Genetic Breast Cancer Susceptibility Variants and Prognosis in the Prospectively Randomized SUCCESS A Study.

Large-scale genotyping studies have identified over 70 single nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk. However, knowledge regarding genetic risk factors associated with the prognosis is limited. The aim of this study was therefore to investigate the prognostic effect of nine known breast cancer risk SNPs. BC patients (n = 1687) randomly sampled in an adjuvant, randomized phase III trial (SUCCESS A study) were genotyped for nine BC risk SNPs: rs17468277 (CASP8) , rs2981582 (FGFR2) , rs13281615(8q24), rs3817198 (LSP1) , rs889312 (MAP3K1) , rs3803662 (TOX3) , rs13387042(2q35), rs4973768 (SLC4A7) , rs6504950 (COX11) . Cox proportional hazards models were used to test the SNPs' association with overall survival (OS) and progression-free survival (PFS). Additional analyses were carried out for molecular subgroups. rs3817198 in LSP1 (lymphocyte-specific protein 1) was the only SNP that significantly influenced OS (p = 0.01) and PFS (p < 0.01) in the likelihood ratio test comparing the genetic survival model with the clinical survival model. In the molecular subgroups, triple-negative patients with two minor alleles in rs3817198 had a much better prognosis relative to OS (adjusted HR 0.03; 95% CI 0.002 - 0.279) and PFS (HR 0.09; 95% CI 0.02 - 0.36) than patients with the common alleles. The same effect on PFS was shown for patients with luminal A tumors (HR 0.19; 95% CI 0.05 - 0.84), whereas patients with luminal B tumors had a poorer PFS with two minor alleles (HR 2.13; 95% CI 1.02 - 4.40). The variant in rs3817198 has a prognostic effect particularly in the subgroup of patients with triple-negative BC, suggesting a possible link with immunomodulation and BC.

Adjuvant sequential chemoradiation therapy in high-risk endometrial cancer: results of a prospective, multicenter phase-II study of the NOGGO (North-Eastern German Society of Gynaecological Oncology).

PURPOSE: The management of high-risk endometrial cancer (HREC) remains controversial. We conducted a prospective multicenter phase-II clinical trial to evaluate an adjuvant chemotherapy (CT) with sequential radiotherapy (RT) in patients with HREC. METHODS: Patients with HREC from 8 institutions in Germany were enrolled. After surgery, patients received four cycles of paclitaxel 175 mg/m² (P) and carboplatin AUC5 (C) (d1, q21d) and subsequent external pelvic radiation therapy (1.8 Gy/d, d1-5) at a total dose of 45 Gy with vaginal brachytherapy (3 × 5 Gy). Quality of life (QoL) was assessed using the EORTC-QLQ-C30 questionnaire. Primary endpoints were tolerability, toxicity and QoL. Progression-free survival (PFS) was defined as secondary endpoint. RESULTS: Thirty-five patients were enrolled from 2004 through 2008. Median follow-up was 24 months (range 3-24 months). All patients received 4 cycles of P and C and completed RT. Overall, grade 3/4 haematological toxicity was 25.6 %. Three cycles were delayed because of leukopenia. Grade 3/4 non-haematologic toxicities were rare (≤3 %). No overall change in QoL occurred during treatment. Two-year median PFS and OS rates were both 75.8 %. CONCLUSIONS: Adjuvant combination CT with P + C and sequential RT is well tolerated and a feasible regimen in patients with HREC. Subsequent phase-III trials are warranted.

Role of serum concentration of VEGFR1 and TIMP2 on clinical outcome in primary cervical cancer: results of a companion protocol of the randomized, NOGGO-AGO phase III adjuvant trial of simultaneous cisplatin-based radiochemotherapy vs. carboplatin and paclitaxel containing sequential radiotherapy.

