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.

Timing of re-irradiation in recurrent high-grade gliomas: a single institution study.

There is no standard treatment available for recurrent high-grade gliomas. This monoinstitutional retrospective analysis evaluates the differences in overall survival and progression-free survival in patients according to the timing of re-irradiation. Patients suffering from a glioblastoma who received re-irradiation for recurrence were evaluated retrospectively. The median overall survival (OS) and the median progression-free survival were compared with different treatment options and within various time periods. From January 2007 until March 2015, 41 patients suffering from recurrent high-grade gliomas received re-irradiation [median dose of 30.6 Gy (range 20-40 Gy) in median 4 Gy fractions (range 1.8-5 Gy)] in our institution after initial postoperative irradiation or combined radiochemotherapy. The OS in this population was 34 months, and the OS after recurrence (OS-R) was 13 months. After diagnosis of recurrence, patients underwent additional surgical resection after a median of 1.2 months, received a second-line systemic therapy after 2.2 months with or without re-irradiation after 5.7 months. Growth of the tumour was assessed 4.3 months after the start of re-irradiation. The OS after the second surgical resection was 12.2 months, 11.7 months after the start of the second-line systemic therapy, and 6.7 months after the start of re-irradiation. The OS-R was not significantly correlated with the start of re-irradiation after a diagnosis of recurrence or the time period after the previous surgery. At this institution, re-irradiation was performed later compared to other treatment options. However, select patients could benefit from irradiation at an earlier time point. A precise time point should still be evaluated on an individual basis due to the patient's diverse conditions.

Determination of 'recruited volume' following a PEEP step is not a measure of lung recruitability.

BACKGROUND: It has been proposed that the analysis of positive end-expiratory pressure (PEEP)-induced volume changes can quantify alveolar recruitment. The potential of a lung to be recruited is expected to be high in acute respiratory distress syndrome (ARDS), where collapsed lung tissue is very common. The volume change that is beyond the delta volume because of the patient's compliance has been termed 'recruited volume' (RecV). However, data of patients with low and high RecV showed less severe lung disease in high 'recruiters', indicating that RecV may not equal the 'potentially recruitable lung tissue' seen in computed tomography scans. We hypothesized that RecV is higher in lung-healthy (LH) patients with little collapsed lung compared with ARDS patients. METHODS: RecV and inspiratory capacity (IC) were determined in 12 LH and in 25 ARDS patients during incremental PEEP (steps of 2 cmH2 O). RecV was determined as the time-dependent increase in end-expiratory volume following the first expiration to the new PEEP level (ΔTDV). Gas distribution in LH patients was analyzed by electric impedance tomography. RESULTS: Cumulative RecV(ΔTDV) and IC were higher (P < 0.01) in LH compared with ARDS patients, 1739 ml vs. 832 ml and 4432 ml vs. 2020 ml, respectively. In both groups, RecV correlated excellently with IC (R(2) = 0.86). In LH, RecV emanated mainly from nondependent lung regions at PEEP below 15 cmH2O. Maximum plateau pressure was reached with fewer PEEP steps in ARDS compared with LH patients (11 vs. 14, P < 0.01). CONCLUSION: Our findings suggest that RecV predominately measures a slow fraction of inflation of already aerated lung tissue and not recruitment of collapsed alveoli.

Proxy assessment of patients before and after radiotherapy for brain metastases. Results of a prospective study using the DEGRO brain module.

