Integration of radiation oncology teaching in medical studies by German medical faculties due to the new licensing regulations : An overview and recommendations of the consortium academic radiation oncology of the German Society for Radiation Oncology (DEGRO).

The new Medical Licensing Regulations 2025 (Ärztliche Approbationsordnung, ÄApprO) will soon be passed by the Federal Council (Bundesrat) and will be implemented step by step by the individual faculties in the coming months. The further development of medical studies essentially involves an orientation from fact-based to competence-based learning and focuses on practical, longitudinal and interdisciplinary training. Radiation oncology and radiation therapy are important components of therapeutic oncology and are of great importance for public health, both clinically and epidemiologically, and therefore should be given appropriate attention in medical education. This report is based on a recent survey on the current state of radiation therapy teaching at university hospitals in Germany as well as the contents of the National Competence Based Learning Objectives Catalogue for Medicine 2.0 (Nationaler Kompetenzbasierter Lernzielkatalog Medizin 2.0, NKLM) and the closely related Subject Catalogue (Gegenstandskatalog, GK) of the Institute for Medical and Pharmaceutical Examination Questions (Institut für Medizinische und Pharmazeutische Prüfungsfragen, IMPP). The current recommendations of the German Society for Radiation Oncology (Deutsche Gesellschaft für Radioonkologie, DEGRO) regarding topics, scope and rationale for the establishment of radiation oncology teaching at the respective faculties are also included.

New flow relaxation mechanism explains scour fields at the end of submarine channels.

Particle-laden gravity flows, called turbidity currents, flow through river-like channels across the ocean floor. These submarine channels funnel sediment, nutrients, pollutants and organic carbon into ocean basins and can extend for over 1000's of kilometers. Upon reaching the end of these channels, flows lose their confinement, decelerate, and deposit their sediment load; this is what we read in textbooks. However, sea floor observations have shown the opposite: turbidity currents tend to erode the seafloor upon losing confinement. Here we use a state-of-the-art scaling method to produce the first experimental turbidity currents that erode upon leaving a channel. The experiments reveal a novel flow mechanism, here called flow relaxation, that explains this erosion. Flow relaxation is rapid flow deformation resulting from the loss of confinement, which enhances basal shearing of the turbidity current and leads to scouring. This flow mechanism plays a key role in the propagation of submarine channel systems.

Platelet-rich plasma stimulates dermal microvascular endothelial cells and adipose derived stem cells after external radiation.

BACKGROUND: Platelet-rich plasma (PRP) products are currently suggested in the treatment of chronic wounds due to possible pro-angiogenic effects. Microvascular compromise represents the major component in radiogenic wound healing complications. The effects of PRP on irradiated cells of the cutaneous wound healing process are still poorly understood. MATERIAL AND METHODS: Human dermal microvascular endothelial cells (HDMEC) and human adipose derived stem cells (hASC) were cultured and irradiated with doses of 2 to 12 Gy. PRP was activated, characterized and added to the incubation media in different concentrations after external radiation. Cell count was determined 48 h after radiation using a semi-automated cell counting system. Levels of interleukin-6 (IL-6), basic fibroblast growth factor (bFGF) and soluble intercellular adhesion molecule-1 (sICAM-1) in the supernatants of HDMEC and hASC co-cultures were determined by enzyme-linked immunosorbent assay (ELISA). Non-irradiated hASC and HDMEC served as controls. RESULTS: The employed PRP preparations were characterized and contained platelet derived growth factor (PDGF-AB), vascular endothelial growth factor (VEGF), bFGF and high levels of sICAM-1. Addition of PRP to irradiated cultures of HDMEC and hASC prevented profound radiation-induced decline in cell numbers. 10% PRP restored cell numbers to levels of untreated, non-irradiated cultures. Basic FGF expression was decreased significantly in hASC monocultures treated with 10% PRP without external radiation and after irradiation with 6 and 12 Gy. These inhibitory effects of PRP were also observed in HDMEC. In contrast, co-cultures of HDMEC-ASC showed a dose-dependent increase in bFGF expression when treated with 5 or 10% PRP. Doses of 6 and 12 Gy increased IL-6 expression in cultures stimulated with 5% PRP. CONCLUSIONS: Use of PRP in co-cultures of hASC and HDMEC restores proliferative defects caused by external radiation probably by induction of bFGF. Under irradiated conditions, PRP might induce pro-inflammatory stimuli which could be beneficial in treatment of chronic wounds where healing processes are defective. Combined use of hASC and PRP products might be helpful in the treatment of radiogenic wounds.