OBJECTIVE: Aim of the present study was to analyze the expression-profile of IGF1, IGFBP3, sICAM1, sVCAM1, MMP2, MMP9, TIMP2, VEGFA, VEGFD, VEGFC and VEGFR1 in patients with high-risk FIGO-stage Ib-IIb cervical cancer. METHODS: Serum from 68 cervical cancer patients treated within a phase-III-trial with either simultaneous cisplatin radiochemotherapy or sequential systemic carboplatin and paclitaxel followed by percutaneous irradiation was analyzed by ELISA. Both target expression and correlation with important clinicopathological factors were analyzed following standard statistic procedures. RESULTS: All 68 patients underwent a primary radical hysterectomy with pelvic and/or paraaortic lymphadenectomy. 85.3% of the extirpated tumors had clear surgical margins (R0). Increased levels of VEGFR1, TIMP2 and MMP2 were significantly associated with positive surgical margins (p=0.004, p=0.018 and p=0.004, respectively). High concentration of MMP2 and TIMP2 correlated additionally with an advanced age at time of diagnosis (p=0.001 and p=0.007, respectively). For the cut-off value of 100 pg/ml, an increased VEGFR1 was significantly associated with poor overall (OS) and progression-free (PFS) survival (p=0.017 and p=0.015, respectively). A TIMP2 concentration of lower than 90 ng/ml was significantly associated with poorer OS and PFS (p=0.009 and p=0.043, respectively). In the multivariate analysis, TIMP2 expression in serum was the only independent prognostic factor for OS (p=0.032, HR=6.51, 95% CI=1.17-36.01). CONCLUSIONS: Expression-profile of specific biomarkers associated with tumor invasion, cell migration and angiogenesis seems to be of prognostic value for both OS and PFS in patients undergoing surgery due to primary cervical cancer. Further analyses are warranted to allow an implementation of such markers into clinical practice.

A randomized phase III adjuvant study in high-risk cervical cancer: simultaneous radiochemotherapy with cisplatin (S-RC) versus systemic paclitaxel and carboplatin followed by percutaneous radiation (PC-R): a NOGGO-AGO Intergroup Study.

BACKGROUND: Simultaneous adjuvant platinum-based radiochemotherapy in high-risk cervical cancer (CC) is an established treatment strategy. Sequential paclitaxel (Taxol) and platinum followed by radiotherapy may offer further advantages regarding toxicity. PATIENTS AND METHODS: An open-labeled randomized phase III trial was conducted to compare paclitaxel (175 mg/m(2)) plus carboplatin (AUC5) followed by radiation (50.4 Gy) (experimental arm-A) versus simultaneous radiochemotherapy with cisplatin (40 mg/m(2)/week) (arm-B) in patients with stage IB-IIB CC after surgery. Primary objective was progression-free survival (PFS). RESULTS: Overall, 271 patients were randomized and 263 were eligible for evaluation; 132 in arm-A and 131 in arm-B appropriately balanced. The estimated 2-year PFS was 81.8% [95% confidence interval (CI) 74.4-89.1] in arm-B versus 87.2% (95% CI 81.2-93.3) in arm-A (P = 0.235) and the corresponding 5-year survival rates were 85.8% in arm-A and 78.9% in arm-B (P = 0.25). Hematological grade 3/4 toxicity was higher in arm-B. Alopecia (87.9% versus 4.1%; P < 0.001) and neurotoxicity (65.9% versus 15.6%; P < 0.001) were significantly higher in arm-A. Early treatment termination was significantly more frequent in arm-B than in arm-A (32.1% versus 12.9%; P = 0.001). CONCLUSIONS: Sequential chemotherapy and radiation in high-risk CC could not show any significant survival benefit; however, a different toxicity profile appeared. This sequential regime may constitute an alternative option when contraindications for immediate postoperative radiation are present.

Can complete tumor resection be predicted in advanced primary epithelial ovarian cancer? A systematic evaluation of 360 consecutive patients.

BACKGROUND: Postoperative tumor-residual-mass is the most important prognostic factor in epithelial ovarian cancer (EOC). Aim of our study was to define risk factors for incomplete tumor resection in advanced primary EOC. PATIENTS & METHODS: A validated intraoperative documentation tool ("Intraoperative-Mapping of Ovarian-Cancer" = "IMO") was applied to systematically evaluate intraabdominal tumor dissemination pattern, maximal tumor load, tumor residuals and operative morbidity for all EOC-patients who underwent primary surgery in our institution during 09/2000-08/2009. Univariate- and multivariate analysis were performed to identify independent risk factors of incomplete tumor resection and operative complications. RESULTS: We evaluated 360 consecutive EOC-patients of FIGO-stage-III/IV. In 221(61%) patients a complete tumor resection could be obtained. In 50(14%) patients tumor residuals were <0.5 cm. Sixty (17%) patients developed a major (14%) complication. Multivariate analysis identified intestinal resection (OR:2.0; 95%CI:1.14-3.4; p = 0.01) and macroscopical tumor residuals (OR:0.5; 95%CI:0.2-1.2; p = 0.05) as independent predictors of major operative morbidity. Tumor dissemination pattern and maximal tumor load were significantly different between tumor-free and not-tumor-free operated patients, with less extrapelvic tumor involvement in the tumor-free group (p < 0.001). More than 4 IMO-fields of tumor involvement (OR:3.3; 95%CI:1.5-7.0; p = 0.002) were identified to be of predictive significance for incomplete tumor resection. FIGO-stage, histology, age, CA125-levels, bowel resection and ascites did not affect optimal tumor resectability. CONCLUSIONS: Tumor expanding in multiple (>4) abdominal quadrants was the major negative predictors for complete tumor resection in primary EOC-patients. Bowel resection and macroscopical tumor residuals were of predictive value for a higher operative major morbidity. Identifying high-risk patients for suboptimal tumor resection and operative complications may improve surgical outcome in advanced primary EOC.

