The three pillars in treating antibody-mediated encephalitis.

The rapid initiation of immunotherapy has a decisive impact on the course of the disease in patients with antibody-mediated encephalitis (AE). The importance of treating AE with antiseizure medication and antipsychotics is discussed controversially; however, standardized procedures should be ensured, especially for the initiation of treatment in severe disease. Recommendations and guidelines for further interventions in refractory courses are needed. In this review, we contrast the three mainstays of treatment options in patients with AE and attempt to highlight the importance of 1) antiseizure therapy, 2) antipsychotic therapy, and 3) immunotherapy/tumor resection from today's perspective.

Depression, anxiety, fatigue, and quality of life in a large sample of patients suffering from head and neck cancer in comparison with the general population.

BACKGROUND: Treatment of head and neck cancer (HNC) often leads to visible and severe functional impairments. In addition, patients often suffer from a variety of psychosocial problems, significantly associated with a decreased quality of life. We aimed to compare depression, anxiety, fatigue and quality of life (QoL) between HNC patients and a large sample of the general population in Germany and to examine the impact of sociodemographic, behavioral and clinical factors on these symptoms. METHODS: We assessed data of HNC patients during the aftercare consultation at the Leipzig University Medical Center with a patient reported outcome (PRO) tool named "OncoFunction". Depression, anxiety, fatigue and QoL were assessed using validated outcome measures including the PHQ-9, the GAD-2, and the EORTC QLQ-C30 questionnaire. RESULTS: A total of 817 HNC patients were included in our study and compared to a sample of 5018 individuals of the general German population. HNC patients showed significantly higher levels of impairment in all dimensions assessed. Examination of association between depression, anxiety, fatigue and QoL and clinical as well as sociodemographic variables showed significant relationships between occupational status, ECOG-state, body mass index and time since diagnosis. CONCLUSIONS: HNC patients suffer significantly from psychological distress. The used questionnaires are suitable for the use in daily routine practice and can be helpful to increase the detection of depression, anxiety and fatigue and therefore can improve HNC aftercare.

Iron Rims in Patients With Multiple Sclerosis as Neurodegenerative Marker? A 7-Tesla Magnetic Resonance Study.

Introduction: Multiple sclerosis (MS) is a demyelinating and neurodegenerative disease of the central nervous system, characterized by inflammatory-driven demyelination. Symptoms in MS manifest as both physical and neuropsychological deficits. With time, inflammation is accompanied by neurodegeneration, indicated by brain volume loss on an MRI. Here, we combined clinical, imaging, and serum biomarkers in patients with iron rim lesions (IRLs), which lead to severe tissue destruction and thus contribute to the accumulation of clinical disability. Objectives: Subcortical atrophy and ventricular enlargement using an automatic segmentation pipeline for 7 Tesla (T) MRI, serum neurofilament light chain (sNfL) levels, and neuropsychological performance in patients with MS with IRLs and non-IRLs were assessed. Methods: In total 29 patients with MS [15 women, 24 relapsing-remitting multiple sclerosis (RRMS), and five secondary-progressive multiple sclerosis (SPMS)] aged 38 (22-69) years with an Expanded Disability Status Score of 2 (0-8) and a disease duration of 11 (5-40) years underwent neurological and neuropsychological examinations. Volumes of lesions, subcortical structures, and lateral ventricles on 7-T MRI (SWI, FLAIR, and MP2RAGE, 3D Segmentation Software) and sNfL concentrations using the Simoa SR-X Analyzer in IRL and non-IRL patients were assessed. Results: (1) Iron rim lesions patients had a higher FLAIR lesion count (p = 0.047). Patients with higher MP2Rage lesion volume exhibited more IRLs (p <0.014) and showed poorer performance in the information processing speed tested within 1 year using the Symbol Digit Modalities Test (SDMT) (p <0.047). (2) Within 3 years, patients showed atrophy of the thalamus (p = 0.021) and putamen (p = 0.043) and enlargement of the lateral ventricles (p = 0.012). At baseline and after 3 years, thalamic volumes were lower in IRLs than in non-IRL patients (p = 0.045). (3) At baseline, IRL patients had higher sNfL concentrations (p = 0.028). Higher sNfL concentrations were associated with poorer SDMT (p = 0.004), regardless of IRL presence. (4) IRL and non-IRL patients showed no significant difference in the neuropsychological performance within 1 year. Conclusions: Compared with non-IRL patients, IRL patients had higher FLAIR lesion counts, smaller thalamic volumes, and higher sNfL concentrations. Our pilot study combines IRL and sNfL, two biomarkers considered indicative for neurodegenerative processes. Our preliminary data underscore the reported destructive nature of IRLs.