Childhood craniopharyngioma - changes of treatment strategies in the trials KRANIOPHARYNGEOM 2000/2007.

BACKGROUND: Prognosis in childhood cranio-pharyngioma, is frequently impaired due to sequelae. Radical surgery was the treatment of choice for decades. Even at experienced facilities radical surgery can result in hypothalamic disorders such as severe obesity. OBJECTIVE: We analyzed, whether treatment strategies for childhood craniopharyngioma patients recruited in GPOH studies have changed during the last 12 years. MATERIALS AND METHODS: We compared the grade of pre-surgical hypothalamic involvement, treatment, degree of resection and grade of surgical hypothalamic lesions between patients recruited in KRANIOPHARYNGEOM 2000 (n=120; 2001-2007) and KRANIOPHARYNGEOM 2007 (n=106; 2007-2012). RESULTS: The grade of initial hypothalamic involvement was similar in patients treated 2001-2007 and 2007-2012. The realized treatment was more radical (p=0.01) in patients recruited 2001-2007 (38%) when compared with patients treated 2007-2012 (18%). In patients with pre-surgical involvement of anterior/posterior hypothalamic areas, the rate of hypothalamus-sparing operations resulting in no (further) hypothalamic lesions was higher (p=0.005) in patients treated 2007-2012 (35%) in comparison with the 2001-2007 cohort (13%). Event-free-survival rates were similar in both cohorts. CONCLUSIONS: A trend towards less radical surgical approaches is observed, which was accompanied by a reduced rate of severe hypothalamic lesions. Radical surgery is not an appropriate treatment strategy in patients with hypothalamic involvement. Despite previous recommendations to centralize treatment at specialized centers, a trend towards further decentralization was seen.

Effects of radiation on the expression of adhesion molecules and cytokines in a static model of human dermal microvascular endothelial cells.

BACKGROUND: Radiation-induced wound healing complications represent an important clinical problem. Microvascular compromise is an important component of its pathogenesis and the microvascular endothelial cell is the key representative affected at the cellular level. MATERIAL AND METHODS: Human dermal microvascular endothelial cells (HDMEC) were cultured and irradiated with doses of 2 to 12 Gy. Cell density was determined 48 h after radiation using a semi-automated cell counting system. Levels of interleukin-6 (IL-6), basic fibroblast growth factor (FGF), intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in the supernatants of HDMEC were determined by polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA). Non irradiated HDMEC were used as controls. RESULTS: Cell density was significantly impaired in irradiated cells compared to non irradiated controls. Radiation resulted in significant elevation of levels of IL-6, FGF, ICAM-1 and VCAM-1 in the supernatants of HDMEC in a dose dependent manner. CONCLUSION: The inflammatory response observed clinically after radiation seems to correlate with elevated expression of cytokines and adhesion molecules by microvascula endothelial cells. The model of HDMEC documents the impairment of microcirculation. These in vitro changes may enhance our understanding of the pathomechanisms leading to radiation-induced vasculitis and associated wound healing problems.

[Perioperative pain management in major reconstructive surgery in pediatric urology: a plea for continuous epidural anesthesia]. / Perioperatives Schmerzmanagement bei großen plastisch-rekonstruktiven Eingriffen in der Kinderurologie: Ein Plädoyer für die Periduralanästhesie.