Adult granulosa cell tumors of the ovary: tumor dissemination pattern at primary and recurrent situation, surgical outcome.

OBJECTIVE: Granulosa-cell-tumors of the ovary (GCT) constitute a rare group of neoplasms with malignant potential. Due to the rarity of the disease intraoperative tumor-dissemination-patterns are not well defined and are mostly based on retrospective data. Aim of the present study was to describe surgical and clinical outcome and dissemination pathways in the primary and recurrent situation of the disease. METHODS: All primary and relapsed GCT-patients, operated between 01/2001 and 02/2010 in our institution were evaluated using a systematic intraoperative documentation-tool (IMO). Surgical outcome, intraoperative tumor-dissemination-pattern and pathological and findings were separately analyzed for the primary and recurrent situation. RESULTS: Overall, 45 patients were analyzed; including eighteen patients with primary and 27 patients with recurrent GCT. Tumor-dissemination-patterns differed significantly between primary and recurrent patients, by the latter having significantly higher rates of diffuse peritoneal involvement (15.8% vs. 52%; p=0.027) and of extraovarian tumor involvement of the middle (15.8% vs. 48.1%; p=0.05) and upper abdomen (0 vs. 33.3%; p=0.006). While all primary patients could be operated tumor-free, this was the case for 85.2% of the relapsed patients (p=0.13). A multivisceral operative approach with extensive peritonectomy, intestinal or diaphragmatic resection, splenectomy and partial hepatectomy/panceratectomy had to be performed only in recurrent GCT (55.6%). CONCLUSIONS: Tumor-dissemination-pathways followed in primary and recurrent GCT differ significantly by higher rates of multivisceral tumor involvement in the recurrent situation of the disease. While at primary presentation extrapelvic involvement with peritoneal carcinosis appears only rare, surgical cytoreduction during relapse is more challenging involving a multivisceral approach.

External iliac artery ligation due to late postoperative rupture after radical lymphadenectomy for advanced ovarian cancer--two case reports.

According to the present guidelines for advanced epithelial ovarian cancer (EOC), bulky lymph nodes should be removed as part of the routine surgical staging and the primary goal being removal of all macroscopic tumor residuals. Furthermore, EOC-patients with bulky lymph node relapse seem to benefit from lymphadenectomy in terms of recurrence and overall survival.We present two cases of severe postoperative hemorrhage due to external iliac artery rupture ten and 12 days after radical bulky lymph node removal in primary and recurrent EOC-patients. Both cases were successfully managed by ligation of the two arms of the external iliac artery achieving immediate hemostasis. No crossover bypass was required to maintain lower extremity perfusion. Late rupture of the iliac vessels is a rare complication of systematic lymphadenectomy in EOC. This complication can be managed by unilateral external iliac artery ligation without mandatory subsequent graft interposition or crossover bypass.

Epirubicin and cyclophosphamide versus epirubicin and docetaxel as first-line therapy for women with metastatic breast cancer: final results of a randomised phase III trial.

BACKGROUND: This randomised phase III trial was carried out to compare the efficacy and safety of epirubicin and cyclophosphamide (EC) with epirubicin and docetaxel (Taxotere) (ED) as first-line chemotherapy for metastatic breast cancer. PATIENTS AND METHODS: Patients (n = 240) were randomly assigned to receive either ED (epirubicin 75 mg/m(2) and docetaxel 75 mg/m(2)) or EC (epirubicin 90 mg/m(2) and cyclophosphamide 600 mg/m(2)). The primary end point was objective response rate (ORR). Secondary end points were progression-free survival (PFS), overall survival (OS), and safety. RESULTS: ORR for patients randomly assigned to receive EC and ED were 42% and 47%, respectively (P = 0.63). Median PFS [10.1 versus 10.3 months; hazard ratio (HR) 0.98; log-rank P = 0.38] and OS (19.9 versus 30.0 months; HR 0.663; log-rank P = 0.21) were comparable in both arms. Although grade 3/4 leucopenia occurred more frequently with ED (81% versus 73%; P = 0.01), there were no significant differences in the incidence of febrile neutropenia and grade 3/4 infections. Grade 3/4 non-haematologic toxicity was infrequent in both arms. Congestive heart failure was observed in one patient in each arm. CONCLUSION: In this randomised trial, no differences in the efficacy study end points were observed between the two treatment arms.

