Determinants of transplantation success with cryopreserved ovarian tissue: data from 196 women of the FertiPROTEKT network.

STUDY QUESTION: What are the pregnancy and live birth rates for ovarian tissue transplantation and which factors are associated with the success rate? SUMMARY ANSWER: Pregnancy and live birth rates per transplanted woman are 32.7% and 26.5% and success rate is associated with female age and first versus repeated transplantation. WHAT IS KNOWN ALREADY: Live birth rates after ovarian tissue transplantations have been reported to be between around 24% and 41% per patient. Success rates seem to be negatively associated with increasing female age at the time of tissue cryopreservation and with pelvic radiation. Success rates are apparently not reduced after overnight transportation of ovarian tissue before freezing. STUDY DESIGN, SIZE, DURATION: Registry analysis of 244 transplantations in 196 women, performed by 26 FertiPROTEKT network centres from 2007 to 2019 with follow-up till December 2020. PARTICIPANTS/MATERIALS, SETTING, METHODS: Orthotopic ovarian tissue transplantations were performed in 196 women, 191 with previous malignant and 5 with previous non-malignant diseases. Size of transplanting centres varied between 1 and 100 transplantations per centre (median: 2). Factors possibly associated with success rate such as female age, first and repeated transplantation, experience of the transplanting centre and overnight transportation of the ovarian tissue before freezing were analysed. MAIN RESULTS AND THE ROLE OF CHANCE: Average age of all 196 transplanted women was 31.3 years (SD 5.2; range 17-44) at the time of cryopreservation of tissue and 35.9 years (SD 4.8; range 23-47) at the time of transplantation. Pregnancy rate was 30.6% (95% CI, 24.2-37.6%) per first transplantation and 32.7% (95% CI, 26.1-39.7%) per patient. Pregnancy rate was higher after first transplantation (30.6% (95% CI, 24.2-37.6%)) compared to second and subsequent transplantations (11.8% (95% CI, 3.3-27.5%)). Live birth rate per first transplantation was 25.0% (95% CI, 19.1-31.7%) and per patient 26.5% (95% CI, 20.5-33.3%). Success rate decreased with increasing age at the time of ovarian tissue freezing. Live birth rate was 28.2% (95% CI, 20.9-36.3%) in women <35 years and 16.7% (95% CI, 7.9-29.3%) in women >35 years. Pregnancy rates after first transplantation were higher in centres who had performed ≥10 transplantations (35.1%) compared to centres with <10 transplantation (25.4%) (P = 0.12). Corresponding live birth rates were 27.0% and 18.6%. Success rates were not different in women with and without overnight transportation of tissue before cryopreservation. LIMITATIONS, REASONS FOR CAUTION: The data were drawn from a registry analysis. Data such as ovarian reserve and premature ovarian insufficiency were not available for all women. Data might be influenced by different follow-up policies of the centres. WIDER IMPLICATIONS OF THE FINDINGS: The study reveals the high potential of ovarian tissue freezing and transplantation, but only if freezing is performed in younger women. The study suggests focus should be placed on the first and not on repeated transplantations. It also opens the discussion of whether transplantation should rather be performed by experienced centres. STUDY FUNDING/COMPETING INTEREST(S): No funding. No competing interests. TRIAL REGISTRATION NUMBER: N/A.

Dusseldorf autopsies 1914-1918.

This article presents an evaluation of 4255 autopsy cases recorded at the Dusseldorf Pathology Institute in the years 1914 to 1918. Diagnoses were coded according to the International Classification of Diseases, 10th edition (ICD-10), and the contemporaneous history of the Pathology Institute was reviewed. We found a proportion of 54.1% adults and 45.5% children in our cohort, with a male predominance of 63.9%. Infectious diseases account for the majority of all cases (35.5%), among which tuberculosis is the most frequent, reported in 22.7% of all cases. The second largest diagnosis group is the one of respiratory diseases (16.9%), including pneumonia and influenza. Cases of perinatal conditions account for 10.5% of the collective, followed by neoplasms, injuries, intoxications, or external causes, each representing 6.6%. Cardiovascular diseases account for 5.3% of the cases. In 4.4% of the pediatric and 0.8% of adult cases, a diagnosis of the ICD-10 group "nutritional and endocrine diseases" was made. No diagnosis of hunger edema is reported. Parts of the cohort are 272 war pathology cases (6.4%), made up by soldiers who mainly had died of shotgun injuries. The whole cohort represents the disease spectrum of a German big city population at times of World War I. The data exemplify the epidemiological shift that has occurred in industrialized countries over the last 100 years, from infectious to neoplastic and cardiovascular diseases.

