"More life and more days"-patient and care characteristics in a specialized acute pediatric palliative care inpatient unit.

Only a few acute hospital inpatient units dedicated to pediatric palliative care (PPC) patients exist today. Clinical data on the patients and care provided at specialized acute PPC inpatient units (PPCUs) are scarce. This study aims at describing patient and care characteristics on our PPCU to learn about the complexity and relevance of inpatient PPC. A retrospective chart analysis was performed on the 8-bed PPCU of the Center for Pediatric Palliative Care of the Munich University Hospital, including demographic, clinical, and treatment characteristics (487 consecutive cases; 201 individual patients; 2016-2020). Data were analyzed descriptively; the chi-square test was used for comparisons. Patients' age (1-35.5 years, median: 4.8 years) and length of stay (1-186 days, median 11 days) varied widely. Thirty-eight percent of patients were admitted repeatedly (range 2-20 times). Most patients suffered from neurological diseases (38%) or congenital abnormalities (34%); oncological diseases were rare (7%). Patients' predominant acute symptoms were dyspnea (61%), pain (54%), and gastrointestinal symptoms (46%). Twenty percent of patients suffered from > 6 acute symptoms, 30% had respiratory support incl. invasive ventilation, 71% had a feeding tube, and 40% had full resuscitation code. In 78% of cases, patients were discharged home; 11% died on the unit. CONCLUSION: This study shows the heterogeneity, high symptom burden, and medical complexity of the patients on the PPCU. The high dependency on life-sustaining medical technology points to the parallelism of life-prolonging and palliative treatments that is typical for PPC. Specialized PPCUs need to offer care at the intermediate care level in order to respond to the needs of patients and families. WHAT IS KNOWN: • Pediatric patients in outpatient PPC or hospices present with a variety of clinical syndromes and different levels of complexity and care intensity. • There are many children with life-limiting conditions (LLC) in hospitals, but specialized PPC hospital units for these patients are rare and poorly described. WHAT IS NEW: • Patients on a specialized PPC hospital unit show a high symptom burden and a high level of medical complexity, including dependency on medical technology and frequent full resuscitation code. • The PPC unit is mainly a place for pain and symptom management as well as crisis intervention, and needs to be able to offer treatment at the intermediate care level.

Exposure considerations in human safety assessment: Report from an EPAA Partners' Forum.

Understanding and estimating the exposure to a substance is one of the fundamental requirements for safe manufacture and use. Many approaches are taken to determine exposure to substances, mainly driven by potential use and regulatory need. There are many opportunities to improve and optimise the use of exposure information for chemical safety. The European Partnership for Alternative Approaches to Animal Testing (EPAA) therefore convened a Partners' Forum (PF) to explore exposure considerations in human safety assessment of industrial products to agree key conclusions for the regulatory acceptance of exposure assessment approaches and priority areas for further research investment. The PF recognised the widescale use of exposure information across industrial sectors with the possibilities of creating synergies between different sectors. Further, the PF acknowledged that the EPAA could make a significant contribution to promote the use of exposure data in human safety assessment, with an aim to address specific regulatory needs. To achieve this, research needs, as well as synergies and areas for potential collaboration across sectors, were identified.

Reference Chemical Potency List (RCPL): A new tool for evaluating the accuracy of skin sensitisation potency measurements by New Approach Methodologies (NAMs).

Considerable progress has been made in the design of New Approach Methodologies (NAMs) for the hazard identification of skin sensitising chemicals. However, effective risk assessment requires accurate measurement of sensitising potency, and this has proven more difficult to achieve without recourse to animal tests. One important requirement for the development and adoption of novel approaches for this purpose is the availability of reliable databases for determining the accuracy with which sensitising potency can be predicted. Some previous approaches have relied on comparisons with potency estimates based on either human or animal (local lymph node assay) data. In contrast, we here describe the development of a carefully curated Reference Chemical Potency List (RCPL) which is based on consideration of the best available human and animal data. The RCPL is comprised of 33 readily available chemicals that span a wide range of chemistry and sensitising potency, and contain examples of both direct and indirect (pre- and pro-) haptens. For each chemical a potency value (PV) was derived, and chemicals ranked according to PV without the use of potency categories. It is proposed that the RCPL provides an effective resource for assessment of the accuracy with which NAMs can measure skin sensitising potency.

