Patient-reported outcomes before treatment for localized prostate cancer: are there differences among countries? Data from the True North Global Registry.

INTRODUCTION: Similar Patient-Reported Outcomes (PROs) at diagnosis for localized prostate cancer among countries may indicate that different treatments are recommended to the same profile of patients, regardless the context characteristics (health systems, medical schools, culture, preferences…). The aim of this study was to assess such comparison. METHODS: We analyzed the EPIC-26 results before the primary treatment of men diagnosed of localized prostate cancer from January 2017 onwards (revised data available up to September 2019), from a multicenter prospective international cohort including seven regions: Australia/New Zealand, Canada, Central Europe (Austria / Czech Republic / Germany), United Kingdom, Italy, Spain, and the United States. The EPIC-26 domain scores and pattern of three selected items were compared across regions (with Central Europe as reference). All comparisons were made stratifying by treatment: radical prostatectomy, external radiotherapy, brachytherapy, and active surveillance. RESULTS: The sample included a total of 13,483 men with clinically localized or locally advanced prostate cancer. PROs showed different domain patterns before treatment across countries. The sexual domain was the most impaired, and the one with the highest dispersion within countries and with the greatest medians' differences across countries. The urinary incontinence domain, together with the bowel and hormonal domains, presented the highest scores (better outcomes) for all treatment groups, and homogeneity across regions. CONCLUSIONS: Patients with localized or locally advanced prostate cancer undergoing radical prostatectomy, EBRT, brachytherapy, or active surveillance presented mainly negligible or small differences in the EPIC-26 domains before treatment across countries. The results on urinary incontinence or bowel domains, in which almost all patients presented the best possible score, may downplay the baseline data role for evaluating treatments' effects. However, the heterogeneity within countries and the magnitude of the differences found across countries in other domains, especially sexual, support the need of implementing the PRO measurement from diagnosis.

[The interoperability of IIEF-5 with EPIC-26 : Sexual function after radical prostatectomy]. / Die Übertragbarkeit von IIEF-5 (International Index of Erectile Function 5 Item Short Form) auf EPIC-26 (Expanded Prostate Cancer Index Composite 26) : Sexuelle Funktion nach radikaler Prostatektomie.

BACKGROUND: In the past, the IIEF­5 (International Index of Erectile Function 5 ) was predominantly used to measure erectile function in prostate cancer patients. Following international developments, the domain "sexuality" of the EPIC-26 (Expanded Prostate Cancer Index Composite 26) is increasingly used in Germany. OBJECTIVE: The aim of this work is to create a practicable comparison of the domain "sexuality" of the EPIC-26 with the IIEF­5 for treatment in Germany. This is particularly necessary for the evaluation of historical patient collectives. MATERIALS AND METHODS: For the evaluation, 2123 patients with prostate cancer confirmed by biopsy from 2014-2017 who completed both the IIEF­5 and the EPIC-26 were considered. Linear regression analyses are calculated to convert IIEF­5 sum scores to EPIC-26 sexuality domain scores. RESULTS: The correlation between IIEF­5 and the EPIC-26 domain score "sexuality" was 0.74, suggesting a high degree of content convergence between the constructs measured. While the standard error of the predicted values is relatively small, the prediction intervals are very wide. For example, for the critical IIEF­5 value of 22, the predicted value is 78.88 with a 95% prediction interval of 55.09 to 102.66. CONCLUSION: IIEF­5 and the Sexuality scale of the EPIC-26 measure a similar construct. The analysis shows that conversion of individual values is associated with great uncertainty. However, at the group level, the observed EPIC-26 "sexuality" score could be predicted quite accurately. This opens up the possibility of comparing the erectile function of cohorts of patients/test persons, even if this was collected with different measuring instruments.

Current clinical practice and outcome of neoadjuvant chemotherapy for early breast cancer: analysis of individual data from 94,638 patients treated in 55 breast cancer centers.

