Early tumor regrowth is a contributor to impaired survival in patients with completely resected advanced ovarian cancer. An exploratory analysis of the Intergroup trial AGO-OVAR 12.

OBJECTIVE: Surgical assessment of residual tumor provides the strongest prognostic information in advanced ovarian cancer (AOC), with the best outcome observed after complete resection. Postoperative radiological assessment before initiation of chemotherapy can supplement the information obtained by surgical assessment; however, it may also reveal conflicting findings. METHODS: Patients with AOC enrolled in the AGO-OVAR 12 trial underwent baseline imaging before the first chemotherapy cycle. The findings from surgical and radiologic assessment for disease extend were compared. Additionally, an integrated approach was assessed. RESULTS: Complete data from all 3 assessment methods were available for 1345 patients. Of 689 patients with complete resection, tumor was observed in 28% and 22% of patients undergoing radiologic and integrated assessment, respectively. Patients with surgical- radiological and surgical-integrated concordant findings showed a 5-year overall survival (5Y-OS) of 72% and 71%, whereas patients with surgical-radiological and surgical-integrated discordant results showed inferior 5Y-OS of 47% and 49%, respectively. Patients with surgically assessed residual disease had a 5-YOS of 37%. The interval between surgery and baseline assessment was independently associated with discordance between assessment methods, which might reflect early tumor regrowth. CONCLUSIONS: Baseline tumor assessment before chemotherapy provides information that stratifies patients with complete resection into different prognostic groups. Integrating the data from different assessment methods might lead to improved definitions of prognostic groups. Further investigation to determine if earlier initiation of chemotherapy after debulking surgery could increase survival of patients with early tumor regrowth is warranted.

Fifth Ovarian Cancer Consensus Conference of the Gynecologic Cancer InterGroup: recurrent disease.

This manuscript reports the consensus statements regarding recurrent ovarian cancer (ROC), reached at the fifth Ovarian Cancer Consensus Conference (OCCC), which was held in Tokyo, Japan, in November 2015. Three important questions were identified: (i) What are the subgroups for clinical trials in ROC? The historical definition of using platinum-free interval (PFI) to categorise patients as having platinum-sensitive/resistant disease was replaced by therapy-free interval (TFI). TFI can be broken down into TFIp (PFI), TFInp (non-PFI) and TFIb (biological agent-free interval). Additional criteria to consider include histology, BRCA mutation status, number/type of previous therapies, outcome of prior surgery and patient reported symptoms. (ii) What are the control arms for clinical trials in ROC? When platinum is considered the best option, the control arm should be a platinum-based therapy with or without an anti-angiogenic agent or a poly (ADP-ribose) polymerase (PARP) inhibitor. If platinum is not considered the best option, the control arm could include a non-platinum drug, either as single agent or in combination. (iii) What are the endpoints for clinical trials in ROC? Overall survival (OS) is the preferred endpoint for patient cohorts with an expected median OS < or = 12 months. Progression-free survival (PFS) is an alternative, and it is the preferred endpoint when the expected median OS is > 12 months. However, PFS alone should not be the only endpoint and must be supported by additional endpoints including pre-defined patient reported outcomes (PROs), time to second subsequent therapy (TSST), or time until definitive deterioration of quality of life (TUDD).

Recommendations of the German Central Committee against Tuberculosis (DZK) and the German Respiratory Society (DGP) for the Diagnosis and Treatment of Non-tuberculous Mycobacterioses.

Non-tuberculous mycobacterioses comprise a group of diseases caused by mycobacteria which do not belong to the Mycobacterium (M.) tuberculosis-complex and are not ascribed to M. leprae. These mycobacteria are characterized by a broad variety as to environmental distribution and adaptation. Some of the species may cause specific diseases, especially in patients with underlying immunosuppressive diseases, chronic pulmonary diseases or genetic predisposition, respectively. Worldwide, a rising prevalence and significance of non-tuberculous mycobacterioses is recognized. The present recommendations summarise current aspects of epidemiology, pathogenesis, clinical aspects, diagnostics - especially microbiological methods including susceptibility testing -, and specific treatment for the most relevant species. Diagnosis and treatment of non-tuberculous mycobacterioses during childhood and in HIV-infected individuals are described in separate chapters.