Sequential chemotherapy with carboplatin followed by weekly paclitaxel in advanced ovarian cancer: results of a multicenter phase II study of the northeastern German society of gynecological oncology.

BACKGROUND: For the adjuvant setting of advanced ovarian cancer (AOC) after primary radical surgery the combination of paclitaxel and platinum in a 3-week schedule has emerged as the current standard. In preclinical studies additional anti-angiogenic effects of low dose paclitaxel infusion were demonstrated. A sequential schedule of carboplatin and paclitaxel has the potential to improve the therapeutic index. METHODS: In this multicenter phase II trial four cycles of carboplatin at a dose of AUC 5 (d1/q21d) followed by 12 cycles of weekly paclitaxel at a dose of 80 mg/m(2) (d1/q7d) were applied after primary radical surgery. Eligible were all optimally or sub-optimally debulked patients with FIGO IA-IV ovarian cancer. All patients with hemoglobin levels <12 mg/dl received erythropoietin additionally. RESULTS: Between July 2003 and May 2005, 105 patients from 27 institutions were enrolled. The median age was 60 years (range: 23-80 years). A median number of 16 courses (range 1-16) were applied. The incidence of non-hematological toxicities was very low. Only 41% of patients experienced alopecia (grade 1-2). Neurotoxicity (grade 3-4) was not observed. Grade 3-4 hematological toxicity (43% of all patients) included thrombocytopenia (17%), anemia (3%), leucopenia (23%), and neutropenic fever (0%). Ninety-seven percent received erythropoietin. Thromboembolic events (4%) were not increased in patients who received erythropoietin. After a median time of 23 months (range: 1-42 months) 32 patients had died, and the median overall survival was not reached. The progression-free survival was 25.4 months (95% CI: 18.8-40+). CONCLUSION: These results suggest that this sequential regimen using weekly paclitaxel represents an efficacious and well-tolerated regimen. A randomized study comparing this new schedule with the conventional 3-week protocol is warranted.

Venous thromboembolism in recurrent ovarian cancer-patients: A systematic evaluation of the North-Eastern German Society of Gynaecologic Oncology Ovarian Cancer Study Group (NOGGO).

INTRODUCTION: Systemic chemotherapy and surgery for patients with recurrent ovarian cancer (ROC) constitute a therapeutic challenge. Venous thromboembolism (VTE) seems to have a negative prognostic impact in patients with solid tumors including primary ovarian cancer in many series. Only limited contemporary data exist regarding the impact of VTE on ROC. PATIENTS AND METHODS: Two large multicenter prospective controlled phase I/II-III studies on 2nd-line topotecan-based chemotherapy with platinum-sensitive or resistant ROC (N=525) were conducted on both operated and non-operative patients by the North-Eastern German Society of Gynaecologic Oncology Ovarian Cancer Study Group (NOGGO). Analysis was performed to identify incidence, predictors and prognosis of VTE. Survival analysis, univariate and Cox-regression analysis were performed to identify independent predictors of VTE, overall and progression free survival. RESULTS: Thirty-seven (7%) VTE-episodes during chemotherapy were identified; 70% of them occurred within the first 2 months after initiation of chemotherapy. Ascites, as a sign of peritoneal carcinomatosis and advanced tumor disease, was identified as independent predictor of VTE. Advanced age and high BMI did not appear to affect significantly the VTE-incidence. High performance status, platinum-sensitivity, serous-papillary histology, lack of ascites and surgery appeared to positively affect survival by multivariate analysis. Overall survival and progression free survival were similar between the VTE and no-VTE patients. CONCLUSION: ROC-patients appear to have the highest risk for developing VTE when ascites exists and during the first 2 months following chemotherapy initiation. In contrast to primary ovarian cancer, VTE could not be identified to affect overall survival in relapsed malignant ovarian disease.