Use of New Approach Methodologies (NAMs) in regulatory decisions for chemical safety: Report from an EPAA Deep Dive Workshop.

New Approach Methodologies (NAMs) are considered to include any in vitro, in silico or chemistry-based method, as well as the strategies to implement them, that may provide information that could inform chemical safety assessment. Current chemical legislation in the European Union is limited in its acceptance of the widespread use of NAMs. The European Partnership for Alternative Approaches to Animal Testing (EPAA) therefore convened a 'Deep Dive Workshop' to explore the use of NAMs in chemical safety assessment, the aim of which was to support regulatory decisions, whilst intending to protect human health. The workshop recognised that NAMs are currently used in many industrial sectors, with some considered as fit for regulatory purpose. Moreover, the workshop identified key discussion points that can be addressed to increase the use and regulatory acceptance of NAMs. These are based on the changes needed in frameworks for regulatory requirements and the essential needs in education, training and greater stakeholder engagement as well the gaps in the scientific basis of NAMs.

Finding synergies for the 3Rs - Repeated Dose Toxicity testing: Report from an EPAA Partners' Forum.

The European Partnership for Alternative Approaches to Animal Testing (EPAA) convened a Partners' Forum on repeated dose toxicity (RDT) testing to identify synergies between industrial sectors and stakeholders along with opportunities to progress these in existing research frameworks. Although RTD testing is not performed across all industrial sectors, the OECD accepted tests can provide a rich source of information and play a pivotal role for safety decisions relating to the use of chemicals. Currently there are no validated alternatives to repeated dose testing and a direct one-to-one replacement is not appropriate. However, there are many projects and initiatives at the international level which aim to implement various aspects of replacement, reduction and refinement (the 3Rs) in RDT testing. Improved definition of use, through better problem formulation, aligned to harmonisation of regulations is a key area, as is the more rapid implementation of alternatives into the legislative framework. Existing test designs can be optimised to reduce animal use and increase information content. Greater use of exposure-led decisions and improvements in dose selection will be beneficial. In addition, EPAA facilitates sharing of case studies demonstrating the use of Next Generation Risk Assessment applying various New Approach Methodologies to assess RDT.

Finding synergies for 3Rs - Toxicokinetics and read-across: Report from an EPAA partners' Forum.

The European Partnership for Alternative Approaches to Animal Testing (EPAA) convened a Partners' Forum Toxicokinetics and Read-Across to provide an overview on research activities to develop in vitro toxicokinetics methods and physiologically-based kinetic (PBK) models and to find synergies to enhance use of toxicokinetic data to strengthen read-across. Currently, lacking toxicokinetic data often prevent the application of read-across. Preferably, toxicokinetic data should be generated using in vitro and in silico tools and anchored towards human relevance. In certain sectors, PBK modelling is being used for risk assessment, but less so in others. Specific activities were identified to facilitate the use of in vitro and in silico toxicokinetic data to support read-across: The collation of available tools indicating the parameters and applicability domains covered; endpoint-specific guidance on toxicokinetics parameters required for read-across; case studies exemplifying how toxicokinetic data help support read-across. Activities to enhance the scientific robustness of read-across include the further user-friendly combination of read-across tools and formal guidance by the authorities specifying the minimum information requirements to justify read-across for a given toxicity endpoint. The EPAA was invited to continue dissemination activities and to explore possibilities to collate a contemporaneous list of open toxicokinetics tools that assist risk assessment.

First identification of Ewing's sarcoma-derived extracellular vesicles and exploration of their biological and potential diagnostic implications.