Neoadjuvant chemotherapy (NACT) is frequently used in patients with early breast cancer. Randomized controlled trials have demonstrated similar survival after NACT or adjuvant chemotherapy (ACT). However, certain subtypes may benefit more when NACT contains regimes leading to high rates of pathologic complete response (pCR) rates. In this study we analyzed data using the OncoBox research from 94,638 patients treated in 55 breast cancer centers to describe the current clinical practice of and outcomes after NACT under routine conditions. These data were compared to patients treated with ACT. 40% of all patients received chemotherapy. The use of NACT increased over time from 5% in 2007 up to 17.3% in 2016. The proportion of patients receiving NACT varied by subtype. It was low in patients with HR-positive/HER2-negative breast cancer (5.8%). However, 31.8% of patients with triple-negative, 31.9% with HR-negative/HER2-positive, and 26.5% with HR-positive/HER2-positive breast cancer received NACT. The rates of pCR were higher in patients with HR-positive/HER2-positive, HR-negative/HER2-positive and triple-negative tumors (36, 53 and 38%) compared to HR-positive/HER2-negative tumors (12%). PCR was achieved more often in HER2-positive and triple-negative tumors over time.This is the largest study on use and effects of NACT in German breast cancer centers. It demonstrates the increased use of NACT based on recommendations in current clinical guidelines. An improvement of pCR was shown in particular in HER2-positive and triple-negative breast cancer, which is consistent with data from randomized controlled trails.

Pharmacokinetics and pharmacodynamics of a single dose of sustained-release azithromycin formulation in pigeons.

To date, only a few studies on the azithromycin (AZM) pharmacokinetics in ornamental birds have been published. In the current study AZM concentrations in domestic pigeon (Columba livia domestica) plasma samples were analyzed using a validated ultra-high performance liquid chromatography tandem mass spectrometry method. The aim of the current study was to carry out an analysis of the pharmacokinetics and pharmacodynamics after administration of a single oral dose of a sustained-release AZM formulation and to conduct a simulation of treatment based on selected minimal inhibitory values. The study was performed with 12 healthy adult pigeons, both sexes. The pigeons tolerated AZM very well and no adverse effects were observed in any animal during the study. Based on the observed characteristics of the pharmacokinetics/ /pharmacodynamics profiles of AZM in pigeons, it should be noted that 35 mg/kg per os as a single starting dose and 25 mg/kg every 24 h are recommended for treatment of both suscep- tible and less susceptible pathogens.

Recommendation of adjuvant trastuzumab treatment in HER-2-positive breast cancer patients: insights from quality indicator data collected in certified breast cancer centers in Germany, Italy, Austria, and Switzerland.

PURPOSE: In 2003, a certification system was introduced to ensure high standards of oncological care in breast cancer patients in Germany. Certified breast cancer centers (BCCs) must fulfill specific requirements including quality indicators (QI) derived from the clinical guidelines that are evaluated in annual audits. When target values for QIs are not fulfilled, centers need to give explanations. We analyzed data from BCCs for a selected indicator: the recommendation of trastuzumab for patients with early HER-2-positive invasive breast cancer. We investigated explanations given in cases when trastuzumab was not recommended to see whether this was justified. METHODS: Patient data from 274 BCCs treating 53,777 primary cases in 2015 were analyzed using descriptive statistics. RESULTS: In the 274 BCC sites, 5700 primary patients with early HER-2-positive breast cancer were treated in 2015. 128 sites (46.7%) did not reach the target value of 95% trastuzumab recommendation and thus had to give explanations. In these 128 sites, 2663 primary HER-2-positive breast cancer patients were treated, 343 (12.9%) of whom did not receive a recommendation for adjuvant trastuzumab treatment. All 128 sites delivered explanations. Overall, 450 explanations were given, allowing multiple explanations for single patients. No explanation was given for 8 of the 343 patients (2.3%). The most common given explanation was multi-/comorbidity (45.5%). CONCLUSIONS: The analysis suggests thorough decision-making when quality indicator target values for a trastuzumab recommendation were not fulfilled. Our data do not provide information on whether such decisions have an impact on treatment outcome for these patients.

Pharmacokinetic profiles of 5 mg/kg ibudilast, a phosphodiesterase inhibitor, orally administered to dogs in fasted and non-fasted states. A preliminary study.