Effects of prostaglandin E2 and D2 on cell proliferation and osteogenic capacity of human mesenchymal stem cells.

The manifestation of periodontitis-related inflammatory reaction is inevitably bound to the production of prostaglandins E2 and D2 which have been suggested to mediate osteoclastic and osteogenic effects within the affected tissue. We demonstrated the presence of PGE2 and PGD2 receptors on hMSCs on RNA level and with immunofluorescence. For each Prostaglandin, three concentrations were studied: 0.1; 0.5 or 1.0 µg/ml. A lower expression of EP1 and EP4 (PGE2 receptors 1 and 4) after stimulation with PGE2 was shown, thus a tendency to compromise osteogenic differentiation and metabolism. PGE2 induced a higher growth-rate during the first week, while a continuous inflammatory challenge determined a decrease of the proliferation of hMSCs. PGD2 inhibited cell growth irrespective of the duration of the stimulation. PGE2 and PGD2 have also negative effects on calcium deposition osteogenic, thus on differentiation of hMSCs. PGE2 and PGD2 seem to induce bone resorption also having indirectly a negative impact on the osteogenic differentiation of hMSCs. Thus, inhibitors of PGE2 and PGD2 can be used as adjunct to mechanical periodontal treatment.

Measurements of radiation quality factor on Mars with the Mars Science Laboratory Radiation Assessment Detector.

We report the first long-term measurements of the radiation quality factor of energetic charged particles on the surface of Mars. The Radiation Assessment Detector (RAD) aboard the Mars Science Laboratory rover, also known as Curiosity, has been operating on Mars since 2012. RAD contains thin silicon detectors that record the ionization energy loss of energetic charged particles. The particles are dominantly galactic cosmic rays (GCRs) and the products of their interactions in the Martian atmosphere, with occasional contributions from solar energetic particles (SEPs). The quality factor on the surface of Mars is influenced by two factors: variations in the shielding provided by the atmosphere, and changes in the spectrum of the incident energetic particle flux due to the 11-year solar cycle. The two cannot be easily disentangled using the data alone, but insights can be gained from calculations and Monte Carlo simulations.

The German Aerospace Center M-42 radiation detector-A new development for applications in mixed radiation fields.

In the last few years, the Biophysics Working Group of the Institute of Aerospace Medicine of the German Aerospace Center (DLR) started the development of a small low power consumption radiation detector system for the measurement of the absorbed dose to be applied in various environments, such as onboard aircraft, in space, and also as a demonstration tool for students. These so called DLR M-42 detectors are based on an electronics design, which can easily be adjusted to the user- and mission-requirements. M-42 systems were already applied for measurements in airplanes, during two MAPHEUS (Materialphysikalische Experimente unter Schwerelosigkeit) rocket missions, and are currently prepared for long term balloon experiments. In addition, they will be part of the dosimetry suite of the upcoming Matroshka AstroRad Radiation Experiment on the NASA Artemis I mission. This paper gives an overview of the design and the testing of the DLR M-42 systems and provides highlighted results from the MAPHEUS campaigns where the detectors were tested for the first time under space flight conditions. Results clearly show that the system design enables independent measurements starting upon rocket launch due to the built-in accelerometer sensors and provides data for the relevant 6 min of µ-gravity as given for the MAPHEUS missions. These 6 min of the µ-gravity environment at altitudes between 100 and 240 km lead to a total absorbed dose of 1.21 ± 0.15 µGy being equivalent to half a day of radiation background measured with the M-42 in the laboratory at DLR, Cologne, Germany.

Pro-inflammatory activation of microglia in the brain of patients with sepsis.

AIMS: Experimental data suggest that systemic immune activation may create a pro-inflammatory environment with microglia activation in the central nervous system in the absence of overt inflammation, which in turn may be deleterious in conditions of neurodegenerative disease. The extent to which this is relevant for the human brain is unknown. The central aim of this study is to provide an in-depth characterization of the microglia and macrophage response to systemic inflammation. METHODS: We used recently described markers to characterize the origin and functional states of microglia/macrophages in white and grey matter in patients who died under septic conditions and compared it to those patients without systemic inflammation. RESULTS: We found pro-inflammatory microglia activation in septic patients in the white matter, with very little activation in the grey matter. Using a specific marker for resident microglia (TMEM119), we found that parenchyma microglia were activated and that there was additional recruitment of perivascular macrophages. Pro-inflammatory microglia activation occurred in the presence of homeostatic microglia cells. In contrast to inflammatory or ischaemic diseases of the brain, the anti-inflammatory microglia markers CD163 or CD206 were not expressed in acute sepsis. Furthermore, we found pronounced upregulation of inducible nitric oxide synthase not only in microglia, but also in astrocytes and endothelial cells. CONCLUSION: Our results demonstrate the pronounced effects of systemic inflammation on the human brain and have important implications for the selection of control populations for studies on microglia activation in human brain disease.