Surgical staging and prognosis in serous borderline ovarian tumours (BOT): a subanalysis of the AGO ROBOT study.

BACKGROUND: Incomplete surgical staging is a negative prognostic factor for patients with borderline ovarian tumours (BOT). However, little is known about the prognostic impact of each individual staging procedure. METHODS: Clinical parameters of 950 patients with BOT (confirmed by central reference pathology) treated between 1998 and 2008 at 24 German AGO centres were analysed. In 559 patients with serous BOT and adequate ovarian surgery, further recommended staging procedures (omentectomy, peritoneal biopsies, cytology) were evaluated applying Cox regression models with respect to progression-free survival (PFS). RESULTS: For patients with one missing staging procedure, the hazard ratio (HR) for recurrence was 1.25 (95%-CI 0.66-2.39; P=0.497). This risk increased with each additional procedure skipped reaching statistical significance in case of two (HR 1.95; 95%-CI 1.06-3.58; P=0.031) and three missing steps (HR 2.37; 95%-CI 1.22-4.64; P=0.011). The most crucial procedure was omentectomy which retained a statistically significant impact on PFS in multiple analysis (HR 1.91; 95%-CI 1.15-3.19; P=0.013) adjusting for previously established prognostic factors as FIGO stage, tumour residuals, and fertility preservation. CONCLUSION: Individual surgical staging procedures contribute to the prognosis for patients with serous BOT. In this analysis, recurrence risk increased with each skipped surgical step. This should be considered when re-staging procedures following incomplete primary surgery are discussed.

Age-related prevalence of cross-reactive antibodies against influenza A(H3N2) variant virus, Germany, 2003 to 2010.

To estimate susceptibility to the swine-origin influenza A(H3N2) variant virus (A(H3N2)v) in the German population, we investigated cross-reactive antibodies against this virus and factors associated with seroprotective titre using sera from representative health examination surveys of children and adolescents (n = 815, 2003­06) and adults (n = 600, 2008­10). Antibodies were assessed by haemagglutination inhibition assay (HI); in our study an HI titre ≥ 40 was defined as seroprotective. We investigated associated factors by multivariable logistic regression. Overall, 41% (95% confidence interval (CI): 37­45) of children and adolescents and 39% (95% CI: 34­44) of adults had seroprotective titres. The proportion of people with seroprotective titre was lowest among children younger than 10 years (15%; 95% CI: 7­30) and highest among adults aged 18 to 29 years (59%; 95% CI: 49­67). Prior influenza vaccination was associated with higher odds of having seroprotective titre (odds ratio (OR) for children and adolescents: 3.4; 95% CI: 1.8­6.5; OR for adults: 2.4; 95% CI: 1.7­3.4). Young children showed the highest and young adults the lowest susceptibility to the A(H3N2)v virus. Our results suggest that initial exposure to circulating seasonal influenza viruses may predict long-term cross-reactivity that may be enhanced by seasonal influenza vaccination.

Age-dependent differences in borderline ovarian tumours (BOT) regarding clinical characteristics and outcome: results from a sub-analysis of the Arbeitsgemeinschaft Gynaekologische Onkologie (AGO) ROBOT study.

BACKGROUND: Approximately one-third of all borderline ovarian tumours (BOT) are diagnosed in patients with child-bearing potential. Detailed information regarding their specific characteristics and prognostic factors is limited. METHODS: Clinical parameters of BOT patients treated between 1998 and 2008 in 24 German centres were retrospectively investigated. Central pathology review and prospective follow-up were carried out. Patients <40 versus ≥40 years were analysed separately and then compared regarding clinico-pathological variables and prognosis. RESULTS: A total of 950 BOT patients with a median age of 49.1 (14.1-91.5) years were analysed [280 patients <40 years (29.5%), 670 patients ≥40 years (70.5%)]. Fertility-preserving surgery was carried out in 53.2% (149 of 280) of patients <40 years with preservation of the primarily affected ovary in 32 of these 149 cases (21.5%). Recurrence was significantly more frequent in patients <40 years (19.0% versus 10.1% 5-year recurrence rate, P < 0.001), usually in ovarian tissue, whereas disease-specific overall survival did not differ between the subgroups. In case of recurrent disease, malignant transformation was less frequent in younger than in older patients (12.0% versus 66.7%, P < 0.001), mostly presenting as invasive peritoneal carcinomatosis. Multivariate analysis for patients <40 years identified advanced International Federation of Gynecology and Obstetrics (FIGO) stage and fertility-sparing approach as independent prognostic factors negatively affecting progression-free survival (PFS) while, for patients ≥40 years, higher FIGO stage and incomplete staging was associated with impaired PFS. CONCLUSIONS: Despite favourable survival, young BOT patients with child-bearing potential are at higher risk for disease recurrence. However, relapses usually remain BOT in the preserved ovaries as opposed to older patients being at higher risk for malignant transformation in peritoneal or distant localisation. Therefore, fertility-sparing approach can be justified for younger patients after thorough consultation.