PURPOSE: Proxies of patients with poor performance status could give useful information about the patients' quality of life (QoL). We applied a newly developed questionnaire in a prospective QoL study of patients undergoing radiotherapy for brain metastases in order to make the first move to validate this instrument, and we compared the results with scores obtained using validated patient-completed instruments. MATERIALS AND METHODS: From January 2007 to June 2010, 166 patients with previously untreated brain metastases were recruited at 14 centers in Germany and Austria. The EORTC-QLQ-C15-PAL and the brain module BN20 were used to assess QoL in patients at the start of treatment and 3 months later. At the same time points, 141 of their proxies estimated the QoL with the new DEGRO brain module (DBM), a ten-item questionnaire rating the general condition as well as functions and impairment by symptoms in areas relevant to patients with brain metastases. RESULTS: At 3 months, 85 of 141 patients (60%) with initial response by a proxy were alive. Sixty-seven of these patients (79% of 3-month survivors) and 65 proxies completed the second set of questionnaires. After 3 months, QoL significantly deteriorated in all items of proxy-assessed QoL except headache. Correlations between self-assessed and proxy-assessed QoL were high in single items such as nausea, headache, and fatigue. CONCLUSIONS: The high correlation between self-assessment and proxy ratings as well as a similar change over time for both approaches suggest that in patients with brain metastases, proxy assessment using the DBM questionnaire can be an alternative approach to obtaining QoL data when patients are unable to complete questionnaires themselves. Our self-constructed and first applied DBM is the only highly specific instrument for patients with brain metastases, but further tests are needed for its final validation.

Electrical impedance tomography for verification of correct endotracheal tube placement in paediatric patients: a feasibility study.

BACKGROUND: Endotracheal tubes (ETTs) are frequently used in paediatric anaesthesia. Correct placement is crucial. The aim of this study was to evaluate electrical impedance tomography (EIT) for guiding and confirmation of paediatric ETT placement. In a retrospective analysis of stored EIT data, distribution of ventilation between left and right lung was used to verify correct paediatric ETT placement. METHODS: Left and right lung ventilation was studied by EIT in 18 paediatric patients (median age: 53 months) requiring anaesthesia and endotracheal intubation. EIT was recorded before induction of anaesthesia, during mask ventilation, during ETT placement (including deliberate mainstem intubation), and after ETT repositioning according to the formula: ETT intubation depth (cm) = 3× ETT internal diameter (mm) or the mainstem intubation method (withdrawing the ETT 2 cm). Final ETT position was confirmed by fluoroscopy. RESULTS: Following deliberate mainstem intubation, distribution of ventilation to the right lung was unequivocally demonstrated by EIT. Homogeneous distribution of ventilation between left and right lung monitored with EIT correlated in each patient with correct endotracheal ETT placement. The distribution of left and right lung ventilation differed significantly (P < 0.05) between the initial two-lung ventilation and subsequent right one-lung ventilation, and between right one-lung and subsequent two-lung ventilation according to auscultation and the final ETT position, respectively. In one patient, ETT was misplaced within the oesophagus which was also obvious from the EIT record. CONCLUSION: This study demonstrates that EIT enables non-invasive recognition of correct ETT placement. Homogeneous right-left-lung ventilation is an indicator for correct ETT placement.

Phase-variable expression of lipopolysaccharide contributes to the virulence of legionella pneumophila.

With the aid of monoclonal antibody (mAb) 2625, raised against the lipopolysaccharide (LPS) of Legionella pneumophila serogroup 1, subgroup OLDA, we isolated mutant 811 from the virulent wild-type strain RC1. This mutant was not reactive with mAb 2625 and exhibited an unstable phenotype, since we observed an in vitro and in vivo switch of mutant 811 to the mAb 2625-positive phenotype, thus restoring the wild-type LPS. Bactericidal assays revealed that mutant 811 was lysed by serum complement components, whereas the parental strain RC1 was almost serum resistant. Moreover, mutant 811 was not able to replicate intracellularly in macrophage-like cell line HL-60. In the guinea pig animal model, mutant 811 exhibited significantly reduced ability to replicate. Among recovered bacteria, mAb 2625-positive revertants were increased by fourfold. The relevance of LPS phase switch for pathogenesis of Legionella infection was further corroborated by the observation that 5% of the bacteria recovered from the lungs of guinea pigs infected with the wild-type strain RC1 were negative for mAb 2625 binding. These findings strongly indicate that under in vivo conditions switching between two LPS phenotypes occurs and may promote adaptation and replication of L. pneumophila. This is the first description of phase-variable expression of Legionella LPS.