Clinical management of borderline tumours of the ovary: results of a multicentre survey of 323 clinics in Germany.

The aim of this survey was to analyse the standard of care in diagnostic, surgery, chemotherapy and aftercare management for patients with borderline tumours of the ovary (BOTs) in Germany. A structured questionnaire comprising different dimensions was sent to all 1114 gynaecological departments. The questionnaire could be returned anonymously. The overall response rate was 29.0% (323 departments). Most departments were on secondary care (71.8%), tertiary care (23.2%) or university hospital (5.0%) level. Most clinicians performed not more than five BOT operations (89.2%) per year. Most departments (93.2%) used in addition to classical bimanual examination and vaginal ultrasound, tumour marker CA-125 detection, CT scan, MRI or PET-CT techniques. Departments in university and tertiary care hospitals performed more often a fresh frozen section (87 vs 64%). In young women, clinicians performed much seldom unilateral salpingo-oophorectomy (92%) and only in 53% biopsies of the contralateral ovary. Generally, biopsies of the contralateral ovary were performed in 4-53% of the patients. Chemotherapy was mostly favoured in 'high-risk' patients with tumour residual, microinvasion or invasive implants. Thus, a high grade of insecurity in diagnostic and therapy of BOT exists in some gynaecological departments and underlines the need for more educational and study activities.

Non-pegylated liposomal doxorubicin and docetaxel in metastatic breast cancer: final results of a phase II trial.

BACKGROUND: Non-pegylated liposomal doxorubicin (NPLD) has demonstrated equivalent antitumor activity to conventional doxorubicin and a significantly lower risk of cardiotoxicity when given as single agent or in combination with cyclophosphamide, but there is limited experience with the combination of NPLD and taxanes. This phase II study was performed to evaluate the efficacy and safety of the NPLD and docetaxel in patients with metastatic breast cancer. PATIENTS AND METHODS: A total of 51 patients were treated with NPLD (60 mg/m(2)) and docetaxel (75 mg/m(2)) in 3-weeks intervals for up to eight cycles. RESULTS: The overall response rate was 50% and 78% of patients derived a clinical benefit. Median time to progression and overall survival were 10.0 months (95% CI, 6.9-13.1 months) and 25 months (95% CI, 22.1-29.8 months), respectively. Median duration of response was 12.0 months (95% CI 7.1-16.9). The treatment was generally well tolerated and associated with toxicities that were consistent with the known side-effects of the individual agents and of anthracycline/taxane combinations. There were no symptomatic cardiac averse events and mild asymptomatic LVEF changes were reported in five patients. CONCLUSIONS: The combination of NPLD and docetaxel is well tolerated and has high antitumour activity in MBC patients.

[Imatinib--a possible therapeutic option for cervical carcinoma: results of a preclinical phase I study]. / Imatinib - eine mogliche Therapieoption beim Zervixkarzinom: Ergebnisse einer praklinischen Phase-I-Studie.

BACKGROUND: In the last few years, the therapy of cervical carcinoma has progressed substantially due to the use of simultaneous platinum- containing radiochemotherapy. However, there are no data which evaluate an individualized treatment adapted to tumor biology, in spite of the fact that patients show remarkably different responses to chemotherapy. Therefore this preclinical phase I study aims at finding therapeutic alternatives to the current cytostatic drugs to treat cervical carcinoma. MATERIAL AND METHODS: In a tumor chemosensitivity assay, 8 drugs were tested on freshly isolated tumor cells of 16 patients [carbo- and cisplatin, topotecan, paclitaxel as well as the 2 tyrosine kinase inhibitors imatinib (Glivec) and gefitinib (Iressa (R) ) and the 2 monoclonal antibodies cetuximab (Erbitux) and trastuzumab (Herceptin (R) )]. RESULTS: Overall the test was evaluable for 16 specimens (100%). Ten of 15 tumor samples (66.6%) were sensitive to imatinib. A sensitive therapeutic response could be demonstrated in all tested FIGO stages. An interindividual comparison could establish sensitivity to cetuximab in 12.5% of cases, to gefitinib in 6.25%, to trastuzumab in 6.6%, to cisplatin in 13.3%, to carboplatin in 7.6%, to paclitaxel in 93.8% and to topotecan in 25%. CONCLUSION: Imatinib seems to be an efficacious therapeutic option for patients with cervical carcinoma, independently of tumor subtype.

Decreased IL-1 RA concentration in ascites is associated with a significant improvement in overall survival in ovarian cancer.