Limit of viability: The Swiss experience.

Progress made in the field of perinatology over the past four decades has led to unprecedented low mortality rates for extremely low birth weight infants. However, because rates of important short-term complications and neurodevelopmental impairment among survivors have remained high, the best approach to borderline viable infants continues to be debated. Not surprisingly, guidelines from various national medical societies for the care of infants born at the limit of viability vary considerably. In 2002, the first Swiss recommendations for the care of borderline viable infants were published. They had been developed by a multidisciplinary team of experts from the fields of obstetrics, pediatrics, and neonatology. Despite the availability of national guidelines, center-to-center outcome variability has since persisted, suggesting that care for the most immature infants is not only evidence-based and guideline-driven but also strongly influenced by local neonatal intensive care unit (NICU) culture. In 2011, revised national recommendations for perinatal care at the limit of viability between 22 and 26 completed weeks of gestation were published. It remains to be seen whether this has led to more uniform outcomes across the Swiss centers in the years that followed.

Clinical and neuroradiological differences of paediatric acute disseminating encephalomyelitis with and without antibodies to the myelin oligodendrocyte glycoprotein.

BACKGROUND: Myelin oligodendrocyte glycoprotein (MOG) antibodies have been recently described in children with acute disseminating encephalomyelitis (ADEM), but the clinical and neuroradiological characterisation of this subgroup is lacking. OBJECTIVE: To compare the clinical and neuroradiological features of paediatric ADEM with and without MOG antibodies. METHODS: Clinical course, cerebrospinal fluid (CSF)-, MRI studies, outcome and MOG status of 33 paediatric ADEM prospectively studied were reviewed. RESULTS: MOG antibodies (median 1:2560; range 1:160-1:20 480) were detected in 19 children with ADEM. The majority of children showed a decline of serum MOG-IgG titres over time. Children with MOG antibodies did not differ in their age at presentation, sex ratio, the presence of oligoclonal bands, clinical symptoms or initial severity, apart from a higher CSF cell count (p=0.038), compared with children without MOG antibodies. In addition, further relapsing demyelinating episodes associated with MOG antibodies were observed only in children with MOG antibodies. All 19 children with MOG antibodies had a uniform MRI pattern, characterised by large, hazy and bilateral lesions and the absence of atypical MRI features (eg, mainly small lesions, well-defined lesions), which was significantly different compared to that of children without MOG antibodies (p=0.003; and p=0.032, respectively). In addition, children with MOG antibodies had involvement of more anatomical areas (p=0.035) including the myelon characterised by a longitudinally extensive transverse myelitis (p=0.003), more often a complete resolution of lesions (p=0.036) and a better outcome (p=0.038). CONCLUSIONS: Patients with ADEM with MOG antibodies in our cohort had a uniform MRI characterised by large, bilateral and widespread lesions with an increased frequency of longitudinal extensive transverse myelitis and a favourable clinical outcome in contrast to children lacking MOG antibodies.

Fibrinogen is not a prognostic factor for response to HELP-apheresis in sudden sensorineural hearing loss (SSHL).

Higher levels of fibrinogen or cholesterol were associated with improved hearing recovery in SSHL patients after treatment with HELP-apheresis (Heparin-induced extracorporeal LDL precipitation apheresis). The present trial was performed to demonstrate HELP-related effects on relevant metabolic and inflammatory parameters in the context of SSHL treatment. In the framework of a single arm non-controlled trial, we investigated the variation of metabolic and inflammatory parameters using HELP-apheresis for a defined group of 100 patients with SSHL. Based on cut off inclusion criteria (Serum LDL-cholesterol >1.6 g/l and/or fibrinogen >2.0 g/l, SSHL in minimum three frequencies more than 30 dB, time after event not longer than 6 days), the protocol followed a strict time line with one single shot HELP-apheresis and follow-up monitoring including laboratory parameters at six defined time points. If HELP-apheresis could not effect improvement of hearing on day 5, additional corticosteroid treatment was applied. Concentration of anti-inflammatory IL-10 increased while other proinflammatory parameters declined. Serum levels of all measured sterols and apolipoproteins decreased significantly. None of the investigated parameters were suitable to predict hearing improvement of the patients. Levels of fibrinogen and LDL-cholesterol were not prognostic for outcome after HELP-apheresis. A significant (p < 0.001) increase of anti-inflammatory IL-10 after apheresis was notable, while most of the proinflammatory parameters declined. Despite the limited validity of a single arm non-controlled trial, these alterations on immune modulating factors indicate possible secondary pleiotropic effects caused by HELP-apheresis.