[Cricoid pressure]. / Krikoiddruck.

The vast majority of anaesthetists considers application of cricoid pressure for reasons of patient safety an integral part of rapid sequence induction. Cricoid pressure is applied with the idea that it will prevent regurgitation of gastric content into the pharynx, thereby reducing the incidence of pulmonary aspiration. This review describes the background of the introduction of cricoid pressure into clinical practice, analyzes published data concerning clinical relevance of perioperative pulmonary aspiration and efficacy of cricoid pressure in reducing it, discusses problems associated with its use, assesses knowledge and technical performance of cricoid pressure and presents various recent recommendations regarding application of cricoid pressure. The combination of complete lack of evidence for the efficacy of cricoid pressure in preventing pulmonary aspiration and numerous reports of clinically relevant interference with airway management during its use, seriously question the rationale of recommending the general use of cricoid pressure during rapid sequence induction.

[Acute intoxication with isopropanol]. / Akute Intoxikation mit Isopropanol.

Isopropanol is an ingredient of commonly used industrial and household agents. Intoxication can occur unintentionally, in suicide attempts or by alcohol abusers when used as a substitute for ethanol. Symptoms involve the gastrointestinal tract, the central nervous system, and the cardiovascular system at higher doses. Mortality is especially high in patients with deep coma and marked hypotension. This report describes a case of life-threatening isopropanol intoxication of a prison inmate successfully treated by haemodialysis.

Electrical impedance tomography to confirm correct placement of double-lumen tube: a feasibility study.

BACKGROUND: Double-lumen tubes (DLTs) are frequently used to establish one-lung ventilation (OLV). Their correct placement is crucial. We hypothesized that electrical impedance tomography (EIT) reliably displays distribution of ventilation between left and right lung and may thus be used to verify correct DLT placement online. METHODS: Regional ventilation was studied by EIT in 40 patients requiring insertion of left-sided DLTs for OLV during thoracic surgery. EIT was recorded during two-lung ventilation before induction of anaesthesia and after DLT placement, and during OLV in the supine and subsequently in the lateral position. EIT measurements were made before and after verification of correct DLT placement by fibreoptic bronchoscopy (FOB). RESULTS: EIT accurately displayed distribution of ventilation between left and right lung online. All cases (n=5) of initially misplaced DLTs in the contralateral right main bronchus were detected by EIT. However, EIT did not allow prediction of FOB-detected endobronchial cuff misplacement requiring DLT repositioning. Furthermore, after DLT repositioning, distribution of ventilation, as assessed by EIT, did not change significantly (all P>0.5). CONCLUSIONS: This study demonstrates that EIT enables accurate display of left and right lung ventilation and, thus, non-invasive online recognition of misplacement of left-sided DLTs in the contralateral main bronchus. However, as distribution of ventilation did not correlate with endobronchial cuff placement, EIT cannot replace FOB in the routine control of DLT position.

[Teaching emergency medicine at the University Medical Center Freiburg: establishment of an integrative concept]. / Lehrveranstaltung Notfallmedizin am Universitätsklinikum Freiburg : Etablierung eines integrativen Gesamtkonzeptes.

Efforts to improve the quality of undergraduate medical education are commonly hampered by limited human and financial resources. This deficiency may be offset by the development of well structured and innovative teaching concepts, which optimize available assets. The newly conceived modular course "Emergency Medicine" at the University Medical Center Freiburg was conducted for the first time in the winter semester 2006/2007. The core of the course is a 3-day practical training period. It provides the possibility to teach a maximum number of medical students with only four lecturers using patient simulators, interactive case scenarios (simulation software MicroSim), and case scenarios with standardized patients. Evaluation of the course revealed standardized patients to be the best of all teaching methods with an overall average grade of 1.1 (patient simulators 1.2, computer simulation 1.4). Of the students, 88% stated that the practical training encouraged their interest in the speciality emergency medicine. The excellent student evaluation results show that the new course "Emergency Medicine" for medical students constitutes a successful balance between the constraint of resource limitation and the goal of excellent medical education.