Ibudilast (AV-411) is a non-selective inhibitor of cyclic nucleotide phosphodiesterase (PDE). It is currently marketed for human use in Asian countries for the treatment of asthma, cerebrovascular disorders and ocular allergies. Ibudilast has also been found to have an analgesic action for neuropathic pain at doses 5-10 times higher than those used in asthma therapy. Six healthy Labrador dogs were randomly assigned to two treatment groups using an open, single-dose, two-treatment, two-phase, cross-over design (2x2 Latin-square). Dogs in group 1 (n=3) were fasted for at least 10 hours overnight before the beginning of the experiment and 4 h following dosing while dogs in group 2 (n=3) received food ad libitum. During the first phase, each dog in group 1 and 2 received a single dose of 5 mg/kg ibudilast administered orally. After 1-week washout period the groups were rotated and the experiment was repeated. The analytical method, validated for dog plasma, was shown to be linear in the range 0.10-20 µg/mL. The limit of detection (LOD) and quantification (LOQ) were 0.03 and 0.1 µg/mL, respectively. No behavioural or health alterations were observed in the animals during or after the study. Ibudilast was detectable in plasma for up to 24 h showing a wide variability between animals. Although no statistically significant differences were observed in the present study between the fed and fasted states, examination of the raw data suggests that an effect may be present. The wide degree of variation observed in area under the curve (AUC) suggests that the investigation of population pharmacokinetic modelling is warranted.

Impact of milk yield on pharmacokinetics of six intramammary drugs - a population approach.

The aim of the research was an examination of potential impact of milk yield on the intercompartmental clearance - distribution clearance as well as determination of the variability of obtained pharmacokinetic parameters by the population approach using a two-compartmental structural model. Blood perfusion has a considerable impact on physiology of the udder and kinetics of drugs that are distributed in this organ. The research was performed on healthy Holstein- Friesian and Polish Black-White cows at the age of 4-10 years. Determination of antibiotics (ampicillin, amoxicillin, cefoperazone, penicillin G prokaine, cloxacillin, cefacetril) concentration was carried out after their every intramammary administration to one quarter of the udder. A population pharmacokinetic model was created to fit milk concentration data. General milk yield of a single cow was used as a variable. A population analysis was conducted using non-linear mixed-effect modeling. The impact of milk productivity was set solely by reference to intercompartmental clearance only in case of penicillin G, cloxacillin and ampicillin. It, has been found that milk yield, depending on a drug, influenced the distribution clearance of the drug to varying degrees. It means indirectly that increased perfusion of the udder has a different impact on drug distribution from the udder to the bloodstream.

Withdrawal of cefoperazone with milk after intramammary administration in dairy cows - prospective and retrospective analysis.

The aim of the study was to carry out retrospective and prospective comparative analyses of the pharmacokinetics of CEF after single intramammary (IMM) administration in cows. The prospective study (study A) was conducted on 9 dairy cows of the Polish Black-White race with clinical mastitis during the lactation period. Milk samples were collected at 2, 4, 6, 8, 10, 24, 36, 48, 72 and 84 h after single IMM administration of 250 mg of CEF to one quarter. Drug concentrations in milk samples were determined by HPLC-MS/MS technique and the results of the pharmacokinetic analysis were compared to those obtained in previous studies based on the microbiological (study B) and HPLC-UV methods (study C and D). Pharmacokinetic parameters were calculated based on adapted two-compartment model of drug distribution. One of the findings of the comparison of the analysed investigations is that the CEF kinetics determined with the microbiological method is consistent with the results obtained by the authors of this paper. Both studies yielded similar results of the key pharmacokinetic parameters related to the level of the drug distribution to tissues and elimination half-life. In the pharmacodynamic analysis, the observations in all four studies were entirely consistent and have shown lower values of T>MIC90 in healthy animals and significantly higher values in infected dairy cows. The comparison of studies A, B, C, and D revealed that the time of complete CEF wash-out of 90.90% varied and amounted to 5.7, 8.0, 2.2, and 2.2 days after administration of the drug, respectively. It was confirmed that not only the type of the analytical method but also correct sampling have a significant impact on determination of the correct value of the drug half-life after IMM administration. The comparative analysis of studies in which the milk yield was high and low allows a conclusion that this parameter in the case of CEF has no significant effect on T>MIC90.

Determination of cloxacillin residues in dairy cows after intramammary administration.