Complementary and alternative medicine and musculoskeletal pain in the first year of adjuvant aromatase inhibitor treatment in early breast cancer patients.

BACKGROUND: Patients with breast cancer (BC) show strong interest in complementary and alternative medicine (CAM), particularly for adverse effects of adjuvant endocrine treatment - e.g., with letrozole. Letrozole often induces myalgia/limb pain and arthralgia, with potential noncompliance and treatment termination. This analysis investigated whether CAM before aromatase inhibitor (AI) therapy is associated with pain development and the intensity of AI-induced musculoskeletal syndrome (AIMSS) during the first year of treatment. PATIENTS AND METHODS: The multicenter phase IV PreFace study evaluated letrozole therapy in postmenopausal, hormone receptor-positive patients with early BC. Patients were asked about CAM use before, 6 months after, and 12 months after treatment started. They recorded pain every month for 1 year in a diary including questions about pain and numeric pain rating scales. Data were analyzed for patients who provided pain information for all time points. RESULTS: Of 1396 patients included, 901 (64.5%) had used CAM before AI treatment. Throughout the observation period, patients with CAM before AI treatment had higher pain values, for both myalgia/limb pain and arthralgia, than non-users. Pain increased significantly in both groups over time, with the largest increase during the first 6 months. No significant difference of pain increase was noted regarding CAM use. CONCLUSIONS: CAM use does not prevent or improve the development of AIMSS. Pain intensity was generally greater in the CAM group. Therefore, because of the risk of non-compliance and treatment discontinuation due to the development of higher pain levels, special attention must be paid to patient education and aftercare in these patients.

[TILGen study-immunological targets in patients with breast cancer : Influence of tumor-infiltrating lymphocytes]. / TILGen-Studie ­ Immunologische Angriffspunkte bei Patientinnen mit Brustkrebs : Einfluss der tumorinfiltrierenden Lymphozyten.

BACKGROUND: The interaction of our immune system with breast cancer (BC) cells prompted the investigation of tumor-infiltrating lymphocytes (TILs) and targeted, tumor antigen-specific immunotherapy. OBJECTIVES: Correlation between TILs and pathological complete response (pCR) after neoadjuvant systemic therapy (NACT). Tumor-specific antigens (TSAs) in HER2+ and triple negative BC and establishment of TSA-specific therapies within the interdisciplinary TILGen study. METHODS: Illustration of the TILGen study design. Assessment of TILs and correlation with pCR within this BC study. RESULTS: pCR was achieved in 38.4% (56/146) and associated with estrogen receptor/progesterone receptor negative (ER-/PR-) and HER2+ tumors. Lymphocytic predominant BC (LPBC) was found in 16.4% (24/146), particularly in ER-/PR- (ER-: 27.3% vs. ER+: 9.9%, PR-: 22.3% vs. PR+: 8.2%), large, and poorly differentiated BC. TILs were significantly correlated with pCR in multivariate analysis. In LPBC, pCR was achieved in 66.7%, whereas it was 32.8% in non-LPBC. CONCLUSIONS: First results confirm the influence of the human immune system on the response to NACT in HER2+ and triple negative BC. TSA-specific immunotherapy might improve the outcome in BC patients but there is an urgent need for comprehensive studies to further investigate this issue.

Influence of side-effects on early therapy persistence with letrozole in post-menopausal patients with early breast cancer: Results of the prospective EvAluate-TM study.