Spectrum of ATM gene mutations in a hospital-based series of unselected breast cancer patients.

Blood relatives of patients with the inherited disease ataxia telangiectasia (A-T) have an increased susceptibility for breast cancer. We therefore looked for sequence alterations of the ATM gene in a large hospital-based series of unselected breast cancer patients. The whole ATM coding sequence was analyzed in genomic DNA samples from a core group of 192 consecutive breast cancer cases to define the spectrum of ATM gene mutations. Common sequence alterations were then screened in the whole series of 1000 breast cancer patients and in 500 random individuals. In the core group, 21 distinct sequence alterations were identified throughout the ATM coding region, and 1 common splicing mutation was uncovered in intron 10. Almost half of the breast cancer patients (46%) were heterozygotes for 1 of 16 different amino acid substitutions, and three patients (1.6%) carried a truncating mutation. These data indicate that approximately 1 in 50 German breast cancer patients is heterozygous for an A-T-causing mutation. In our extended series, the most common A-T mutation 1066-6T-->G was disclosed in 7 of 1000 (0.7%) breast cancer patients. Transcript analyses indicated that the loss of exon 11 in the ATM mRNA was the pathogenic consequence of this splicing mutation, which produced a <10% of full-length ATM mRNA and ATM protein in a homozygous A-T patient. We also found an excess of rare missense substitutions in the breast cancer cohort compared with random individuals (7.9% versus 5.3% of alleles; odds ratio = 1.6; P < 0.01). One missense substitution, S707P in exon 15, was two times more frequent in breast cancer patients (odds ratio = 2.4; 95% confidence interval, 1.0-5.8) and five times more frequent in patients with bilateral disease than in random individuals (P < 0.001). We conclude that a large variety of distinct ATM mutations and variants exist among breast cancer patients, some of which can contribute to the etiology and progression of the malignancy. Screening for frequent A-T mutations such as the 1066-6-->G splice site substitution can be effective to prospectively identify A-T heterozygotes in an unselected cancer patient population.

A Model-Based Product Evaluation Protocol for Comparison of Safety-Engineered Protection Mechanisms of Winged Blood Collection Needles.

OBJECTIVE: To evaluate differences in product characteristics and user preferences of safety-engineered protection mechanisms of winged blood collection needles. DESIGN: Randomized model-based simulation study. SETTING: University medical center. PARTICIPANTS: A total of 33 third-year medical students. METHODS: Venipuncture was performed using winged blood collection needles with 4 different safety mechanisms: (a) Venofix Safety, (b) BD Vacutainer Push Button, (c) Safety-Multifly, and (d) Surshield Surflo. Each needle type was used in 3 consecutive tries: there was an uninstructed first handling, then instructions were given according to the operating manual; subsequently, a first trial and second trial were conducted. Study end points included successful activation, activation time, single-handed activation, correct activation, possible risk of needlestick injury, possibility of deactivation, and preferred safety mechanism. RESULTS: The overall successful activation rate during the second trial was equal for all 4 devices (94%-100%). Median activation time was (a) 7 s, (b) 2 s, (c) 9 s, and (d) 7 s. Single-handed activation during the second trial was (a) 18%, (b) 82%, (c) 15%, and (d) 45%. Correct activation during the second trial was (a) 3%, (b) 64%, (c) 15%, and (d) 39%. Possible risk of needlestick injury during the second trial was highest with (d). Possibility of deactivation was (a) 0%, (b) 12%, (c) 9%, and (d) 18%. Individual preferences for each system were (a) 11, (b) 17, (c) 5, and (d) 0. The main reason for preference was the comprehensive safety mechanism. CONCLUSION: Significant differences exist between safety mechanisms of winged blood collection needles.