BACKGROUND INFORMATION: Exosomes are small RNA- and protein-containing extracellular vesicles (EVs) that are thought to mediate hetero- and homotypic intercellular communication between normal and malignant cells.Tumour-derived exosomes are believed to promote re-programming of the tumour-associated stroma to favour tumour growth and metastasis. Currently, exosomes have been intensively studied in carcinomas. However, little is known about their existence and possible role in sarcomas. RESULTS: Here, we report on the identification of vesicles with exosomal features derived from Ewing's sarcoma(ES), the second most common soft-tissue or bone cancer in children and adolescents. ES cell line-derived EV shave been isolated by ultracentrifugation and analysed by flow-cytometric assessment of the exosome-associated proteins CD63 and CD81 as well as by electron microscopy. They proved to contain ES-specific transcripts including EWS-FLI1, which were suitable for the sensitive detection of ES cell line-derived exosomes by qRT-PCRin a pre-clinical model for patient plasma. Microarray analysis of ES cell line-derived exosomes revealed that they share a common transcriptional signature potentially involved in G-protein-coupled signalling, neurotransmitter signalling and stemness. CONCLUSIONS: In summary, our results imply that ES-derived exosomes could eventually serve as biomarkers for minimal residual disease diagnostics in peripheral blood and prompt further investigation of their potential biological role in modification of the ES-associated microenvironment

Survey of compartment syndrome of the lower extremity after gynecological operations.

PURPOSE: This study was aimed to investigate incidence, circumstances and consequences of acute compartment syndrome (CS) of the lower extremity after gynecological operations in lithotomy position by collecting data from departments of Obstetrics and Gynecology in Germany. DESIGN: Retrospective observational study. SETTING: Departments of Obstetrics and Gynecology in the area of North Rhine (Germany) METHODS: A 24-item questionnaire was sent to 168 gynecological departments. In addition, cases anonymously reported to the Expert Committee for Medical Malpractice Claims of the Medical Association of North Rhine between 2002 and 2012 were analyzed. MAIN OUTCOME MEASURE: Incidence of acute CS after gynecological operations. RESULTS: A total of 59 questionnaires (35 %) were returned for analysis, reporting 21 cases of CS. Based on the collected data, we calculated an incidence of postoperative CS ranging between 0.067 % and 0.28 %. All reported cases of postoperative CS occurred after surgeries in lithotomy position, 57.1 % of cases occurred after laparoscopic procedures and 76.2 % after procedures longer than 4 h. Overall, 61.0 % of departments do not routinely inform about the risk of this complication when they get patients' informed consent. Reported prevention strategies were inconsistent and ranged from none to multiple measures. CONCLUSION: CS is a complication clearly associated with long lasting gynecological operations in Lithotomy position. Despite a relatively high incidence, so far no guidelines on perioperative management and medicolegal aspects exist and preventive measures are heterogeneous among institutions. The need for guidelines and recommendations by an expert committee has been identified.

Switching a baby from IV levomethadone to IV fentanyl.

Methadone, or in Germany levomethadone, may be used for the treatment of iatrogenic opioid withdrawal syndrome in pediatric intensive care units. The limited literature on opioid rotation in children does not provide data for the switch from methadone to another opioid. We report switching a very ill preterm baby in an unstable condition from IV levomethadone to IV fentanyl identifying a possible conversion ratio of 6.0-4.5:1 emphasizing critical steps as equipotency appropriate for neonates and dose reduction for incomplete cross-tolerance. If clinical deterioration occurs in infants on opioid tapering with levomethadone, we hope that our observations may be helpful.

Status quo and current trends of operating room management in Germany.

PURPOSE OF REVIEW: Ongoing healthcare reforms in Germany have required strenuous efforts to adapt hospital and operating room organizations to the needs of patients, new technological developments, and social and economic demands. This review addresses the major developments in German operating room management research and current practice. RECENT FINDINGS: The introduction of the diagnosis-related group system in 2003 has changed the incentive structure of German hospitals to redesign their operating room units. The role of operating room managers has been gradually changing in hospitals in response to the change in the reimbursement system. Operating room managers are today specifically qualified and increasingly externally hired staff. They are more and more empowered with authority to plan and control operating rooms as profit centers. For measuring performance, common perioperative performance indicators are still scarcely implemented in German hospitals. In 2008, a concerted time glossary was established to enable consistent monitoring of operating room performance with generally accepted process indicators. These key performance indicators are a consistent way to make a procedure or case - and also the effectiveness of the operating room management - more transparent. SUMMARY: In the presence of increasing financial pressure, a hospital's executives need to empower an independent operating room management function to achieve the hospital's economic goals. Operating room managers need to adopt evidence-based methods also from other scientific fields, for example management science and information technology, to further sustain operating room performance.

