian carcinoma [Fédération Internationale de Gynécologie et d'Obstétrique (FIGO) stage IIIB-IV] undergoing primary surgery in our tertiary gynecologic oncology unit between 1997 and 2007 were eligible for this study. The impact of established prognostic factors and the interaction with extent of surgical procedures on survival were assessed. RESULTS: A total of 267 patients aged between 29 and 88 years (median 64 years) were eligible for this study. Overall survival time was improved in patients who underwent complete tumor resection [hazard ratio (HR) 3.61 (1.91-6.61), P < 0.001]. No significant survival difference was observed between completely operated patients in whom extended or standard surgical procedures were applied [HR 1.37 (0.70-2.69), P = 0.358], and severe surgical complications were found to be equally distributed between the two patient groups. CONCLUSIONS: Our results may encourage the application of extended surgical procedures in patients who would otherwise be rendered incompletely debulked after primary cytoreduction. We could demonstrate an impact of complete tumor resection on patient prognosis and this was not traded off for extensive additional surgical morbidity.

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.

Clinicopathological differences between breast cancer in patients with primary metastatic disease and those without: a multicentre study.

OBJECTIVE: Approximately 6% of breast cancer (BC) patients present with primary metastatic disease (pmBC) at first diagnosis. The clinicopathological differences between tumours from patients who have metastatic disease and those who do not are unclear. METHODS: This study was an exploratory analysis of patients with pmBC treated in 8 German breast cancer centres between 1998 and 2010. Phenotypes were defined using the following immunohistochemical markers: oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (Her2). The control arm included the group of patients who had neither local recurrence nor distant metastases at a follow-up of at least 30 months after initial diagnosis. RESULTS: A total of 2214 patients were included. Of these, 1642 had non metastatic BC, and 572 had pmBC. Eighty-five patients (15%) with pmBC were diagnosed at stage T1. On multivariate analysis, factors associated with pmBC were as follows: positive lymph node status, grade 3, lobular histology and Luminal B phenotype (Her 2 positive). Of the sample, 197 patients (34%) with pmBC were diagnosed as stage T2, 90 patients (16%) were diagnosed as stage T3, and 200 patients (35%) were diagnosed as stage T4. Only positive lymph node status and grade 3 were reported as risk factors for distant metastases in patients with stage T3 and T4 cancer. CONCLUSION: There are differences in the clinicopathological features among breast cancer patients with primary metastases and those without. Receptor expression and histological type play a minor role in the risk for metastasis in patients with stage T3 and T4 disease when compared to patients with T1 pmBC tumours. On initial diagnosis, lobular histology and Luminal B positivity (Her 2 positive) in T1 pmBC were determined to be risk factors for primary metastatic disease.

Chemotherapy for 70-Year-Old Women with Breast Cancer in Germany: A Survey by the German Breast Group.

Aim: Around half of all women in Germany with breast cancer are older than 65 and approximately one third of them is older than 70 years of age. In theory, the preferred therapeutic management of women with breast cancer aged 65 and above corresponds to that formulated for younger patients and complies with the S3 Guidelines and the therapy recommendations formulated by AGO. To study the current therapies used to treat women with breast cancer aged 70 and above in Germany, a survey of the clinics of the German Breast Group (GBG) was done. Method: An online survey was carried out with requests sent to 599 physicians registered as principal investigators in the database of the GBG. The 12-item questionnaire was used to investigate the systematic therapeutic management of 70-year-old patients in different settings. The indication for chemotherapy was taken as a given. Results: In a neoadjuvant setting, 62 % of physicians opted for anthracycline and taxane-based therapy as did 56.6 % of physicians in an adjuvant setting. One third of physicians preferred a taxane-based therapy with the anti-angiogenesis inhibitor bevacizumab as first-line therapy for primary metastatic cancer and after anthracycline-based therapy. Capecitabine (around 30 %) and navelbine (around 20 %) were proposed as second-line neoadjuvant and adjuvant therapies after prior anthracycline- and taxane-based therapy. Conclusion: The chemotherapy regimen prescribed for women with breast cancer aged 70 and above in Germany appears to be relatively standardised and corresponds to the recommendations given in the S3 Guidelines and by the AGO Breast Committee.