Toxicity Assessment of a Phase III Study Evaluating FEC-Doc and FEC-Doc Combined with Gemcitabine as an Adjuvant Treatment for High-Risk Early Breast Cancer: the SUCCESS-A Trial.

Introduction: This paper aims to evaluate the toxicity profile of additive gemcitabine to adjuvant taxane-based chemotherapy in breast cancer patients. Methods: Patients enrolled in this open-label randomized controlled Phase III study were treated with 3 cycles of epirubicin-fluorouracil-cyclophosphamide (FEC) chemotherapy followed by 3 cycles of docetaxel with those receiving 3 cycles of FEC followed by 3 cycles of gemcitabine-docetaxel (FEC-DG). 3690 patients were evaluated according to National Cancer Institute (NCI) toxicity criteria (CTCAE). The study medications were assessed by the occurrence of grade 3-4 adverse events, dose reductions, postponements of treatment cycles and granulocyte colony-stimulating factor (G-CSF) support. Results: No differences in neutropenia or febrile neutropenia were demonstrated. However, thrombocytopenia was significantly increased with FEC-DG treatment (2.0 vs. 0.5 %, p < 0.001), as was leukopenia (64.1 vs. 58.5 %, p < 0.001). With FEC-DG significantly more G-CSF support in cycles 4 to 6 (FEC-DG: 57.8 %, FEC-D: 36.3 %, p < 0.001) was provided. Transaminase elevation was significantly more common with FEC-DG (SGPT: 6.3 %, SGOT: 2 %), whereas neuropathy (1.2 %), arthralgia (1.6 %) and bone pain (2.6 %) were more common using FEC-D. Dose reductions > 20 % (4 vs. 2.4 %) and postponement of treatment cycles (0.9 vs. 0.4 %) were significantly more frequent in the FEC-DG arm. Eight deaths occurred during treatment in the FEC-DG arm and four in the FEC-D arm. Conclusion: The addition of gemcitabine increased hematological toxicity and was associated with more dose reductions and postponements of treatment cycles.

Assessment of University Gynaecology Clinics Based on Quality Reports.

Introduction: Quality reporting was initially implemented to offer a better means of assessing hospitals and to provide patients with information to help them when choosing their hospital. Quality reports are published every 2 years and include parameters describing the hospital's structure and general infrastructure together with specific data on individual specialised departments or clinics. Method: This study investigated the 2010 quality reports of German university hospitals published online, focussing on the following data: number of inpatients treated by the hospital, focus of care provided by the unit/department, range of medical services and care provided by the unit/department, non-medical services provided by the unit/department, number of cases treated in the unit/department, ICD diagnoses, OPS procedures, number of outpatient procedures, day surgeries as defined by Section 115b SGB V, presence of an accident insurance consultant and number of staff employed. Results: University gynaecology clinics (UGCs) treat 10 % (range: 6-17 %) of all inpatients of their respective university hospital. There were no important differences in infrastructure between clinics. All UGCs offered full medical care and were specialist clinics for gynaecology (surgery, breast centres, genital cancer, urogynaecology, endoscopy), obstetrics (prenatal diagnostics, high-risk obstetrics); many were also specialist clinics for endocrinology and reproductive medicine. On average, each clinic employs 32 physicians (range: 16-78). Half of them (30-77 %) are specialists. Around 171 (117-289) inpatients are treated on average per physician. The most common ICD coded treatments were deliveries and treatment of infants. Gynaecological diagnoses are underrepresented. Summary: UGCs treat 10 % of all inpatients treated in university hospitals, making them important ports of entry for their respective university hospital. Around half of the physicians are specialists. Quality reports offer little information on the differences in competencies or medical specialties. The statutory quality reports are not useful for patients and referring physicians when choosing a clinic.

Impact of Patient and Procedure Mix on Finances of Perinatal Centres - Theoretical Models for Economic Strategies in Perinatal Centres.