Single large inguinal lymph node metastasis in human papillomavirus-induced early invasive vulvar cancer of the anterior fourchette in two young women.

The incidence of human papillomavirus (HPV)-induced vulvar cancer in young women is increasing and often presents as microinvasive or early invasive tumors in a grade 3 vulvar intraepithelial neoplasia. So far, the risk of lymph node metastases in early invasive vulvar carcinoma (depth of invasion 1.1-2.0 mm) is reported to be less than 8%. We present 2 cases of young women with early invasive vulvar cancers (depth of invasion 1.5 and 2.0 mm) induced by HPV 16 and 42. In both cases, the cancers are located between the clitoris and urethra and are each accompanied by one groin macro-metastatic lymph node. This case report highlights the necessity for complete inguinofemoral lymphadenectomy and/or adequate radiation therapy of the groin in early invasive tumors in young women to prevent cancer recurrence in the groin. Additionally, the indication for a sentinel node procedure in these specific cases requires particular caution.

How work context affects operating room processes: using data mining and computer simulation to analyze facility and process design.

The complexity of the operating room (OR) requires that both structural (eg, department layout) and behavioral (eg, staff interactions) patterns of work be considered when developing quality improvement strategies. In our study, we investigated how these contextual factors influence outpatient OR processes and the quality of care delivered. The study setting was a German university-affiliated hospital performing approximately 6000 outpatient surgeries annually. During the 3-year-study period, the hospital significantly changed its outpatient OR facility layout from a decentralized (ie, ORs in adjacent areas of the building) to a centralized (ie, ORs in immediate vicinity of each other) design. To study the impact of the facility change on OR processes, we used a mixed methods approach, including process analysis, process modeling, and social network analysis of staff interactions. The change in facility layout was seen to influence OR processes in ways that could substantially affect patient outcomes. For example, we found a potential for more errors during handovers in the new centralized design due to greater interdependency between tasks and staff. Utilization of the mixed methods approach in our analysis, as compared with that of a single assessment method, enabled a deeper understanding of the OR work context and its influence on outpatient OR processes.

Invasive breast cancer cells exhibit increased mobility of the actin-binding protein CapG.

The CapG protein, a Gelsolin-related actin-binding protein, is expressed at higher levels in breast cancer, especially in metastasizing breast cancer, than in normal breast epithelium. Furthermore, it is known that an increased expression of the CapG protein triggers an increase in cell motility. According to in vitro experiments, it was supposed that it is the nuclear fraction of the protein, which causes the increase in cell motility. Here, we examined the dynamical distribution of the CapG protein within the living cell, i.e. the import of the CapG protein into the nucleus. The nuclear import kinetics of invasive, metastasizing breast cancer cells were compared to the import kinetics of non-neoplastic cells similar to normal breast epithelium. FRAP kinetics showed a highly significant increase in the recovery of photobleached CapG-eGFP in the cancer cells, so that a differentiation of invasive, metastasizing cells and non-invasive, non-metastasizing cells on the basis of transport processes of the CapG protein between the nucleus and the cytoplasm seems to be possible. Comprehension of the mobility and compartmentalization of the CapG protein in normal and in cancer cells in vivo could constitute a new basis to characterize the invasiveness and metastasizing potential of breast cancer.

PRODH variants and risk for schizophrenia.

Schizophrenia is a common, devastating neuropsychiatric disorder whose etiology is largely unknown. Multiple studies in humans and in mouse and fly models suggest a role for proline and PRODH, the gene encoding the first enzyme in the pathway of proline catabolism, in contributing risk for schizophrenia. Other studies, however, reach contradictory conclusions. Here, we provide a critical review of the data in the context of what is known about proline metabolism and suggest studies for the future. Overall, there is considerable evidence supporting a role for certain loss of function PRODH variants conferring risk for schizophrenia in some individuals.