Regional analgesia is firmly established in modern pediatric anesthetic practice and its popularity continues to grow. In our department continuous epidural anesthesia (CEA) is a frequently used technique of pain management following major reconstructive procedures of the lower urinary tract. The aim of this study was to investigate the efficacy, safety, and potential benefits of CEA over standard analgesics.We retrospectively reviewed the records of 21 infants who underwent single-stage bladder exstrophy repair in our department. In 15 children an epidural catheter was placed preoperatively for CEA; 6 patients treated without CEA served as controls. Total doses of narcotics and analgesics, length of intensive care unit (ICU) stay and ventilatory assistance, time to first bowel activity, anticholinergic requirements, and CEA-related side effects were documented and compared for both groups.Children given epidural anesthesia required six- to tenfold lower doses of morphine intra- and postoperatively compared to those without CEA; ventilatory support upon completion of surgery was remarkably shorter (59 versus 210 min) in the CEA group as well as ICU stay (1.1 versus 1.8 days). The total consumption of anticholinergics was twice as high as in patients without CEA. There were no relevant CEA-related complications.Being a retrospective audit of practice in our institution with a small number of patients, our results are in line with previously published data on CEA in pediatric patients. CEA has been shown to significantly reduce the need for anesthetics and morphine and allows early extubation with all subsequent advantages for a speedy recovery post surgery. Thus, the technique is to be recommended as a safe and efficacious method for pain management following major reconstructive surgery in pediatric urology. Importantly, this type of anesthesia should be performed only by experienced anesthesiologists in institutions where appropriate equipment, staff, and monitoring are available.

[Requirements and performance profile of the Paediatric Radiation Oncology Working Group (APRO): evaluation of the present situation and description of future developments]. / Anforderungen und Leistungsprofile der Arbeitsgemeinschaft Pädiatrische Radioonkologie (APRO): Eine Bestandsaufnahme und Darstellung zukünftiger Entwicklungen.

BACKGROUND: Radiation therapy is an integral component in the management of childhood malignancies and undergoes a continuous process of optimization within the prospective trials of the GPOH. At present there are approximately 20 active protocols, some specifying radio-oncological study questions, in which about 500 to 600 children annually are given radiotherapy. MATERIALS/METHODS: The Pediatric Radiation Oncology Working Group (APRO) of the German Society for Radiation Oncology (DEGRO) represents the organizational link between GPOH and DEGRO. Their activities range from phrasing guidelines of radio-oncological therapy, through writing a protocol for a prospective study on radiation-induced late effects (RISK--in co-operation with GPOH, 695 patients registered so far) and organizing meetings for information transfer, to implementing radio-oncology within the prospective studies of the GPOH by establishing study chairs for radio-oncology when radio-oncological questions are a primary focus and/or to function as a reference institution for quality assurance. These activities also include individual case consultations outside the study proper. Twice annually the members of the APRO meet for an update on current knowledge and future directions where a representative of the GPOH is invited to contribute special aspects of pediatric oncology. CONCLUSIONS: In the future, modern technology (intensity modulated radiotherapy, proton therapy, inclusion of imaging in treatment planning) will be part of disease management in pediatric oncology. A working group for modern radiotherapy technology was established to enhance this development. Prospective studies of the GPOH with primary or secondary radio-oncological questions require the implementation of corresponding tasks (documentation, monitoring, etc.) in order to meet future demands on clinical trials and to achieve the aims of the protocol. Consequently adequate financial support is indispensable.

[Survival with distant metastatic disease in head and neck cancer. A retrospective analysis]. / Uberleben mit hämatogen metastasierten HNO-Tumoren: Eine retrospektive monozentrische Analyse.

QUESTIONS: The objective of this retrospective analysis was to investigate parameters with a potential impact on survival in a collective of 114 patients with distant metastatic disease after head and neck cancer. PATIENTS AND METHODS: The primary endpoint was the survival with distant metastatic disease, the secondary endpoint was overall survival. Primary therapy, local recurrence, second neoplasms, palliative chemotherapy (CHT) and radiotherapy (RT), as well as Karnofsky performance status (KPS) at the time of diagnosis of the metastases were analyzed as potential impact parameters using the log-rank test with subsequent Cox regression analysis. RESULTS: Palliative CHT (P=0.0020) and KPS (P=0.0011) had a significant positive impact on the median survival probability with metastases (8.2 months) using the log-rank test, KPS at the time of diagnosis of metastases remained as an independent prognostic parameter in the Cox regression (P=0.0013). Primary therapy, local tumor control and KPS had a significant positive influence on the median overall survival probability (18.5 months) univariately (P=0.0139, P=0.0106, P= 0.0096) and multivariately (P=0.0123, and P=0.0063, P=0.0197, respectively). CONCLUSIONS: KPS at the time of diagnosis of metastases is an independent prognostic parameter for both endpoints. Lacking evidence for life prolongation, palliative therapies should therefore first and foremost focus on the stabilization of the KPS.