BACKGROUND: Endocrine treatment (ET) with an aromatase inhibitor (AI) is the treatment of choice in post-menopausal patients with hormone receptor-positive early breast cancer (EBC). However, adverse events (AEs) often lead to treatment discontinuation. This analysis aimed to identify side-effects that lead to patients failing to persist with letrozole treatment. PATIENTS AND METHODS: Post-menopausal hormone receptor-positive EBC patients starting ET with letrozole were enroled in EvAluate-TM, a non-interventional study. Information regarding treatment compliance and persistence was gathered in months 6 and 12. Persistence was defined as the time from 30 d after the start to the end of treatment. The influence on persistence of musculoskeletal syndrome, menopausal disorder, sleep disorder and other AEs within the first 30 d was analysed using Cox regression analyses. RESULTS: Among 3887 patients analysed, the persistence rate after 12 months was >85%. In all, 568 patients (14.6%) discontinued the treatment, 358 of whom (63.0%) did so only because of side-effects. The main AEs influencing persistence were musculoskeletal symptoms (hazard ratio [HR] 2.55; 95% confidence interval [CI], 1.90-3.42), sleep disorders (HR 1.95; 95% CI, 1.41-2.70) and other AEs (HR 2.03; 95% CI, 1.51-2.73). Menopausal disorder was not associated with non-persistence (HR 1.17; 95% CI, 0.74-1.84). CONCLUSIONS: These results suggest that side-effects of AIs such as musculoskeletal syndrome and sleep disorder lead to ET discontinuation within the first treatment year in significant numbers of EBC patients. Compliance programmes adapted for subgroups that are at risk for early non-persistence might help to ensure the recommended therapy duration. CLINICAL TRIALS NUMBER: CFEM345DDE19.

Influence of patient and tumor characteristics on early therapy persistence with letrozole in postmenopausal women with early breast cancer: results of the prospective Evaluate-TM study with 3941 patients.

Background: Patients' compliance and persistence with endocrine treatment has a significant effect on the prognosis in early breast cancer (EBC). The purpose of this analysis was to identify possible reasons for non-persistence, defined as premature cessation of therapy, on the basis of patient and tumor characteristics in individuals receiving adjuvant treatment with letrozole. Patients and methods: The EvAluate-TM study is a prospective, multicenter, noninterventional study in which treatment with the aromatase inhibitor letrozole was evaluated in postmenopausal women with hormone receptor-positive EBC in the early therapy phase. Treatment persistence was evaluated at two pre-specified study visits after 6 and 12 months. As a measure of early therapy persistence the time from the start to the end of treatment (TTEOT) was analyzed. Cox regression analyses were carried out to identify patient characteristics and tumor characteristics predicting TTEOT. Results: Out of the total population of 3941 patients with EBC, 540 (13.7%) events involving treatment cessation unrelated to disease progression were observed. This was due to drug-related toxicity in the majority of cases (73.5%). Persistence rates were 92.2%, 86.9%, and 86.3% after 6, 12, and 15 months, respectively. The main factors influencing premature treatment discontinuation were older age [hazard ratio (HR) 1.02/year], comorbidities (HR 1.06 per comorbidity), low body mass index, and lower tumor grade (HR 0.85 per grade unit). Conclusion: These results support the view that older, multimorbid patients with low tumor grade and low body mass index are at the greatest risk for treatment discontinuation and might benefit from compliance and support programs.

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.

The International Endometriosis Evaluation Program (IEEP Study) - A Systematic Study for Physicians, Researchers and Patients.

INTRODUCTION: Endometriosis is a heterogeneous disease characterized by a range of different presentations. It is usually diagnosed when patients present with pain and/or infertility, but it has also been diagnosed in asymptomatic patients. Because of the different diagnostic approaches and diverse therapies, time to diagnosis can vary considerably and the definitive diagnosis may be delayed, with some cases not being diagnosed for several years. Endometriosis patients have many unmet needs. A systematic registration and follow-up of endometriosis patients could be useful to obtain an insight into the course of the disease. The validation of biomarkers could contribute to the development of diagnostic and predictive tests which could help select patients for surgical assessment earlier and offer better predictions about patients who might benefit from medical, surgical or other interventions. The aim is also to obtain a better understanding of the etiology, pathogenesis and progression of the disease. MATERIAL AND METHODS: To do this, an online multicenter documentation system was introduced to facilitate the establishment of a prospective multicenter case-control study, the IEEP (International Endometriosis Evaluation Program) study. We report here on the first 696 patients with endometriosis included in the program between June 2013 and June 2015. RESULTS: A documentation system was created, and the structure and course of the study were mapped out with regard to data collection and the collection of biomaterials. CONCLUSION: The documentation system permits the history and clinical data of patients with endometriosis to be recorded. The IEEP combines this information with biomaterials and uses it for scientific studies. The recorded data can also be used to evaluate clinical quality control measures such as the certification parameters used by the EEL (European Endometriosis League) to assess certified endometriosis centers.