New aspects of vulvar cancer: changes in localization and age of onset.

OBJECTIVE: To characterize the changes in incidence, age of disease onset, tumor site and patients characteristics in women with invasive vulvar cancer in a German University Hospital unit over a 28-year period. METHODS: The clinical records for women treated for invasive vulvar cancer from 01/1980 until 06/2007 were analyzed. We performed a retrospective analysis for three 9-year periods: 1/1980 to 02/1989; 3/1989 to 04/1998 and 05/1998 to 06/2007. For each cohort, the number of cases treated, age of disease onset, tumor site and further characteristics were extracted and statistically evaluated. RESULTS: A total of 224 patients with vulvar cancer were identified between 1/1980 and 6/2007. The number and mean age changed significantly over time: between 1/1980 and 02/1989 53 women with a mean age of 65.6 years were treated for invasive vulvar cancer, between 03/1989 and 04/1998 this number increased to 69 women with a mean age of 63.9 years and in the last period, 102 women with a mean age of 57.0 years were treated for vulvar cancer. The total increase was 192%. In the first period 11% of the women were aged 50 years or less compared with over 41% in the third period (p=0.001). Two-third of the tumors women aged<50 years were HPV-positive. Significant changes in the tumor site were observed; from labial position to the region between clitoris and urethra: 37% in the last period compared with 19% in the first period (p>0.05). CONCLUSIONS: Although in the literature the incidence of invasive cancer has been reported to be stable or only minimally increased, the results of this study show that the number of patients presenting with invasive vulvar cancer has doubled within the last three decades at one university hospital unit in Germany, with a nearly 4-time increase in younger patients (+372%) due to HPV high risk infection. The tumor localization changed significantly from the labia to the area between the clitoris and urethra. Assuming that these limited data reflect the general trend in the incidence of HPV-induced vulvar cancer, widely-implemented prophylactic quadrivalent HPV vaccination, which has been proven to be highly effective against anogenital disease, could make an important contribution to the reduction of the risk of vulvar carcinomas in younger women.

An unusual case of advanced bilateral male breast cancer.

BACKGROUND: Breast cancer in men is an uncommon disease. Little is known about its etiology, clinical behavior, treatment, and outcome. Retrospective data indicate that stage- and age-matched male and female breast cancer is similar in presentation. The aim is to find an adequate treatment for male breast cancer, which is not just extrapolated from its female counterpart. CASE REPORT: We present the history of a 41-year-old man who was diagnosed with pT2 (3 cm) breast cancer in 2001. After mastectomy without axillary dissection, 4 cycles of adjuvant epirubicin and cyclophosphamide and radiation therapy were performed followed by hormonal treatment with tamoxifen until 2003. In 2003, 2004, 2005, and 2006, there were relapses with skin metastases, treated with several courses of chemotherapy. In 2006, an inflammatory carcinoma in the contralateral breast was revealed during the course of epirubicin chemotherapy. In May 2007, the patient passed away from extensive tumor progression despite numerous attempts of local and systemic chemotherapeutic treatment. CONCLUSION: Here, an unusual case of male breast cancer is reported. It was first diagnosed at the age of 41 years, which is relatively young for male breast cancer. Although the treatment was started at an early stage, several relapses and contralateral breast cancer occurred within 5 years and could no be controlled.

Comprehensive analysis of 130 multicentric intraepithelial female lower genital tract lesions by HPV typing and p16 expression profile.