Photo-physical properties of 2-(1-ethynylpyrene)-adenosine: influence of hydrogen bonding on excited state properties.

The photo-physical properties of 2-(1-ethynylpyrene)-adenosine (PyA), a fluorescent probe for RNA dynamics, were examined by solvation studies. The excited-state dynamics display the influence of the vicinity on the spectral features. Combining improved transient absorption and streak camera measurements along with a new analysis method provide a detailed molecular picture of the photophysics. After intramolecular vibrational energy redistribution (IVR), two distinct states are observed. Solvent class (protic/aprotic) and permittivity strongly affect the properties of these states and their population ratio. As a result their emission spectrum is altered, while the fluorescence quantum yield and the overall lifetime remain nearly unchanged. Consequently, the hitherto existing model of the photophysics is herein refined and extended. The findings can serve as basis for improving the information content of measurements with PyA as a label in RNA.

Influenza vaccine effectiveness estimates in Europe in a season with three influenza type/subtypes circulating: the I-MOVE multicentre case-control study, influenza season 2012/13.

In the fifth season of Influenza Monitoring Vaccine Effectiveness in Europe (I-MOVE), we undertook a multicentre case-control study (MCCS) in seven European Union (EU) Member States to measure 2012/13 influenza vaccine effectiveness against medically attended influenza-like illness (ILI) laboratory confirmed as influenza. The season was characterised by substantial co-circulation of influenza B, A(H1N1)pdm09 and A(H3N2) viruses. Practitioners systematically selected ILI patients to swab ≤7 days of symptom onset. We compared influenza-positive by type/subtype to influenza-negative patients among those who met the EU ILI case definition. We conducted a complete case analysis using logistic regression with study as fixed effect and calculated adjusted vaccine effectiveness (AVE), controlling for potential confounders (age, sex, symptom onset week and presence of chronic conditions). We calculated AVE by type/subtype. Study sites sent 7,954 ILI/acute respiratory infection records for analysis. After applying exclusion criteria, we included 4,627 ILI patients in the analysis of VE against influenza B (1,937 cases), 3,516 for A(H1N1)pdm09 (1,068 cases) and 3,340 for influenza A(H3N2) (730 cases). AVE was 49.3% (95% confidence interval (CI): 32.4 to 62.0) against influenza B, 50.4% (95% CI: 28.4 to 65.6) against A(H1N1)pdm09 and 42.2% (95% CI: 14.9 to 60.7) against A(H3N2). Our results suggest an overall low to moderate AVE against influenza B, A(H1N1)pdm09 and A(H3N2), between 42 and 50%. In this season with many co-circulating viruses, the high sample size enabled stratified AVE by type/subtype. The low estimates indicate seasonal influenza vaccines should be improved to achieve acceptable protection levels.

[Recommendations for diagnosis and treatment of nontuberculous mycobacterioses of the German Central Committee against tuberculosis and the German Respiratory Society]. / Empfehlungen zur Diagnostik und Therapie nichttuberkulöser Mykobakteriosen des Deutschen Zentralkomitees zur Bekämpfung der Tuberkulose (DZK) und der Deutschen Gesellschaft für Pneumologie und Beatmungsmedizin (DGP).