Dynamics of fertility impairment in childhood brain tumour survivors.

PURPOSE: Fertility impairment and recovery after chemo- and radiotherapy have been reported in both male and female childhood cancer survivors, but little is known about the dynamics. Our aim, therefore, was to describe the development of fertility impairment and possible recovery in childhood brain tumour survivors. METHODS: In this longitudinal study, we included 144 survivors, who were treated in two German paediatric oncology centres between 2000 and 2005. Fertility parameters were retrieved from medical records up to 12 years after diagnosis. RESULTS: Participants with age ≥13 years and formerly cranial irradiation ≥30 Gray (n = 23), including 83 % (n = 19) with craniospinal irradiation ≥30 Gray, had a higher median FSH concentration compared to 29 patients without chemoradiotherapy: 8.3 IU/l (IQR 6.5-11.2) versus 4.1 IU/l (IQR 3.2-5.1) 2 years after initial treatment; 8.9 IU/l (IQR 8.5-10.8) versus 4.2 IU/l (IQR 2.4-6.7) after 8 years; and 7.1 IU/l (IQR 6.7-7.7) versus 3.5 IU/l (IQR 2.8-4.2) after 10 years. Altogether, 11/65 women reported the occurrence of amenorrhoea 6.0 years (range 1-10) after diagnosis. Five of these women later developed a regular menstrual cycle without hormone replacement therapy. Patients' chance of recovery from fertility impairment was increased with time since diagnosis (p = 0.074). CONCLUSION: Signs of fertility impairment such as amenorrhoea and elevated FSH levels were observed at variable time points between 1 and 12 years after chemoradiotherapy. Decreasing FSH levels were observed 1-7 years after elevation and were interpreted either as an atrophy of the pituitary gland or as recovery from fertility impairment.

Anaesthetic management of emergency caesarean section in a parturient with systemic mastocytosis.

Mastocytosis is a rare disorder caused by the proliferation and accumulation of mast cells in various organs. It has a broad variety of clinical manifestations, including cardiovascular collapse. Diverse stimuli trigger the release of vasoactive substances and parturients with systemic mastocytosis are at high risk for precipitating mast cell degranulation. As a result, women with systemic mastocytosis should have an anaesthetic plan for labour and delivery. Anxiety, stress, sleep deprivation, pain and numerous pharmacological agents are all triggers for mast cell degranulation. For pain relief in labour, epidural analgesia is recommended. Pharmacological agents with a high potential for triggering mast cell degranulation should be avoided. This is particularly important in the case of an emergency caesarean section. Resuscitation equipment must be available should life-threatening haemodynamic instability occur during surgery. We report the case of a pregnant woman with systemic mastocytosis who required emergency caesarean section.

[Acute obstruction of the endotracheal tube]. / Akute Obstruktion des endotrachealen Tubus.

Acute occlusion of an endotracheal tube (ETT) is a feared, potentially life-threatening complication of mechanical ventilation. In the presence of a thoracic trauma, a blood clot needs to be taken into consideration as the cause of airway obstruction. This report describes a case of sudden ventilation failure due to acute ETT obstruction by a blood clot caused by intrapulmonary haemorrhaging in a child following multiple trauma accompanied by blunt thoracic trauma in the absence of dyspnoe or haemoptysis.

Anti-inflammatory activity of croconazole, a broad-spectrum antimycotic agent, in the arachidonic acid-induced mouse ear swelling test.

Investigations on croconazole, a novel imidazole compound, suggested antiphlogistic properties in vitro. Hence, its anti-inflammatory capacity was tested in vivo using the arachidonic acid-induced mouse ear swelling test, which is a suitable model for screening inhibitors of the lipoxygenase and/or the cyclooxygenase. Topical application of croconazole (1%/0.01%) to the mouse ear induced a maximal inhibition of edema (inhibition: 39%/33%; p = 0.01) which was as strong as the reference nordihydroguaiaretic acid (inhibition: 38.9%; p = 0.01). These results justify further investigations on croconazole to study potential inhibitory effects on proinflammatory arachidonic acid metabolites.