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.

[Metastasis of pancreatic tumors]. / Metastasierung von Pankreastumoren.

With a 5-year survival rate that has remained stagnant at 6 % for decades, pancreatic ductal adenocarcinoma (PDAC) is still one of the most fatal malignancies. Despite intensive research, currently available therapy options are less than adequate. As more than half of the patients already show distant metastases at the time of diagnosis, metastatic disease should be a primary focus in the development of new therapeutic strategies. New findings from basic research provide various interesting approaches: molecular profiling of the primary tumor seems to be a possible method to gain knowledge about the prognosis, metastatic potential and therapy response of each individual case of PDAC. Certain subpopulations of cancer stem cells also seem to be of importance in metastasis of PDAC and could become potential therapeutic targets in the future. Interactions between tumor cells and their microenvironment are another crucial factor in the metastasis of pancreatic cancer and present various new starting points for potential therapies. As the number of cell types and signaling pathways that are found to play a role in PDAC metastasis continue to grow, the next big challenge will be to translate these findings into viable clinical applications.

Hormone Therapy and its Effect on the Prognosis in Breast Cancer Patients.

Introduction: Use of hormone therapy (HT) has declined dramatically in recent years. Some studies have reported that HT use before a diagnosis of breast cancer (BC) may be a prognostic factor in postmenopausal patients. This study aimed to examine the prognostic relevance of HT use before BC diagnosis. Methods: Four BC cohort studies in Germany were pooled, and 4492 postmenopausal patients with HT use data were identified. Patient data and tumor characteristics were compared between users and nonusers, along with overall survival (OS), distant metastasis-free survival (DMFS), and local recurrence-free survival (LRFS). Cox proportional hazards models were stratified by study center and adjusted for age at diagnosis, tumor stage, grading, nodal status, and hormone receptors. Results: Women with HT use before the diagnosis of BC were more likely to have a lower tumor stage, to be estrogen receptor-negative, and to have a lower grading. With regard to prognosis there were effects seen for OS, DMFS and LRFS, specifically in the subgroup of women with a positive hormone receptor. In these subgroups, BC patients had a better prognosis with previous HT use. Conclusions: HT use before a diagnosis of BC is associated with a more favorable prognosis in women with a positive hormone receptor status. It may be recommended that the prognostic factor HT should be documented and analyzed as a confounder for prognosis in studies of postmenopausal hormone-responsive breast cancers.

Biomarkers in Patients with Metastatic Breast Cancer and the PRAEGNANT Study Network.

Progress has been made in the treatment of metastatic breast cancer in recent decades, but very few therapies use patient or tumor-specific characteristics to tailor individualized treatment. More than ten years after the publication of the reference human genome sequence, analysis methods have improved enormously, fostering the hope that biomarkers can be used to individualize therapies and offer precise treatment based on tumor and patient characteristics. Biomarkers at every level of the system (genetics, epigenetics, gene expression, micro-RNA, proteomics and others) can be used for this. This has led to changes in clinical study designs, with drug developments often only focusing on small or very small subgroups of patients and tumors. The screening and registration of patients and their molecular tumor data has therefore become very important for the successful completion of clinical studies. This new form of medicine presents particular challenges for patients and physicians. Even in this new age of genome-wide analysis, the focus should still be on the patients' quality of life. This review summarizes recent developments and describes how the PRAEGNANT study network manages the aforementioned medical challenges and changes to create a professional infrastructure for patients and physicians.

Effects of exercise on fracture reduction in older adults: a systematic review and meta-analysis.