Nontuberculous mycobacterioses comprise a group of diseases caused by mycobacteria which do not belong to the Mycobacterium (M.) tuberculosis complex and are not ascribed to M. leprae. These mycobacteria are characterized by a broad variety as to environmental distribution and adaptation. Some of the species may cause specific diseases, especially in patients with underlying immunosuppressive diseases, chronic pulmonary diseases or genetic predisposition, respectively. Worldwide a rising prevalence and significance of nontuberculous mycobacterioses can be recognized. The present recommendations summarise actual aspects of epidemiology, pathogenesis, clinical aspects, diagnostics - especially microbiological methods including susceptibility testing -, and specific treatment for the most relevant species. Diagnosis and treatment of nontuberculous mycobacterioses during childhood and in HIV-infected individuals are described in separate chapters.

Estimating vaccination coverage in the absence of immunisation registers--the German experience.

Immunisation registers are regarded as an appropriate solution to measure vaccination coverage on a population level. In Germany, a decentralised healthcare system and data protection regulations constrain such an approach. Moreover, shared responsibilities in the process of immunisation and multiple providers form the framework for public health interventions on vaccination issues. On the national level, those interventions consist mainly of conceptualising immunisation strategies, establishing vaccination programmes, and issuing recommendations. This paper provides an overview on sources and methods for collecting appropriate coverage data at national level and their public health relevance in Germany. Methods of data collection and available information on immunisations are described for three approaches: school entrance health examination, population surveys and insurance refund claim data. School entrance health examinations allow regional comparisons and estimation of trends for a specific cohort of children and for all recommended childhood vaccinations. Surveys deliver population based data on completeness and timeliness of selected vaccinations in populations defined by age or socio-demographic parameters and on knowledge and attitudes towards vaccination. Insurance refund claim data inform continuously on immunisation status (e.g. of children aged two years) or on vaccination incidence promptly after new or modified recommendations. In a complex healthcare system, the German National Public Health Institute (Robert Koch Institute, RKI) successfully compiles coverage data from different sources, which complement and validate one another. With the German approach of combining different data sources in the absence of immunisation registers, it is possible to gain solid and reliable data on the acceptance of vaccination programmes and target groups for immunisation. This approach might be of value for other countries with decentralised healthcare systems.

Monozygotic twins discordant for trisomy 18.

We report on the pre- and postnatal cytogenetic, molecular genetic and clinical findings in monochorionic-diamniotic twins discordant for trisomy 18. Structural anomalies were identified in one of the twins on prenatal ultrasound examination at 20 weeks' gestation and sampling of amniotic fluid from both sacs was performed for karyotyping. This revealed trisomy 18 in the twin with abnormalities and a normal karyotype in the other twin. Elective Cesarean section was performed at 31 + 5 weeks and the aneuploid twin died shortly after delivery. The surviving twin showed low-grade mosaicism for trisomy 18 on postnatal analysis but has shown normal development. For prenatal diagnosis in monochorionic-diamniotic twin pregnancy the sampling of both amniotic sacs is recommended, especially if one twin has structural anomalies on ultrasound scan.

[Determination of vaccination coverage and disease incidence using statutory health insurance data]. / Bestimmung von Impfquoten und Inzidenzen von Erkrankungen anhand von Daten der Kassenärztlichen Vereinigungen.

BACKGROUND: The KV-Sentinel, established in 2004, is a joint project of the Robert Koch Institute and the 17 associations of statutory health insurance physicians (ASHIPs) in Germany. The ASHIPs provide anonymous physicians billing data to the Robert Koch Institute. The aim of this article is to describe methodological approaches for processing these routine data to determine vaccination coverage and incidence of vaccine preventable diseases. Furthermore, we discuss limitations in interpreting these data. METHODS: The ASHIPs perform a data query of all vaccinations and of ICD-10 codes for pertussis, measles, mumps, varicella and herpes zoster and send anonymous data to the Robert Koch Institute. We perform routine tests to ensure data quality. Study population is the statutory health insured population (85.5% of the German population). Vaccination coverage is determined by the number of vaccinated persons and the number of statutory health insured persons. Incidence is calculated by the number of diseased persons per 100 000 statutory health insured persons. RESULTS: All 17 ASHIPs participate in the project. In total, 95 905 605 data records for vaccinations and 4 570 919 data records for pertussis, measles, mumps, varicella and herpes zoster were provided from 2004 to 2007. After performing routine tests with regard to structure and content of data, more than 99% of the data records can be analysed. In 2007, the majority of given vaccinations were monovalent vaccinations against influenza (39%) and tick-borne encephalitis (17%). In 2006 and 2007, 1 893 790 data records for diagnoses were provided. Of these, 75% were acute diagnoses and of these 70% were confirmed diagnoses. Most often, ICD-10 codes for herpes zoster (57%) and varicella (35%) were reported. CONCLUSION: Nationwide vaccination coverage of statutory health insured persons by age group can be determined by using billing data. It is possible to validate billing data of vaccinations with available data from other studies. Interpretation of billing data of acute vaccine preventable diseases remains challenging because it is difficult to assess potential under- or overestimation without the possibility of external validation. Therefore, further research is needed.