Relapse pattern after complete resection and early progression after incomplete resection of childhood craniopharyngioma.

In HIT Endo data on therapy and prognosis of 306 patients with childhood craniopharyngioma (CP) were analyzed. The 5 years-overall survival rate was 94 +/- 4 % in irradiated patients and 93 +/- 5 % in non-irradiated patients. Aims of the prospective study KRANIOPHARYNGEOM 2000 were to collect data on the incidence and time course of relapses after complete surgery and tumour progressions after incomplete resection. Furthermore, the impact of irradiation therapy (XRT) on tumour relapse and recurrence rates was analyzed. Since 2001 ninety-eight patients with CP were recruited at a median age at diagnosis of 9.9 years ranging from 1.8 to 18.0 years. Complete resection was achieved in 44 %, incomplete resection in 54 %. XRT was performed in 24 of 98 CP patients; in 10 early after incomplete resection, in 14 of 24 after progression of residual tumour or relapse, in 3 of 14 after second surgery of relapse. XRT was performed at a median age of 12.0 years ranging from 5.0 to 18.9 years and in median after an interval of 9 months after first diagnosis. The analysis of event-free survival rates (EFS) in patients with CP showed a high rate of early events in terms of tumour progression after incomplete resection (3y-EFS: 0.22 +/- 0.09) and relapses after complete resection (3y-EFS: 0.60 +/- 0.10) during the first three years of follow-up. A high rate of early events (1y-EFS: 0.78 +/- 0.10; 2y-EFS: 0.57 +/- 0.15) was also found for patients after XRT (3 cystic progressions, 3 progressions of solid tumour; in 24 patients after XRT). We conclude that tumour progression and relapse are frequent and early events even in irradiated patients. Monitoring of cerebral imaging and clinical status is recommended in follow-up of patients with childhood CP. In order to analyze the appropriate time point of XRT after incomplete resection, QoL, EFS and overall survival in patients (age > or = 5 years) will be analyzed in KRANIOPHARYNGEOM 2007 after stratified randomization of the time point of irradiation after incomplete resection (early irradiation versus irradiation at progression of residual tumour).

Impact of the Narcotrend Index on propofol consumption and emergence times during total intravenous anaesthesia with propofol and remifentanil in children: a clinical utility study.

BACKGROUND AND OBJECTIVE: The electroencephalographic Narcotrend Index (NI) is a measure of the hypnotic component of general anaesthesia. The purpose of this study was to evaluate the impact of Narcotrend guidance on propofol consumption and emergence times in children receiving total intravenous anaesthesia with propofol and remifentanil. METHODS: Thirty children, aged 1-11 yr, scheduled for paediatric urological surgery were enrolled. Remifentanil was given to all patients at a constant infusion rate of 0.3 microg kg [-1] min[-1] throughout anaesthesia. Patients were randomly allocated to receive a continuous propofol infusion adjusted either according to a conventional clinical practice (Group C: n=15) or guided by Narcotrend monitoring (Group NI: n=15; target NI 60+/-5). All patients were connected to the Narcotrend Monitor, but in Group C the anaesthetist was blinded to the screen of the monitor. Propofol consumption (mg kg[-1]h[-1]) and emergence times (min) were the primary and secondary outcome measures. RESULTS: Propofol consumption (median [inter-quartile range]) was significantly lower in Group NI compared to Group C (NI: 7.0 [6.4--8.2] vs. C: 9.3 [8.3--11.0] mg kg[-1]h[-1]; P<0.001), whereas Log-Rank-analysis revealed no intergroup difference in emergence times (Group NI: mean [95% confidence interval (CI)] 12.8 [11.2--14.4] min; Group C: 16.4 [12.6--20.2] min; P=0.10). Haemodynamic variables remained stable within age-related limits, and there were no observations of adverse events, especially no clinical signs of intraoperative awareness in any patient. CONCLUSION: Narcotrend monitoring for guidance of propofol/remifentanil anaesthesia in children results in reduced propofol consumption compared to a conventional clinical practice.