UNLABELLED: In this meta-analysis, we evaluated the effect of exercise on fracture reduction in the elderly. Our results determined a significantly positive effect on overall fractures, whereas the possibility of a publication bias indicates the need for well-designed (multi-center) trials that generate enough power to focus on osteoporotic fractures. INTRODUCTION: The preventive effect of exercise on fracture incidence has not been clearly determined yet. Thus, the purpose of this study is to evaluate the effectiveness of exercise in preventing overall and vertebral fractures in older adults by meta-analyses technique. METHODS: This study followed the PRISMA recommendations for systematic reviews and meta-analyses. A systematic review of English articles between 1980 and March 2012 was performed. Terms used were: "exercise", "fractures", "bone", "falls", "osteoporosis", "BMD", "BMC", "bone turnover", while the search was limited to "clinical trial" and "humans". Controlled exercise trials that reported fracture number as endpoint or observation in subjects 45 years and older were included. RESULTS: Ten controlled exercise trials that reported overall fractures and three exercise trials that reported vertebral fractures met our inclusion criteria. Overall fracture number in the exercise group was 36 (n = 754) compared with 73 fractures in the CG (n = 670) (relative risk [RR] = 0.49; 95 % confidence interval [CI], 0.31-0.76). No significant heterogeneity of trial results (p = 0.28; I (2) = 17) was determined; however, there was some evidence to suggest a publication bias. The overall RR for vertebral fracture number (0.56; 95 % CI, 0.30-1.04) (EG: 19 fractures/103 subjects vs. CG: 31 fractures/102 subjects) was borderline non-significant while the heterogeneity of trial results also cannot be ruled out. CONCLUSION: Although there is evidence that exercise reduces overall and, to a lesser degree, vertebral fractures in the elderly, the possibility of publication bias weakens our result and demonstrates the imperative for large exercise studies with dedicated exercise protocols that focus on fractures as a primary endpoint.

Mild hydronephrosis after uncomplicated hysterectomy.

OBJECTIVE: To explore differences in the incidence of hydronephrosis following different hysterectomy methods for benign gynecological disease. STUDY DESIGN: Retrospective chart review of ultrasound findings on all patients undergoing simple hysterectomy for benign gynecological pathology between July 2004 and September 2008. Elective renal ultrasonography was performed pre-operatively and within 3 days after hysterectomy as part of the routine follow-up in our hospital. RESULTS: Of 385 eligible patients, six were excluded because of pre-existing hydronephrosis or suspected intra-operative ureteral injury. In the resulting group of 379 patients, abdominal (33.3%), vaginal (11.8%) or laparoscopic hysterectomy (54.9%) was performed. The last group included total laparoscopic hysterectomy (TLH, 20.3%), laparoscopic supracervical hysterectomy (LASH, 19.3%), and laparoscopically assisted vaginal hysterectomy (LAVH, 15.3%). Overall, 56.7% of patients showed mild hydronephrosis (5-15 mm pelvicalyceal dilatation) after surgery. Mostly, it occurred unilaterally. The incidence varied according to the type of procedure, the highest being documented following vaginal hysterectomy (64.4%) and the lowest after LASH (46.6%), but this did not reach statistical significance. CONCLUSION: Mild hydronephrosis is a frequent finding after uncomplicated hysterectomy for benign pathology in otherwise asymptomatic patients. Although not statistically significant, there may be variability of mild hydronephrosis depending on the hysterectomy method.

Automatic texture-based analysis in ultrasound imaging of ovarian masses.

PURPOSE: To assess the diagnostic accuracy of a new automatic texture-based algorithm (ATBA) in ultrasound imaging of ovarian masses and to compare its performance to subjective assessment by examiners with different levels of ultrasound experience. MATERIALS AND METHODS: A total of 105 ultrasound images from three different groups of ovarian lesions (malignancies, functional cysts, and dermoid cysts) were evaluated using ATBA and by a total of 36 examiners with four different levels of experience (9 junior trainees, 8 senior trainees, 11 senior gynecologists, and 8 experts). Cohen's κ, Youden's indices, and the sensitivity and specificity of ATBA and of each observer were calculated for every subgroup of ovarian lesions. RESULTS: ATBA classified 78 of the 105 masses correctly (κ = 0.62) - results that were significantly better than those of the junior and senior trainees (p = 0.02 and p < 0.01), while differences from the group of level II examiners did not reach statistical significance (p = 0.27). The best diagnostic performance (κ = 0.70) was obtained by the group of expert level III ultrasonographers. The best classification rates overall, including both ATBA and subjective assessments, were achieved in the detection of functional cysts (Youden's indices from 0.73 to 0.85), while the poorest diagnostic performance was obtained for the classification of dermoid cysts (Youden's indices from 0.28 to 0.55). CONCLUSION: ATBA showed a significantly better diagnostic performance than observers with low or medium levels of experience, emphasizing its potential value for training purposes and in providing additional diagnostic assistance for inexperienced observers.