Introduction: In Germany, cost and revenue structures of hospitals with defined treatment priorities are currently being discussed to identify uneconomic services. This discussion has also affected perinatal centres (PNCs) and represents a new economic challenge for PNCs. In addition to optimising the time spent in hospital, the hospital management needs to define the "best" patient mix based on costs and revenues. Method: Different theoretical models were proposed based on the cost and revenue structures of the University Perinatal Centre for Franconia (UPF). Multi-step marginal costing was then used to show the impact on operating profits of changes in services and bed occupancy rates. The current contribution margin accounting used by the UPF served as the basis for the calculations. The models demonstrated the impact of changes in services on costs and revenues of a level 1 PNC. Results: Contribution margin analysis was used to calculate profitable and unprofitable DRGs based on average inpatient cost per day. Nineteen theoretical models were created. The current direct costing used by the UPF and a theoretical model with a 100 % bed occupancy rate were used as reference models. Significantly higher operating profits could be achieved by doubling the number of profitable DRGs and halving the number of less profitable DRGs. Operating profits could be increased even more by changing the rates of profitable DRGs per bed occupancy. The exclusive specialisation on pathological and high-risk pregnancies resulted in operating losses. All models which increased the numbers of caesarean sections or focused exclusively on c-sections resulted in operating losses. Conclusion: These theoretical models offer a basis for economic planning. They illustrate the enormous impact potential changes can have on the operating profits of PNCs. Level 1 PNCs require high bed occupancy rates and a profitable patient mix to cover the extremely high costs incurred due to the services they are legally required to offer. Based on our theoretical models it must be stated that spontaneous vaginal births (not caesarean sections) were the most profitable procedures in the current DRG system. Overall, it currently makes economic sense for level I PNCs to treat as many low-risk pregnancies and neonates as possible to cover costs.

Accuracy of radiological tumour size assessment and the risk for re-excision in a cohort of primary breast cancer patients.

BACKGROUND: Re-operations after breast conserving surgery (BCS) are necessary, when specimen margins are not free of breast cancer cells. This study explored the accuracy of preoperative tumour size assessment and its influence on the rate of re-excisions and mastectomies. METHODS: The study included 1591 patients with invasive breast cancer, who were planned for BCS. Patient, staging and tumor characteristics were evaluated concerning their influence on re-excision and mastectomy rates. Patient and tumor characteristics comprised histopathological tumour size, HER2 status, multifocality, in situ component, grading (G), nodal status and hormone receptor (HR) status. Staging characteristics included deviation from pathological tumour size as measured by clinical examination, sonography and mammography. RESULTS: In 1316 patients (83%) sufficient treatment was possible with one operation. 275 patients (17%) had to undergo at least one further surgery as a result of positive specimen margins. In 138 patients (9%) mastectomy was ultimately necessary. In patients with a positive HER2 status, a larger tumour size, underestimation by ultrasound, an in situ component and multifocality, the risk for a re-operation was about doubled. Tumour size deviation in the mammogram or the clinical tumour size assessment did not have significant influence to the re-excision rates. CONCLUSION: Tumour size and accurate presurgical assessment of the tumour size itself are independent predictors for the need of a second surgery or even a mastectomy in patients for whom a primary BCS was planned.

The era of centers: the influence of establishing specialized centers on patients' choice of hospital.

PURPOSE: It is considered that establishing accredited specialized centers can serve as a marketing tool. This study investigated whether accredited specialized centers influence patients' choice of hospital. METHODS: A total of 2,389 patients was included in a questionnaire survey: 468 at the Department of Gynecology, 745 at the certified University Breast Center of Franconia, 1,000 at the University Perinatal Center of Franconia and 176 for whom classification details were lacking. RESULTS: Among the oncological patients, physicians in private practice played an important role in the choice of hospital (58.4 vs. 25.7%; P < 0.001; OR 4.058). Among obstetric patients, the primary factors were recommendations from family [odds ratio (OR) 0.495], friends (OR 0.218), and previous personal experience of the hospital (OR 0.695). For oncological patients, treatment quality (OR 2.693), availability of a center (OR 1.785), and certification (OR 3.939) were comparatively more important. For obstetric patients, friendliness (OR 0.409) and attractive accommodation (OR 0.153) were more important. CONCLUSIONS: Physicians are the most important source of recommendations for oncological patients. From the marketing point of view, intensive involvement of local private-practice physicians is necessary. The availability of certified perinatal centers does not currently play any part in patients' choice of hospital.

Health Services Research and Health Economy - Quality Care Training in Gynaecology, with Focus On Gynaecological Oncology.