Is nCPAP of value in extreme preterms with no access to neonatal intensive care?

This prospective study was undertaken to investigate the efficacy of nasal continuous positive airway pressure (nCPAP) in a group of extremely small infants denied access to a neonatal intensive care unit (NICU) in South Africa. Consecutive infants weighing less than 1200 g and/or of a gestational age below 28 weeks admitted to the neonatal ward with respiratory distress syndrome (RDS), and who were refused admission to the NICU, received either nCPAP (Infant Flow System E.M.E., UK) of headbox oxygen. Of 22 infants, 11 infants were included in the treatment group (nCPAP) and 10 in the control group. Within the first 24 h, two infants (18 per cent) in the nCPAP group and eight infants (80 per cent) in the control group died (p = 0.007) (survival OR = 18; RR = 4.09). A statistically significant improvement in the arterial-alveolar (a/A) oxygen ratio occurred in the nCPAP group between postnatal day 1 and day 3 of life (0.17 vs. 0.36; p < 0.005). Neonatal complications occurred in six (55 per cent) infants who survived the first 24 h of life. Eighty per cent of the infants with intraventricular haemorrhage (IVH) died, as well as all the infants who were born before arrival at the hospital. At the time of discharge from hospital, 45 per cent (five infants) in the nCPAP group survived vs. 20 per cent (two infants) in the control group. The neurodevelopmental outcome of six of the surviving seven infants were evaluated at 1 year of corrected age. The neurodevelopmental outcome as assessed by the Griffith Score was within normal limits in all infants. One infant has sensorineural deafness and one is deaf and has a possible mild spastic diplegia (both in the treatment group). We conclude that nCPAP significantly improves the short-term survival of very low birth-weight (VLBW) infants with moderate to severe respiratory distress syndrome who could not be admitted to intensive care. nCPAP significantly improves the a/A oxygen ratio between day 1 and day 3 of life.

Radiation-induced suppression of the Bmp2 signal transduction pathway in the pluripotent mesenchymal cell line C2C12: an in vitro model for prevention of heterotopic ossification by radiotherapy.

Heterotopic ossification is a common complication after total hip replacement. Clinical studies showed the effectiveness of radiation for prevention of heterotopic ossification. The mechanism of radiotherapy responsible for the reduction of heterotopic ossification is unclear. The purpose of this study was to study an analogue model showing a time- and dose-dependent effect of radiation. Using cells of the defined embryonic mouse cell line C2C12, the influence of ionizing radiation on the Bmp-induced signal cascade leading to osteogenic differentiation was analyzed. Binding of iodinated Bmp2 to the receptors, Smad1 activation, and alkaline phosphatase (ALP) activity were determined in cells with or without irradiation. The cytotoxic effect of radiotherapy was evaluated using viability tests. Radiotherapy reduced formation of the Bmp2/Bmp receptor complex. This effect was dependent on dose. The phosphorylation (activation) of Smad1 decreased after irradiation in a time-dependent manner, whereas the level of total Smads was not influenced by radiotherapy. The ALP activity decreased after radiotherapy. A dose of 7 Gy delivered 6 h before or after incubation with Bmp resulted in about a 30% decrease in ALP activity. No signs of cytotoxic effects were observed within the time window studied using doses of 0 to 20 Gy. The time- and dose-dependent effect of radiotherapy for prevention of heterotopic ossification known from the results of clinical studies has an analogue in the C2C12 cell model. The primary mechanism of radiotherapy seems to be an influence on cellular responsiveness to the Bmp2-induced osteoblastic differentiation. The results suggest a down-regulation of the Bmp2/receptor complex.

Radiation-induced reduction of BMP-induced proteoglycan synthesis in an embryonal mesenchymal tissue equivalent using the chicken "limb bud" test.