[Pandemic preparedness planning. What did we learn from the influenza pandemic (H1N1) 2009?]. / Pandemieplanung. Was haben wir aus der Pandemie (H1N1) 2009 gelernt?

Since 2001, the German states and federal institutions have been engaged in systematic pandemic preparedness planning. Preparedness was largely in an advanced stage and most probably contributed to successful control of the influenza H1N1 (2009) pandemic in Germany. Adaptation and improvement are needed most in the fields of vaccine logistics and communication. In the future, the national plan as well as the WHO pandemic plan should distinguish more clearly between pandemic warning phases for preparation of structures, on the one hand, and epidemiologic situations for activation of measures, on the other hand. The proper balance between a uniform national approach and the local adaptation of measures within Germany remains another challenge. Although the course of the influenza pandemic (H1N1) 2009 was moderate, pandemic preparedness planning remains of utmost importance and must be adapted rigorously and early according to the recent experience.

[Management of a new influenza A/H1N1 virus pandemic within the hospital. Statement of the German Society of Pneumology]. / Management der Influenza A/H1N1 - Pandemie im Krankenhaus: Update Januar 2010. Eine Stellungnahme der Deutschen Gesellschaft für Pneumologie und Beatmungsmedizin.

This update summarized the hospital experience from the first wave of the new influenza A/H1/N1 pandemic.

[Overview and assessment of available data sources to determine incidence of vaccine preventable diseases, vaccination coverage, and immune status in Germany]. / Uberblick und Bewertung der verfügbaren Datenquellen zur Inzidenz impfpräventabler Krankheiten, zum Durchimpfungsgrad und zum Immunstatus in Deutschland.

The surveillance of vaccine preventable diseases and vaccination coverage is necessary in order to deliver epidemiological data with respect to national vaccination recommendations and control targets. The data available on the incidence of vaccine preventable diseases, vaccination coverage, and immune status of the population are fragmentary and do not allow the epidemiological situation to be fully assessed. Although the majority of vaccine preventable diseases are under surveillance nationwide (by statutory reporting or sentinel surveillance), data are not available for some diseases. In addition, data on vaccination coverage are not collected centrally. Nationwide data on vaccination coverage are only available for children at school entry. Use of secondary data such as data from health insurance companies or associations of statutory health insurance physicians provides an opportunity to close gaps in knowledge and to improve the surveillance of vaccine preventable diseases.

Prognostic factors in young ovarian cancer patients: An analysis of four prospective phase III intergroup trials of the AGO Study Group, GINECO and NSGO.