In the era of cost increases and reduced resources in the German healthcare system, the value of health services research and health economics is increasing more and more. Health services research attempts to develop concepts for the most effective ways to organise, manage, finance and deliver high-quality care and evaluates the implementation of these concepts with regard to daily routine conditions. Goals are the assessment of benefits and the economic advantages and disadvantages of new and established diagnostic methods, drugs and vaccines. Regarding these goals, it is clear that health services research goes hand in hand with health economics, which evaluates the benefits of diagnostic and therapeutic procedures in relation to the costs. Both scientific fields have focus principally on gynaecology and particularly on gynaecological oncology in Germany, as can be seen by numerous publications. These present several advantages compared with clinical trials - they uncover gaps in health care, question the material, staffing and consequently the financial resources required and they allow the estimation of value and the comparison of different innovations to identify the best options for our patients.

Assessment of pituitary and steroid hormones and members of the TGF-beta superfamily for ovarian function in patients with congenital uterus and vaginal aplasia (MRKH syndrome).

Patients with Mayer-Rokitanski-Kuster-Hauser (MRKH) syndrome have congenital uterine and vaginal aplasia. The main question of this study was, if the absence of a uterus along with other genital and organ malformations could contribute to hormone or other growth factor protein fluctuations involved in communication between the hypothalamus-pituitary axis, ovaries and uterus. Serum from 56 MRKH patients (mean 27.6 years) and 22 female controls (mean 30.7 years) were analyzed using ELISA to determine levels of pituitary and steroid hormones (LH, FSH, estradiol, progesterone), growth factors of the TGF-beta superfamily like activin A, inhibin B, and anti-Müllerian hormone (AMH). All serum levels were analyzed in relation to other organ malformations. Compared to controls, all 56 patients, including 5% with streak ovaries or unilateral ovarian aplasia, were generally similar in hormone and growth factor levels and could be grouped into hormonal phases. However, compared to controls LH/FSH and FSH/LH ratios of patients had significantly higher and lower mean values, of 2.75-fold (p=0.015) and 1.9-fold (p=0.002), respectively. Undetectable inhibin B levels of<10 pg/ml (p=0.05) were noted in 41.1% of MRKH patients, resulting in significantly higher activin A/inhibin B ratios (p<0.001). MRKH patients have hormonal phases supporting ovarian function, but patients with low FSH/LH ratios and undetectable inhibin B levels (<10 pg/ml) could represent cycle phasing irregularities. A model is discussed regarding our findings and the loss of ovarian-uterine communication.

Changes in satisfaction in patients with gynaecological and breast malignancies: an analysis with the Socio-Economic Satisfaction and Quality of Life questionnaire.

Quality of life (QOL) is commonly assessed using health-related questionnaires. The Socio-Economic Satisfaction Quality of Life (SES-QOL) questionnaire includes specific individual coping topics, such as health, leisure activities, sexual life, occupation, financial situation, partnership situation, family situation, accommodation situation and friendship situation. This paper reports the findings of the survey with the SES-QOL with an emphasis on changes in satisfaction during the course of a disease involving a gynaecological or breast malignancy. From February 2000 to October 2002, 1030 women diagnosed with breast or gynaecological cancers were included in this study. The patients responded to the SES-QOL questionnaire as part of an interview. Metastatic disease results in more frequent reporting of dissatisfaction with health issues (63%), sexual life (24.5%) and occupation (20%), whereas patients in the adjuvant setting report deteriorating satisfaction with regard to health (41.7%), sexual life (12.2%) and occupation (11.5%). The SES-QOL reflects individual changes in different aspects of satisfaction during the course of a cancer disease. Identifying as many causing variables as possible, and offering support through an interdisciplinary approach including the physician, a social worker and a psycho-oncologist, appears necessary in order to help patients cope with cancer as a dynamic and individual process.

Risk and risk assessment for breast cancer: molecular and clinical aspects.

Chemoprevention, prophylactic surgery and intensified screening programs are options which can be offered the patients with an increased lifetime risk (p(life)) for breast cancer (BC). Estimation of p(life) includes BRCA mutation analysis and risk estimation based on individual risk factors and family history. MENDEL and BRCAPRO are models which can estimate mutation carrier status probability (p(mut)), p(life) and p(mut) can be estimated using Cyrillic3 software which incorporates BRCAPRO and MENDEL. To integrate age, hormonal factors and benign breast biopsies in risk assessment the Tyrer-Cuzick model can be used. These models support the decision pro or contra genetic analysis and improve the number of positive gene testing results. Estimations of p(life) and p(mut), based on a mathematical model, should deal with algorithms and penetrance/frequency data adequate to the population counselled. Being the main modulatory factors, reproductive/hormonal data should be incorporated like the Tyrer-Cuzick model does.