The aim of this study was to perform a comparative analysis of the characteristics of cloxacillin (CLO) (MRL of withdrawal in bovine milk is 30 ng/g) after a single intramammary (IMM) dose in the dry period (DP) and lactation (LP), and to establish a high-performance liquid chromatography (HPLC) analytical method for CLO detection in milk. The research was conducted on a group of 10 cows in DP and 10 in LP. A single dose of 600 mg of CLO was administrated by the IMM route for a single quarter in DP and 500 mg for a single quarter in LP. CLO concentration was analyzed by HPLC. CLO was monitored at a wavelength of 206 nm. Pharmacokinetic calculations were performed using Phoenix® WinNonlin® 6.4 software. The calibration curve was linear over the range of 13.03-28 019.00 ng/g with the coefficient of determination R2  > 0.999. CLO withdrawal in both the LP and DP group had a biphasic nature. The total CLO elimination in the DP and LP group was reached after 36 and 6.5 days, respectively. A quantitative and confirmatory method for the determination of CLO in fresh milk has been established. We have confirmed that the withdrawal of CLO in the DP group is not a linear process and has a stepwise character.

[The Willingness to Consent to the Linkage of Primary and Secondary Data: An Analysis Based on a Survey of Patients with Primary Breast Cancer in Northrhine Westfalia]. / Die Bereitschaft zum Datenlinkage von Routinedaten und Primärdaten ­ Eine Analyse auf Basis der Befragung von Patientinnen und Patienten mit primärem Mammakarzinom in NRW.

Introduction: By linking data it is possible to merge, for example, survey data with routine data from statutory health insurance (GKV), to gain benefit from the advantages of both. As personal data is involved, it is necessary to obtain consent. Previous studies show that willingness to release this kind of data for scientific research is limited. This fact restricts the number of participants and can cause selection bias. The aim of our study was to analyze willingness to consent to the linkage of survey data with statutory health insurance data in patients with primary breast cancer. Associations between approval and socio-demographic characteristics were explored. Method: In the annual survey of patients with primary breast cancer in certified breast centers in North Rhine-Westphalia, all included patients were questioned concerning their willingness to consent to data linkage. We distinguished between patients insured by AOK Rhineland/Hamburg and all other patients: based on cooperation with AOK Rhineland/Hamburg, we obtained consent to actually link the data for all patients insured there. All other patients were questioned in terms of their insurance and their willingness to consent in general. Results: A total of 2,387 questionnaires were returned, giving a return rate of 49.3%. For the AOK Rhineland/Hamburg-insured patients, the consent rate was at 89.6%. At 75.7%, positive attitudes towards data linkage turned out to be a bit lower for patients with other insurers. Under the assumption that all non-responders disapprove data linkage, still 38.1% of patients showed a positive attitude towards data linkage. As a result of the multivariable model, insurance status (private vs. statutory) and first language turned out to be the only significant factors influencing the response. The consent of patients insured by AOK Rhineland/Hamburg is not significantly influenced by any of the measured socio-demographic factors. Conclusion: Currently, there is not much knowledge on the acceptance of data linkage in patients suffering from an acute illness. Although our results are restricted to breast cancer patients, they are able to uncover problems and chances concerning data linkage.

[Multilevel Analysis in Health Services Research in Healthcare Organizations: Benefits, Requirements and Implementation]. / Mehrebenenanalysen in der organisationsbezogenen Versorgungsforschung ­ Nutzen, Voraussetzungen und Durchführung.

Multilevel Analysis (MLA) are still rarely used in Health Services Research in Germany, though hierarchical data, e. g. from patients clustered in hospitals, is often present. MLA provide the valuable opportunity to study the health care context in health care organizations and the associations between context and health care outcomes. This article's aims are to introduce this particular method of data analysis, to discuss its' benefits and its' applicability particularly for Health Services Research focusing on organizational characteristics and to provide a concise guideline for performing the analysis. First, the benefits and the necessity for MLA compared to ordinary correlation analyses in the case of hierarchical data are discussed. Furthermore, the statistical requirements and key decisions for the performance of MLA are illustrated.

Validation of relationship between milk resistance and daily yield of dairy cows.