OBJECTIVES: We evaluated in a large study meta-database of prospectively randomised phase III trials the prognostic factors for progression-free survival (PFS) and overall survival (OS) in patients < and >40 years of age with advanced epithelial ovarian cancer. METHODS: A total of 5055 patients of the AGO, GINECO, NSGO intergroup studies AGO-OVAR 3, 5, 7 and 9 were merged to identify 294 patients <40 years and 4761 patients ≥40 years. We conducted survival analyses and Cox proportional hazard regression models and additionally analysed a very homogeneous subcohort of 405 patients with serous epithelial ovarian cancer, excellent performance status, who had received complete macroscopic upfront cytoreduction and ≥5 chemotherapy cycles. RESULTS: For patients <40 years, the median PFS was 28.9 months and the median OS was 75.3 months, while the median PFS for patients ≥40 years was 18.1 months and the median OS was 45.7 months. Independent prognostic factors were similar in both age groups. In a multivariate analysis including prognostic factors potentially leading to confounding, young age appeared to improve PFS (hazard ratio [HR], 0.86; 95% confidence interval [CI]: 0.72-1.03) and OS (HR, 0.73; 95% CI: 0.59-0.91). The observed effect was even stronger in the subcohort of optimally treated patients with SEOC: PFS (HR, 0.34; 95% CI: 0.19-0.59) and OS (HR, 0.23; 95% CI: 0.09-0.56). DISCUSSION: Prognostic factors were similar in both age groups. Young age appeared a strong independent protective prognostic factor for PFS and OS in the subcohort.

Brain energy metabolism in early MSA-P: A phosphorus and proton magnetic resonance spectroscopy study.

INTRODUCTION: Recently, mutations in the COQ2 gene, encoding for an enzyme involved in coenzyme Q10 biosynthesis, have been suggested to confer susceptibility risk for multiple system atrophy (MSA). Thus, the possible role of mitochondrial dysfunction in the pathophysiology of MSA has emerged. Here, we studied brain energy metabolism in vivo in early MSA-parkinsonism (MSA-P) patients and compared to healthy controls. METHODS: We have used combined phosphorus and proton magnetic resonance spectroscopy to measure high- and low-energy phosphates in the basal ganglia of early (Hoehn and Yahr stage I-III), probable MSA-P patients (N = 9) compared to healthy controls (N = 9). RESULTS: No significant changes in the high energy phosphates and other parameters reflecting the energy status of the cells were found in the basal ganglia of MSA-P patients compared to healthy controls. N-acetylaspartate was significantly reduced in MSA-P compared to healthy controls and correlated with the Unified Multiple System Atrophy Rating Scale. CONCLUSION: Brain energy metabolism in early MSA-P is not impaired, despite the presence of impaired neuronal integrity. This may imply that mitochondrial dysfunction may not play a primary role in the pathophysiology of MSA, at least in European populations.

Prenatal diagnosis of chromosome abnormalities in the presence of fetal structural defects.

A chromosomal abnormality was found in 42 (10.9%) out of 386 fetuses with a structural defect. Thirty-five of these were diagnosed prenatally, following ultrasonic detection of one or more structural anomalies and associated pathology such as marked intrauterine growth retardation and polyhydramnios. Termination of pregnancy was carried out in 16 fetuses aged less than 26 weeks, intrauterine and neonatal death occurred in 20 cases, the remaining 6 infants were alive at 3 months. The poor outcome in these pregnancies emphasizes the need for prenatal chromosome analysis in the presence of a fetal structural defect.

Interpretation of chromosome mosaicism and discrepancies in chorionic villi studies.

In 3,000 chorionic villi studies (CVS) 33 cases of mosaicism and 7 false-positive cell lines in all cells were seen. The mosaic cell lines were caused by aneuploidy of autosomes (13x), sex chromosomes (9x), and structural anomalies (11x). Mosaics of fetal origin were only 4 cases of trisomy 21 and one 47,XXY mosaic. In 7 cases abnormal karyotype of non-fetal origin was seen in all cells in direct studies, including trisomy 16 (3x) and trisomy 18 (2x). The combined use of direct CVS and cell cultures always uncovered the non-fetal origin of chromosome abnormalities and the study of cultured cells in all cases could have prevented 5 terminations. Complete follow-up studies demonstrated no false-negative results. Therefore, CVS can be nearly 100% accurate when both direct studies and cultures are examined in cases of mosaicism and other cell lines of possible non-fetal origin, such as trisomy 16, trisomy 18, translocation (21;21), and 45,X cells.

Fetal loss rate after chorionic villus sampling and subsequent amniocentesis.

Here we review a group of 82 patients who underwent both chorionic villus sampling (CVS) and amniocentesis in the same pregnancy during the period May 1984-May 1988. A fetal loss rate of 2.5% is documented. This is not essentially different from the sum of fetal loss rates following each of the procedures separately (CVS, 1.9%; amniocentesis, 1.0%) established during the same period.