PURPOSE: HPV associated cervical transformation is characterized by well-defined steps, including persistent HPV infection and deregulated oncogene expression. Recent studies have suggested that a number of lower genital tract lesions are clonally related to cervical lesions. In the current study, HPV infections and oncogene expression were assessed in a large series of patients with multicentric lower genital tract disease to analyze the transformation steps in extracervical disease. METHODS: One hundred and thirty biopsies of 52 women treated for multicentric synchronous or metachronous lower genital tract intraepithelial neoplasias were collected. Up to seven multicentric specimens taken from one patient were studied with a maximum follow up of 20 years. HPV typing and p16(ink4a) immunostaining was performed. RESULTS: HPV DNA was present in 121 of 130 specimens (93%). HPV16 was frequently found in VIN, VaIN and AIN (73, 60 and 77%, respectively), whereas only 37% of CIN were HPV16 positive. Infections with identical HPV types in multicentric lesions were diagnosed in 46% of the HPV positive patients. p16INK4a expression was negative in the nine HPV negative lesions whereas about 90% of the high grade lesions showed diffuse p16 staining. CONCLUSION: Our findings indicate that multicentric lower genital tract disease evolves through different pathways. Some cases were related to a high susceptibility towards HPV infections, while others exhibited features of clonal propagation of transformed cervical cell clones. The clinical management of the latter group is particularly challenging, because malignant cell clones can persist over a long time course.

Role of FDG-PET in the assessment of survival prognosis in melanoma.

Positron-emission tomography (PET) employing fluorodeoxyglucose (FDG) has proven to be a highly sensitive and specific diagnostic method in the staging and restaging of various neoplasms, including melanoma, complementing morphologic imaging. FDG uptake has been correlated with proliferation rate, and thus, the degree of malignancy of a given tumor (i.e., grading). Consecutively, a relationship of survival prognosis and the extent of tumor burden as well as degree of FDG accumulation--determined by FDG-PET--has been suggested in various tumors. The aim of this study was to assess the potential of fluor-18-FDG-PET in order to evaluate the survival prognosis in melanoma. Patient data (n=95) were retrospectively analyzed, and the results of functional FDG-PET staging was correlated with survival data. Time of staging (diagnosis of primary versus recurrence) had no statistically significant effect on survival prognosis when patients were matched for pertaining node metastasis (NM) stages. Differences in survival were owing to the presence of metastatic disease rather than time of staging. Tumor (T)-stage (T1-T4) alone had no effect on survival prognosis when patients were matched for NM stages. Differences in survival were also due to higher rates of lymph node (LN) and organ metastases in higher T-stages. Detection of LN metastases (N1M0) had a statistically significant and predominant impact on 5-year survival (N0M0 80% versus N1M0 45%; p<0.01). Additional presence of distant metastases in LN-positive patients (N1M1) had only a statistically insignificant further impact on survival (5-year survival in N1M0 45% versus N1M1 29%; p>0.05). Exclusive presence of organ metastases (N0M1) showed a statistically significant drop of survival with a 5-year survival of 61% in N0M1 versus 80% in N0M0, respectively (p<0.03). Further, the combined presence of LN and distant metastases had the worst prognosis (5-year survival in N1M1 29% versus N0M1 61%; p<0.02). Based on a qualitative 4-point scoring system, patients with malignancy-typical FDG uptake showed an overall 5-year survival of 38%, as compared to patients with malignancy-suspicious lesions (71%; p

Functional group analysis of starches reacted with urea-phosphoric acid-Correlation of wet chemical measures with FT Raman spectroscopy.

Because the degree of substitution (DS) of chemically modified starches strongly affects their physicochemical properties and applications, rapid techniques for its determination are crucial. In the present work, ammonium starch phosphates carbamates (SPC) were obtained by reacting starch with urea-phosphoric acid. DS of phosphate (DSP), carbamate (DSC), and ammonium groups (DSNH4+) and contents of non-hydrolyzable amides (Nnh) of SPC were determined using the vanadomolybdophosphoric acid and saponification methods, respectively. It was the aim to investigate the extent to which Raman features of SPC relate to their DS values of different functional groups as obtained by wet chemistry. Strong linear correlations (R2=0.967…0.995) were found between DSP, DSNH4+, and the degree of substitution of urea (DSurea) and Raman signals at 820, 1710 and 1015cm-1. Thus, with appropriate calibration, Raman spectroscopy is a promising tool for the simultaneous and rapid determination of the level of phosphorylation and the ammonium and urea contents of SPC.