BACKGROUND: Cytokines play a major role in promoting the growth and metastatic spread of cancer cells. Interleukin-1 alpha and beta (IL-1) and IL-1 RA are known to be critically involved in carcinogenesis and in various solid tumors. There are limited data on expression of IL-1 alpha, beta and RA in serum and ascites in patients with advanced ovarian cancer. Objectives of this study were to investigate the level of IL-1 alpha, IL-1 beta and IL-1 RA in serum and ascites from patients with ovarian cancer and their impact on the prognosis. METHODS: Fifty-three women with ovarian cancer (OC) (33 patients with primary OC and 20 with relapsed OC) and 50 women with benign gynaecological diseases as a control group (CG) were enrolled onto this prospective study. IL-1 alpha, beta and RA levels were analyzed in serum and ascites by ELISA technique. RESULTS: The median age was 55 years (range 19-80) in the ovarian cancer group and 40 years (range 15-89) in the controls. The distribution of histological type of ovarian cancer was as follows: serous-papillary 43 (81.1%), 4 (7.5%) mucinous, 3 (5.7%) endometroid and 3 (5.7%) clear cell carcinoma. The concentrations of IL-1 beta and RA in ascites or peritoneal fluid were significantly increased in patients with OC in comparison to the CG, for both cytokines (p<0.0001); also the concentration of IL-1 RA in serum was increased in OC (p=0.003) vs. CG. An increased level of IL-1 beta in ascites correlated significantly with a poorer histopathological grading (p=0.038). IL-1 RA concentration in ascites was correlated with advanced FIGO stage (p=0.049) and the IL-1 RA serum level with ascites volume (< or =500 ml vs. >500 ml) (p=0.046). Patients with IL-1 RA level in ascites lower than the cut off value of 695.6 pg/ml showed a significant better progression-free median survival (24.6 vs. 12.8 months, p=0.008) and postoperative median overall survival (34.6 vs. 17 months, p=0.01) in comparison to patients with an IL-1 RA level in ascites higher than the cut off level. Additionally, a higher expression of IL-1 beta in serum (p=0.004) and ascites (p=0.05) reduced significantly the progression-free survival. In the multivariate analysis, expression of IL-1 RA in ascites was an independent prognostic factor for good progression-free and postoperative overall survival (HR, 0.39 95% CI, 0.18-0.83, p=0.01, HR, 0.36 95% CI, 0.16-0.8, p=0.01). CONCLUSIONS: IL-1 RA levels in ascites lower than the cut off value of 695.6 pg/ml are associated with a significant improvement in postoperative and progression-free survival. IL-1 RA shows a prognostic relevance in ovarian cancer.

Online tumor conference in the clinical management of gynecological cancer: experience from a pilot study in Germany.

The concept of the online tumor conference was established in 2004 as a pilot project. We developed specific web-based software to organize and conduct online tumor board meetings of gynecologists, surgeons, radiologists, oncologists, and pathologists from different hospitals and gynecological practitioners, discussing individual patient's cases, defining therapy options, and exchanging clinical experience. Following a didactic approach, patient data are presented to the participants, with a special focus toward patient's preference and late toxicity from prior therapy. Then different national (eg, Arbeitsgemeinschaft Gynaekologische Onkologie, Deutsche Gesellschag fur Gynaekologic und Geburtshilfe) and international guidelines (eg, American Society of Clinical Oncology, National Cancer Institute), current study results based on literature review and open clinical trials are discussed. An individual diagnosis and therapy recommendation for each patient is reached by consensus. All protocols, guidelines, and publication data are upgraded and dispersed via Internet for all participants. In the period from December 2004 to August 2006, 39 tumor board conferences were performed with a total of 667 participants. One hundred forty-four patients' cases were presented, and 121 peer-reviewed second-opinions were sought. In an anonymous survey, 84% of the participants reported to be satisfied with the information content and 72% with the technical support. Overall 98% of the individual therapy recommendations were accepted and implemented. The tumor board conference presents an optimal possibility for extensive scientific discussions and exchange (92%) and improves advanced educational training (81%). In conclusion, the online tumor conference is feasible and represents a time-saving possibility for gynecological oncologist to receive a treatment recommendation based on the best available clinical and scientific evidence.

Breast cancer patients' expectations in respect of the physician-patient relationship and treatment management results of a survey of 617 patients.