Breast Cancer Risk - From Genetics to Molecular Understanding of Pathogenesis.

Several advancements over the last decade have triggered the developments in the field of breast cancer risk research. One of them is the availability of the human genome sequence along with cheap genotyping possibilities. Another is the globalization of research, which has led to the growth of research collaboration into large international consortia that facilitate the pooling of clinical and genotype data of hundreds of thousands of patients and healthy control individuals. This review concerns with the recent developments in breast cancer risk research and focuses on the discovery of new genetic breast cancer risk factors and their meaning in the context of established non-genetic risk factors. Finally the clinical application is highly dependent on the accuracy of breast cancer risk prediction models, not only for all breast cancer patients, but also for molecular subtypes, preferably for those which are associated with an unfavorable prognosis. Recently risk prediction incorporates all possible risk factors, which include epidemiological risk factors, mammographic density and genetic risk factors.

Mammographic Density and Prediction of Nodal Status in Breast Cancer Patients.

Aim: Nodal status remains one of the most important prognostic factors in breast cancer. The cellular and molecular reasons for the spread of tumor cells to the lymph nodes are not well understood and there are only few predictors in addition to tumor size and multifocality that give an insight into additional mechanisms of lymphatic spread. Aim of our study was therefore to investigate whether breast characteristics such as mammographic density (MD) add to the predictive value of the presence of lymph node metastases in patients with primary breast cancer. Methods: In this retrospective study we analyzed primary, metastasis-free breast cancer patients from one breast center for whom data on MD and staging information were available. A total of 1831 patients were included into this study. MD was assessed as percentage MD (PMD) using a semiautomated method and two readers for every patient. Multiple logistic regression analyses with nodal status as outcome were used to investigate the predictive value of PMD in addition to age, tumor size, Ki-67, estrogen receptor (ER), progesterone receptor (PR), grading, histology, and multi-focality. Results: Multifocality, tumor size, Ki-67 and grading were relevant predictors for nodal status. Adding PMD to a prediction model which included these factors did not significantly improve the prediction of nodal status (p = 0.24, likelihood ratio test). Conclusion: Nodal status could be predicted quite well with the factors multifocality, tumor size, Ki-67 and grading. PMD does not seem to play a role in the lymphatic spread of tumor cells. It could be concluded that the amount of extracellular matrix and stromal cell content of the breast which is reflected by MD does not influence the probability of malignant breast cells spreading from the primary tumor to the lymph nodes.

[Botulinum toxin a treatment in spastic forms of cerebral palsy: a retrospective clinical study]. / Anwendung von Botulinumtoxin A in der Behandlung der spastischen infantilen Zerebralparese: Retrospektive klinische Beobachtungsstudie.

BACKGROUND: Botulinum toxin therapy now has a firm place in the treatment of spastic forms of cerebral palsy in children. This paper considers the subjective and practical results and the degrees of satisfaction from the point of view of the patients and their families. It also documents the data of infiltrations carried out under anaesthesia. PATIENTS AND METHODS: 57 patients with an average age of 11 (± 6.7; 2-30) and with infantile spastic cerebral palsy underwent altogether 118 botulinum toxin A infiltrations. The patients were divided into two groups: those with spastic hemiparesis or diparesis, and those with tetraparesis, and then compared with each other. The results of the treatment were evaluated from the point of view of the patients and their families with the help of a specially developed questionnaire. RESULTS: The study shows that, broadly-speaking, patients less affected with spastic hemiparesis or diparesis felt they profited more from the treatment than patients more severely affected with tetraparesis. The statistics also show that the first group's expectations were significantly more often fulfilled and that they more frequently perceived greater success after each infiltration than the group with tetraparesis. Most patients and their families from both groups were satisfied with the treatment. CONCLUSION: Patients and their families feel that the use of botulinum toxin in the management of spastic cerebral palsy in children is an effective and accepted form of treatment. The aims of the therapy should be defined accurately and realistically before starting treatment, especially for those severely affected with tetraparesis, and discussed in detail with both the patient and his/her family.