PURPOSE: Heterotopic ossification (HO) is a common complication following total hip replacement. Clinical studies showed the effectiveness of irradiation for prevention of heterotopic ossification. The mechanism of radiotherapy responsible for the reduction of heterotopic ossification is unclear. The purpose of this study was to find a suitable cell system, which can reproduce in-vitro data resulting from clinical in-vivo studies. The establishment of such a cell model allows detailed analyses of the mechanism of radiotherapy. METHOD: The chicken limb bud test was used as an in-vitro model. The cells acquired by the limb bud test were irradiated with different doses (0 Gy, 3 Gy, 7 Gy, 10 Gy, 20 Gy). Irradiation was set either 1 hour before, or 1 or 3 days after BMP-2 incubation. The synthesis of proteoglycans (PGS) upon treatment with bone morphogenetic protein (BMP)-2 was measured in cells incubated with BMP-2 for 4 days followed by 35SO4(2-) labeling for 6 hours. Labeled proteoglycans were precipitated using Alcian blue and measured in a raytest radio-TLC analyzer. The incubation with BMP-2 was defined to correlate the in-vivo stimulus meaning the operation. RESULTS: The proteoglycan synthesis was significantly reduced by irradiation 1 hour before or 1 day after BMP-2 incubation, if the dosage was at least 7 Gy. Higher doses than 7 Gy did not lead to lower proteoglycan levels. There was only a trend for a reduction of proteoglycan synthesis by 3 Gy irradiation, but no significant difference compared to the non-irradiated control. An irradiation 3 days after BMP-2 incubation had no effect on proteoglycan. CONCLUSION: A dose and time dependent effect of radiation on BMP-2-induced proteoglycan synthesis was observed. Therefore the results of clinical in-vivo studies were reproduced exactly by the limb bud test. We established an in-vitro cell model to analyze the mechanism of the prevention of heterotopic ossification by radiotherapy on cellular or sub-cellular level.

[Are morphologic changes in skeletal muscles of patients with malignant hyperthermia diagnostically useful?]. / Sind morphologische Veränderungen im Skelettmuskel von Patienten mit Maligner Hyperthermie diagnostisch verwertbar?

Malignant Hyperthermia (MH) represents a functional myopathy triggered by volatile anesthetics and depolarizing muscle relaxants, and leading to metabolic disturbances of intracellular Calcium homeostasis. Central-Core-like-structures (CCLS) were recently described as central defects in enzyme-histochemical stains and well correlated to the autosomal-dominant MH-predisposition. We studied the correlation of a MH-predisposition with specific myopathological signs. Skeletal muscles of suspected MH-individuals were histochemically stained by SDH-, NADH-, COX-, Gomori-Trichrome-, ATPase-, Acid Phosphatase-, Oil-red O- und PAS-stain und evaluated without knowing MH-diagnosis by the in-vitro-contracture test. Out of 118 patients (30% MHS ["susceptible"], 63% MHN [normal], 7% MHE ["equivocal"]) 19% revealed pathological findings corresponding to CCLS. 45% of these findings were associated with MHS/MHE. With HE-staining internal nuclei were not specific, but increased with the probability of MHS/MHE from 24% to 80%. Central Cores were correlated in 100% with MHS/MHE (4 out of 118 patients). CCLS were found with about similar frequency in skeletal muscle of MHS/MHE and MHN individuals. Internal nuclei were, however, not specifically, associated with MHS. In contrast, Central Cores correlated significantly with MHS/MHE diagnosis. In conclusion, histopathological findings in skeletal muscle seem to be a reliable marker for MH-predisposition only with Central Cores.

Mutant profiles of selectable genetic elements.

A method is presented that allows simultaneous analysis of the effects of all possible point mutations within a specific mutation window of at least 50 base pairs on a DNA fragment that codes for a selectable function. It relies on the detection of mismatched base pairs with hydroxylamine and osmium tetroxide. A mutant plasmid library of randomly distributed point mutations within the lacZ' gene of Escherichia coli was selected for functional alpha-complementation by growth on lactose. The DNA fragments of the selected and unselected library were each heat denatured and again renatured, thereby generating a randomly distributed set of all possible mismatches within the mutagenesis window. Cytidine-containing mismatches were then detected with hydroxylamine, and thymidine-containing mismatches were detected with osmium tetroxide. When this procedure was performed for both DNA strands, all mismatches could be detected. A comparison of the results of the unselected and selected library leads to an estimation of the effects of each detectable mutation on alpha-complementation in vivo. This method, called "mutant profiling," should be applicable to all selectable genetic elements.