BACKGROUND: The following study was conducted to explore patients' information needs and preferences with a special focus on doctor-patient communication. PATIENTS AND METHODS: A 62-item questionnaire developed by a multidisciplinary team and validated in a phase-I study was given to breast cancer patients via the Internet (homepage) or in a hard copy version. RESULTS: A total of 617 patients responded, 552 on line and 65 via the hard copy questionnaire. The median age of the on-line group was 47 (21-85) and 55 (40-92) in the hard copy group. Sixty-five per cent of the patients were treated with the intention of achieving a cure and 35% of the patients had metastatic disease. The median length of the consultation communicating the information 'You have breast cancer' was 15 min (0-300). The most effective and patient-relevant source of information about the disease and the treatment options was consultation with the physician (84%). When asked to suggest areas for improvement, patients' most common answers were: more complementary therapies should be offered by the physician (54%); physicians should take more time to explain things (51%); and cooperation between the physicians involved in the patient's care should be improved (39%). The questions most relevant to patients were: 'Am I getting the right therapy?' (89%); 'How many patients with my condition does my doctor treat?' (46%) and 'Can I be enrolled into a trial?' (46%). An independent second opinion centre was desired by 94% of the respondents but only 20% knew of any such resource. CONCLUSIONS: This study underlines the need to give patients with breast cancer the full details on treatment options and cancer management. The results provide a suitable basis for a broader interdisciplinary discussion of the patient-physician relationship and should be useful in generating hypotheses for subsequent prospective studies.

An estrogen receptor alpha-dependent regulation of estrogen receptor-related receptor alpha in the proliferation of endometrial carcinoma cells.

Estrogen receptor-related receptor alpha (ERRalpha) was reported to compete with estrogen receptor alpha (ERalpha) in a constitutive manner as an orphan nuclear closely related to (ERalpha). To discuss the role of ERRalpha in the endometrial carcinoma cells, this study was performed. ER-responsive endometrial carcinoma cells Ishikawa and ER-nonresponse HEC-1A cells were treated with different concentration of 17beta-E2 or E2 plus ICI 182780. Semiquantitative reverse transcription-polymerase chain reaction and western blot were performed to analysis the expression of human estrogen receptor-related receptor alpha (hERRalpha). Plasmid PLXSN-hERRalpha was constructed and transfected into cells. Selected in the medium containing high-dose G418, the Ishikawa and HEC-1A cells with stable overexpression of hERRalpha were constructed and renamed as Ishikawa/hERRalpha and HEC-1A/hERRalpha, respectively. To discuss the effect of overexpression of hERRalpha in the cell biological behavior (3-[4,5-dimethylth-lazol-2yl]-2,5-diphenyltetrazolium bromid) (MTT) cell assay was performed. Estrogen downregulates ERRalpha expression in ER-positive Ishikawa cells, while upregulates the expression of ERRalpha in ER-negative HEC-1A cells. In Ishikawa cells, the downregulation of 17beta-E2 in ERRalpha expression cells could be blocked by ICI 182780. A decreasing expression of hERalpha was observed in the ER-responsive cells with overexpression of ERRalpha (Ishikawa/hERRalpha). Overexpression of hERRalpha inhibits the cell proliferation in the ERalpha-responsive Ishikawa cells and stimulated the cell proliferation in the ERalpha-nonresponsive HEC-1A cells. Function of hERRalpha depends on the expression and function of hERalpha. ER-mediated signaling might be the important factor resulting in the hormone-dependent endometrial carcinoma, whereas ERRalpha-mediated pathway might act as the vital role in hormone-independent endometrial carcinoma.

Overexpression of the plasminogen activator inhibitor type-1 in epithelial ovarian cancer.