Percent Mammographic Density and Dense Area as Risk Factors for Breast Cancer.

Purpose: Mammographic characteristics are known to be correlated to breast cancer risk. Percent mammographic density (PMD), as assessed by computer-assisted methods, is an established risk factor for breast cancer. Along with this assessment the absolute dense area (DA) of the breast is reported as well. Aim of this study was to assess the predictive value of DA concerning breast cancer risk in addition to other risk factors and in addition to PMD. Methods: We conducted a case control study with hospital-based patients with a diagnosis of invasive breast cancer and healthy women as controls. A total of 561 patients and 376 controls with available mammographic density were included into this study. We describe the differences concerning the common risk factors BMI, parital status, use of hormone replacement therapy (HRT) and menopause between cases and controls and estimate the odds ratios for PMD and DA, adjusted for the mentioned risk factors. Furthermore we compare the prediction models with each other to find out whether the addition of DA improves the model. Results: Mammographic density and DA were highly correlated with each other. Both variables were as well correlated to the commonly known risk factors with an expected direction and strength, however PMD (ρ = -0.56) was stronger correlated to BMI than DA (ρ = -0.11). The group of women within the highest quartil of PMD had an OR of 2.12 (95 % CI: 1.25-3.62). This could not be seen for the fourth quartile concerning DA. However the assessment of breast cancer risk could be improved by including DA in a prediction model in addition to common risk factors and PMD. Conclusions: The inclusion of the parameter DA into a prediction model for breast cancer in addition to established risk factors and PMD could improve the breast cancer risk assessment. As DA is measured together with PMD in the process of computer-assisted assessment of PMD it might be considered to include it as one additional breast cancer risk factor that is obtained from breast imaging.

[Periprosthetic femoral bone reaction after total hip arthroplasty with preservation of the collum femoris : CT-assisted osteodensitometry 1 and 3 years postoperatively]. / Periprothetische femorale Knochenreaktion nach schenkelhalserhaltender Hüftendoprothetik : CT-gestützte Osteodensitometrie 1 und 3 Jahre postoperativ.

BACKGROUND: Short-stemmed cementless femoral components in total hip arthroplasty have been designed to preserve the proximal femoral bone stock by load transfer to the femoral metaphysis. An in vivo method of computed tomography-assisted (CT) osteodensitometry after total hip arthroplasty is presented which differentiates between cortical and cancellous bone density (BD) changes around uncemented femoral components. PATIENTS AND METHODS: Cortical and cancellous periprosthetic femoral BD (mg Ca HA/ml) was determined prospectively in 31 patients at day 10, 1 year and 3 years after total hip arthroplasty with preservation of the collum femoris (C.F.P.-stem, Link, Hamburg, Germany) using computed tomography-assisted osteodensitometry. Clinical results (Harris hip score) and plain x-rays were assessed in all cases. RESULTS: Progressive proximal cortical BD loss was observed between the 1 year (Ø -8%) and 3 year (Ø -22%) postoperative measurements. Distal to the trochanter minor no significant cortical BD changes were observed. Proximal cancellous BD decreased progressively between the 1 year (Ø -33%) and 3 year (Ø -45%) analyses. The Harris hip score improved from 45 points pre-operatively to 93 points at the 3 year follow-up. All x-rays showed signs of stable ingrowth. CONCLUSION: Periprosthetic CT osteodensitometry has the technical ability to discriminate between cortical and cancellous bone structures with respect to strain-adapted remodeling. Progressive proximal cortical and cancellous BD loss indicates that metaphyseal fixation cannot be achieved with the analyzed C.F.P. stem design. The lack of cortical BD loss below the trochanter minor suggests diaphyseal fixation of the implanted stem.