PURPOSE: The reduced value of resistance (R) of milk (<167Ω) or increased conductivity (EC) >6.0 mS/cm indicate the growing number of ions in milk during the initial phase of mastitis. The aim of this study is to demonstrate a linear (verified by a validation procedure) dependency between R and mean daily yield (MDY), which could be used for current monitoring and forecasting of milk yield in dairy cow herds. Although the topic has frequently been examined, a validated model for prediction of MDY based on R has still not been presented. METHODS: Data from 118 dairy cows were analyzed in the study. The validation of model dependency R↔MDY was performed by the live-one-out method (LOO). RESULTS: The minimum geometrical/arithmetical mean of R milk was observed during the 1st month of lactation and was 53.40/254.86 Ω. However, the maximum geometrical/arithmetical mean of R milk was observed during the 7th month of lactation and has 189.62/574.51 Ω. The final model was described by the curve equation MDY = -04461 × R% + 51.58 where R% - percentage share of cows in a herd whose R oscillated within the limits 49.38-154.32 Ω. CONCLUSIONS: Complete predictivity of the model within the above mentioned limits ("prognostic range") was confirmed by the results of validation of the model. The developed model enables the efficiency of a herd at specified percentage share of cows of defined milk R value to be determined.

[Obstacles and facilitators of conducting studies - the perspective of colorectal cancer centers' coordinators]. / Hemmende und fördernde Faktoren bei der Durchführung von Studien - Die Sicht von Darmkrebszentrumskoordinatorinnen und -koordinatoren.

INTRODUCTION: Clinical trials and health services research are crucial pillars for improving patient care. This paper examines factors inhibiting and promoting the study activity and the knowledge and use of trial registries (e. g. DRKS, StudyBox) as an opportunity to learn about existing studies. MATERIAL AND METHODS: The coordinators of 274 cancer center sites certified according to the requirements of the German Cancer Society were surveyed using a standardized online questionnaire. Data were analyzed using descriptive and bivariate statistics to identify associations with characteristics of the sites (e. g. patient volume, ownership, teaching status). RESULTS: 176 sites participated in the survey (64.2 %). The central obstacle to study participa-tion from the centers' view is the low number of existing studies. General knowledge of the population about studies was considered low. Trial registries are known to almost all respondents, but are rarely used. DISCUSSION: The results of the survey suggest that comprehensive measures are needed to sustainably increase the study activity. These include, for example, better information about studies, for example through appropriate databases, and (industry-independent) research funding. One possible way to sensitize patients for studies could be the comprehensive education of the population about the purpose of studies.

Pharmacokinetic investigations of the marker active metabolites 4-methylamino-antipyrine and 4-amino-antipyrine after intramuscular injection of metamizole in healthy piglets.

Metamizole (MT) is a pyrazolone nonsteroidal anti-inflammatory drug labelled for humans and animals. The aim of this study was to assess the pharmacokinetics of its active metabolites 4-methylamino-antipyrine (MAA) and 4-amino-antipyrine (AA) in male piglets after a single intramuscular injection of MT. Eight healthy male piglets were administered MT (100 mg/kg) intramuscularly. Blood was sampled at scheduled time intervals, and drug plasma concentrations evaluated by a validated HPLC method. MAA and AA plasma concentrations were quantitatively detectable from 0.25 to 48 h and 0.50 to 72 h, respectively, in 6 of 8 and 7 of 8 animals. The average maximum concentrations of MAA and AA were of 47.59 and 4.94 mg/mL, respectively. The average half-lives were 8.57 and 13.3 h for MAA and AA, respectively. This study showed that the amount of MAA and AA produced in piglets is different to that in the animal species previously investigated. Further studies are necessary to understand whether these differences in MAA and AA plasma concentrations between animal species necessitate diverse therapeutic drug dosing.

Ten Years of Patient Surveys in Accredited Breast Centers in North Rhine-Westphalia.

Introduction: Patient surveys are an established tool for quality control in healthcare organizations. This report looks at the design and development of the annual patient surveys carried out among breast cancer patients treated in the Breast Centers of North Rhine-Westphalia and discusses selected findings from 10 consecutive years. Material and Methods: Since 2006 the Institute for Medical Sociology, Health Services Research and Rehabilitation Science (IMVR) of the University of Cologne has carried out an annual survey of breast cancer patients using the Cologne Patient Questionnaire for Breast Cancer. The patients included in the survey have been diagnosed with primary breast cancer and undergo surgery between February and July in one of the Breast Centers in North Rhine-Westphalia accredited by the medical association of Westphalia-Lippe. The questionnaire and the type of feedback given to the Breast Centers were comprehensively revised in 2014. Selected results collected over the survey period were analyzed descriptively. Results: The survey period of 10 years provides information on the actual medical care delivered in the Breast Centers based on the data obtained in this period from around 40 000 patients. Some areas showed positive developments over time. Conclusion: The approach used to survey patients, the Cologne Patient Questionnaire for Breast Cancer 2.0 and the benchmark-focused feedback provide an impetus for organizational learning in Breast Centers. The concept could also be used in other healthcare organizations to stimulate learning and improve healthcare services.