Assessment of breast cancer tumor size depends on method, histopathology and tumor size itself*.

PURPOSE: Mammography (MG), breast (BU) and axillary ultrasound (AU), and clinical examination (CE) are commonly used for clinical staging. These different methods were compared in order to assess the accuracy of clinical tumor staging (cT). METHOD: About 503 breast cancer (BC) patients were prospectively measured by MG, ultrasound and clinical examination. Pearson's correlation to pathological tumor size (pT) was tested and the deviation of MG, BU and CE to pT was analyzed in subgroups defined by pT, grading (G), estrogen receptor (ER), progesteron receptor (PR), proliferation (MIB-1) and HER2/neu. Association of AU to pN was examined by chi(2)-test. Receiver operating characteristics (ROC) were used to test the prediction of a pT > 2 cm. RESULTS: Mammography correlated best with pT (r = 0.752). Mammography (mean (MG) = 2.17 cm) overestimated tumors in size (mean (pT) = 2.04 cm) rather than ultrasound (mean (BU) = 1.86 cm) and clinical examination (mean (cT) = 1.70 cm). pT of invasive ductal BC could be estimated significantly better than pT of invasive lobular BC. Smaller tumors were better to assess than larger ones. Tumors with a grading G1 were easier to estimate than tumors with G2/3. Best predictor of a pT > 2 cm was the mammography with an area under the curve of 0.876. The combination of all three modalities by linear regression performed even better with an AUC of 0.906. CONCLUSIONS: The dimension of invasive ductal carcinomas, small and low grading tumors is significantly better to estimate. Concerning treatment decisions, we propose a combination of all three modalities, as the best predictive value was seen for the complementary use of mammography, ultrasound and clinical examination.

Individual assessment of sperm morphology of single spermatozoa used for intracytoplasmic sperm injection.

Intracytoplasmic sperm injection (ICSI) is an integral part of assisted reproduction. Although many papers have shown that global sperm count, sperm motility and sperm morphology of the ejaculate play no role in the fertilization rate after ICSI, embryologists who carry out ICSI, try to use the 'best looking' spermatozoa. The aim of the study was to investigate whether those spermatozoa with the best morphology really achieve the highest fertilization rate. In the present study, a total of 798 spermatozoa used for ICSI were documented by high-resolution photo. After ICSI the oocytes were cultured in single droplets and the formation of pronuclei was assessed 16 h later. The spermatozoa (all normal according to WHO criteria) were classified into four groups of different morphology. Group 1: normal head shape (approximately 5 microm diameter), group 2: like group 1, but with 15-20% smaller diameter, group 3: like group 1, but with 15-20% larger diameter, and group 4: like group 1, but with slight mid-piece cytoplasmic irregularities. Using the Pearson chi-square test, no significant difference in terms of fertilization was found among the different groups, showing that marginal sperm differences do not alter the fertilization process in ICSI.

[Breast cancer: assessment of individual risk and possibilities for prevention]. / Mammakarzinom: Ermittlung des individuellen Erkrankungsrisikos und Möglichkeiten der Prävention.

Today, prevention of breast cancer (BC) is a great demand. The exact estimation of the individual BC-risk is a prerequisite for the participation on early cancer detection or the use of preventive medication or surgery. Various models for risk assessment of BC development or the presence of a predisposing mutation (i.e. BRCA1 or BRCA2) are used, but the statistical individual risk assessment still remains uncertain. Calculating an elevated risk or detection of a predisposing mutation leads to the recommendation of preventive measurements. After detailed assessment, prophylactic bilateral mastectomy is an option to consider for mutation carriers. For women with low BC-risk, chemoprevention can be discussed. Chemoprevention with tamoxifen (TAM)--indirectly supported by BC data from the raloxifen (RLX) prevention trial for osteoporosis and cardio-vascular disease--points to the right direction. Results from the three published TAM prevention trials are variable. Life time risk, age and life style have to be considered in the adapted individual risk-benefit assessment. The lack of long term risk data for chemoprevention and the effect on survival are arguments contra the routine use of TAM as a chemopreventive agent.