RNA interference (RNAi) in hematology.

RNA interference (RNAi), an evolutionary highly conserved process of post-transcriptional gene silencing, can be triggered by small interfering RNAs (siRNAs) that mediate sequence-specific mRNA degradation. Since the first reports in 1998, RNAi has rapidly been developed into an effective tool to specifically knock down gene expression in a wide variety of target cells. Accordingly, RNAi is currently used for both systematic functional genomics in several organisms and for specific therapeutic intervention in preclinical models of different diseases characterized by aberrant gene expression. However, since siRNAs are not replicated in mammalian cells during the process of RNAi, kinetic aspects of RNAi-induced gene silencing that eventually depend on the intracellular level of siRNA must be considered for each analytical or therapeutic application in these cells. We summarize here some aspects of siRNA design and delivery, of RNAi kinetics, potential side effects, and limitations of siRNA-mediated gene silencing, as well as putative RNAi targets for functional and/or therapeutic intervention in hematopoietic cells.

Xanthomonas campestris pv. campestris lpsI and lpsJ genes encoding putative proteins with sequence similarity to the alpha- and beta-subunits of 3-oxoacid CoA-transferases are involved in LPS biosynthesis.

A 2.1-kb SmaI-EcoRI DNA fragment upstream of the xanA and xanB genes of Xanthomonas campestris pv. campestris carries two ORFs encoding putative proteins with sequence similarities to the alpha- and beta-subunits of 3-oxoacid-CoA transferases. The two ORFs were termed lpsI and lpsJ because strains carrying appropriate mutations showed an autoagglutination phenotype and because lipopolysaccharides of these mutant strains were altered according to silver-stained polyacrylamide gels. The monosaccharide composition of the exopolysaccharide xanthan produced by lpsI and lpsJ mutants remained unchanged.

Croconazole: an inhibitor of eicosanoid synthesis in A23187-stimulated human polymorphonuclear leukocytes and human whole blood.

The aim of this investigation was to ascertain possible inhibitory effects of the antimycotic agent croconazole on eicosanoid biosynthesis. Human polymorphonuclear leukocytes (PMN) and whole blood of healthy donors were pretreated with croconazole in different concentrations (0.8-100 microM) for 5 min followed by the addition of Ca ionophore A23187 (10 microM) and subsequent incubation for 10 min (PMN) and 30 min (whole blood), respectively. Thereupon the eicosanoids were determined by reversed-phase high-performance liquid chromatography. Croconazole exhibited dose-dependent inhibitory activity on the 5-lipoxygenase (5-LOX) of neutrophils. The mean half maximum inhibition concentration (IC50) of croconazole for synthesis of leukotriene B4 (LTB4) and 5-hydroxyeicosatetraenoic acid (5-HETE) was determined as 7.8 +/- 1.7 and 7.6 +/- 0.3 microM, respectively. The mean IC50 value for LTB4 estimated in whole blood was distinctly higher (27.0 +/- 3.1 microM) compared with that determined in PMN. Additionally, an inhibitory effect (IC50 9.8 +/- 2.0 microM) on the production of the cyclooxygenase (COX) product 12-hydroxyheptadecatrienoic acid (HHT) was demonstrated, whereas the production and/or releasing of 12-hydroxyeicosatetraenoic acid (12-HETE) was not attenuated by the azole. Our results in the cell-free 5-LOX system favor a direct inhibitory action of croconazole on 5-LOX, with a relatively high portion (45-77%) of reversibility. In spite of distinctly lower inhibitory potency compared with reference inhibitors such as nordihydroguaiaretic acid and indomethacin, croconazole is an effective inhibitor of arachidonic acid metabolism. Our results suggest that croconazole may be of some benefit in anti-inflammatory therapy.