[Indicator analysis of prostate cancer centers certified by the German Cancer Society 2015]. / Kennzahlenanalyse der DKG-zertifizierten Prostatakrebszentren des Jahres 2015.

BACKGROUND: Since the first prostate cancer center was certified by the German Cancer Society (DKG) in 2008, there are currently 94 centers at 95 sites. During certification, data on the implementation of the requirements are collected. These data can be used for benchmarking purposes. OBJECTIVES: This paper describes the development and monitoring of indicators and presents a selection of recent results. MATERIALS AND METHODS: The descriptive results on 18,288 primary cases from 91 sites with complete data are presented. RESULTS: The prostate cancer center certification system has reached a plateau both in regard to the absolute number of centers and the total proportion of all primary cases treated in Germany. The implementation of the requirements is at a high level overall, although some centers have difficulties fulfilling selected key figures, e.g., the study quota requirement. CONCLUSION: The evaluation of current indicators documented good structural and process quality, which correspond for the most part to the target values for the total cohort. In the future, assessing medium and long-term outcome quality will be of greater importance, particularly with regard to patient-reported outcomes.

[Quality of Care in Certified Lung Cancer Centers]. / Versorgungsqualität in zertifizierten Lungenkrebszentren.

BACKGROUND: Since 2008, lung cancer centers can be certified in accordance with the criteria set out by the German Cancer Society (Deutsche Krebsgesellschaft). This paper reports on the certification program for lung cancer centers and presents data on 18 quality indicators collected during certification. METHODS: After checks for plausibility and completeness, data on quality indicators for the 2011 and 2012 patient cohorts as well as data of the treating centers were analyzed descriptively (relative/absolute frequencies, means, site medians). PATIENTS: 23,222 patients with ICD-10 diagnoses C33 und C34 from 35 (2012) and 24 operating sites (2011), respectively. RESULTS: From 2011 to 2012, both the number of certified sites and the number of patients treated increased. Fulfillment of the certification requirements is already high and improved slightly from 2011 to 2012. The implementation of indicators without target values is less advanced. CONCLUSION: Thanks to the medical and professional associations as well as the oncologic medical experts, the lung cancer certification program is evolving continuously. There has been a steady increase both in the number of patients treated and the number of lung cancer centers; certification requirements are also being increasingly fulfilled.

[Oncological healthcare research in urology - perspectives]. / Onkologische Versorgungsforschung in der Urologie - ein Ausblick.

Healthcare research has become established as an interdisciplinary self-contained field of research. It has now arrived in oncology and also provides important knowledge on healthcare events and for analysis of healthcare quality in urology. Because healthcare research covers a broad range both methodologically and in content, it is not always easy to maintain an overview of the many concurrently occurring developments. This article describes three current developments, which will probably be come of great importance for oncological healthcare research in the coming years and will also play a role in urology.

Local and systemic immune response in pigs during subclinical and clinical swine influenza infection.

Local and systemic immune responses in pigs intranasally (IN) and intratracheally (IT) inoculated with swine influenza virus (SIV) were studied. No clinical signs were observed in IN-inoculated pigs, while IT-inoculated pigs developed typical signs of influenza. Significantly higher titres of specific antibodies and changes of haematological parameters were found only in IT-inoculated pigs. Because positive correlations between viral titre, local cytokine concentration, and lung pathology have been observed, we hypothesise that both viral load and the local secretion of cytokines play a role in the induction of lung lesions. It could be that a higher replication of SIV stimulates immune cells to secrete higher amounts of cytokines. The results of the present study indicate that pathogenesis of SIV is dependent on both, the damage caused to the lung parenchyma directly by virus, and the effects on the cells of the host's immune system.