BACKGROUND: The plasminogen activator-plasmin cascade plays a central role in the progression of solid tumors. The type-1 plasminogen activator inhibitor (PAI-1) is the major physiological regulator of plasminogen activation. PAI-1 is suggested to play a crucial role in tumor cell invasion and metastasis of various solid tumors. The aim of this study was to analyze the clinical and prognostic roles of PAI-1 in epithelial ovarian cancer (OC). MATERIALS AND METHODS: Expression analysis was conducted by immunohistochemistry and ELISA. Tissue sections of paraffin-embedded tumor specimens and fresh-frozen tumor samples from patients with benign and malignant ovarian tumors (OT), who had undergone surgical intervention in the Department of Gynaecology and Obstetrics, Charité, Germany, from 02/01 to 06/02, were used. Correlation analysis with conventional clinical factors, univariate and multivariate analyses were performed using SPSS (SPSS Inc., V.11.0). RESULTS: Sixty-five patients (31 primary OC, 20 recurrent OC, 4 low-malignant potential OT, 6 benign OT, 4 normal ovary) were allocated to this trial. The median age was 57 years (range, 34-86) and the median follow-up was 20 months (range, 0-64). The distributions of (FIGO) tumor stage of all primary OC were: I = 16.1%, II = 3.2%, III = 45.2% and IV = 35.5%. PAI-1 was significantly overexpressed in the tumor epithelium of OC in comparison to the ovarian epithelium of benign OT and normal ovary (p < 0.001). The median PAI-1 level was 1.92-fold higher in malignant OT than in benign OT. Statistical analyses showed no significant correlation between the expression of PAI-1 and clinical parameters. The expression of PAI-1 and the PAI-1 level, according to 3 different cut-off values, showed no prognostic impact in univariate analysis. In multivariate analysis, only tumor stage (FIGO) (p = 0.003) and residual tumor (p = 0.009) remained independent prognostic factors for post-operative survival. CONCLUSION: PAI-1 is significantly overexpressed in OC.

Biweekly pegylated liposomal doxorubicin in patients with relapsed ovarian cancer: results of a multicenter phase-II trial.

BACKGROUND: The obvious benefit of pegylated liposomal doxorubicin (PLD) for tumour control in recurrent ovarian cancer is frequently offset by severe palmar-plantar erythrodysesthesia (PPE). There is evidence that dose reduction from 50 to 40 mg/m(2) reduces the incidence of PPE without compromising cytotoxic activity. We set out to investigate whether biweekly application further improves the therapeutic index of PLD. PATIENTS AND METHODS: Patients with recurrent ovarian cancer after surgery and adjuvant chemotherapy with platinum and taxane compounds were eligible to participate in this multi-institutional phase II study. PLD was administered at a dose of 20 mg/m(2) every two weeks. Eligible patients had ECOG performance status of < or =2, and sufficient organ function. We employed an optimized two-stage design to test the hypothesis that biweekly application of PLD reduces the frequency of grade III and IV PPE from 25% to 10%. Response and survival were addressed descriptively. RESULTS: Between October 2001 and February 2004, 64 patients with median age of 59 (range 38-81) years were recruited onto this trial. We evaluated 553 (median 7, range 1-25) courses of PLD treatment. Most patients were in their third or fourth line of chemotherapy. PPE was noted in 30 patients (47.6%), but only three participants progressed to grade 3 severity (4.7%, 95% confidence interval 1.0-13.1%). Partial response, stable disease, and tumour progression were observed in 5, 13, and 24 patients, respectively. Median overall and progression-free survival were 18.2 (range, 1.4-34.0) and 4.3 (range 0.5-22.3) months. CONCLUSIONS: Biweekly PLD may reduce the incidence of PPE while retaining efficacy in relapsed ovarian cancer. Our data support the need for a randomized trial to strengthen these assumptions.

[Breast cancer: analysis of treatment quality in Germany 2004: retrospective survey by Arbeitsgemeinschaft Gynäkologische Onkologie (AGO)]. / Das Mammakarzinom: Versorgungslage und Therapiequalität in Deutschland 2004. Eine retrospektive Analyse der Organgruppe Mamma der Arbeitsgemeinschaft Gynäkologische Onkologie (AGO).

The Organgruppe Mamma der Arbeitsgemeinschaft Gynaekologische Onkologie (AGO) conducted a nationwide 3-phase analysis of the care structure and standard of therapy given to patients with breast cancer from 2002 (4th quarter) to 2004 (4th quarter). The analysis includes 1069 patients from 257 institutions; 34% with early breast cancer and 66% with metastatic disease. No reliable data on the pattern of care of these patients have been published to date in Germany. The extent to which national and international therapy recommendations were implemented in routine clinical practice was unclear. Evaluation of the data shows that treatment based on the guidelines is now being implemented very reliably in certain sectors. This is of particular relevance to the pattern of adjuvant treatment in early breast cancer. At that time 68 % of the patients received an anthracyclin based chemotherapy and in addition 18% received an anthracycline and taxane based chemotherapy. Participation in clinical trials peaked with 30% in the neoadjuvant setting. The problem with metastatic breast cancer is the complexity of the interdisciplinary treatment involved. The present analysis conducted by the AGO was the first attempt to analyse the treatment given to metastatic patients and to systematise the approach to treatment. The fundamental problem remains, irrespective of the stage of the tumour, namely that too few patients are treated in randomised clinical studies.