Characterization of the secondary neutron field produced during treatment of an anthropomorphic phantom with x-rays, protons and carbon ions.

Short- and long-term side effects following the treatment of cancer with radiation are strongly related to the amount of dose deposited to the healthy tissue surrounding the tumor. The characterization of the radiation field outside the planned target volume is the first step for estimating health risks, such as developing a secondary radioinduced malignancy. In ion and high-energy photon treatments, the major contribution to the dose deposited in the far-out-of-field region is given by neutrons, which are produced by nuclear interaction of the primary radiation with the beam line components and the patient's body. Measurements of the secondary neutron field and its contribution to the absorbed dose and equivalent dose for different radiotherapy technologies are presented in this work. An anthropomorphic RANDO phantom was irradiated with a treatment plan designed for a simulated 5 × 2 × 5 cm³ cancer volume located in the center of the head. The experiment was repeated with 25 MV IMRT (intensity modulated radiation therapy) photons and charged particles (protons and carbon ions) delivered with both passive modulation and spot scanning in different facilities. The measurements were performed with active (silicon-scintillation) and passive (bubble, thermoluminescence 6LiF:Mg, Ti (TLD-600) and 7LiF:Mg, Ti (TLD-700)) detectors to investigate the production of neutral particles both inside and outside the phantom. These techniques provided the whole energy spectrum (E ≤ 20 MeV) and corresponding absorbed dose and dose equivalent of photo neutrons produced by x-rays, the fluence of thermal neutrons for all irradiation types and the absorbed dose deposited by neutrons with 0.8 < E < 10 MeV during the treatment with scanned carbon ions. The highest yield of thermal neutrons is observed for photons and, among ions, for passively modulated beams. For the treatment with high-energy x-rays, the contribution of secondary neutrons to the dose equivalent is of the same order of magnitude as the primary radiation. In carbon therapy delivered with raster scanning, the absorbed dose deposited by neutrons in the energy region between 0.8 and 10 MeV is almost two orders of magnitude lower than charged fragments. We conclude that, within the energy range explored in this experimental work, the out-of-field dose from secondary neutrons is lowest for ions delivered by scanning, followed by passive modulation, and finally by high-energy IMRT photons.

Skatole metabolism in the pigs with reduced testicular oestrogen synthesis.

The objectives of the study were to investigate the involvement of oestrogens in the regulation of skatole levels in pigs. In total, 44 intact male pigs, siblings from 10 litters, were included in the study. Pigs were orally treated weekly with either 0.1 mg letrozole/kg body weight to reduce endogenous oestrogens or the canola oil vehicle. Fat and liver samples were collected at slaughter at 16, 20 and 40 weeks of age. Skatole and androstenone levels in fat and activities of hepatic cytochrome P4501A1, CYP1A2, CYP2A19 and CYP2E1 were analysed. Letrozole treatment did not significantly change either the levels of skatole or activities of skatole-metabolising enzymes, suggesting that oestrogens are not responsible for gender-related differences in skatole concentrations in porcine tissues.

Lipocalin 2 performs contrasting, location-dependent roles in APCmin tumor initiation and progression.

Evidence that lipocalin 2 (LCN2) is oncogenic has grown in recent years and comes from both animal models and expression analysis from a variety of human cancers. In the intestine, LCN2 is overexpressed in colitis patients and its overexpression is a negative prognostic indicator in colorectal cancer. Functionally, LCN2 has a number of different activities that may contribute to its oncogenic potential, including increasing matrix metalloproteinase activity, control of iron availability and stimulating inflammation. In this report, we examined APCmin intestinal tumorigenesis in an LCN2-deficient background. We found that the loss of LCN2 increased tumor multiplicity specifically in the duodenum, suggesting a potential tumor-suppressive activity. Concurrently, however, LCN2 increased the average small intestinal tumor size particularly in the distal small intestine. We found that this increase was correlated to tumor iron(II) content, suggesting that an iron-scavenging role is important for LCN2 oncogenic activity in the intestine.

Flotillin-2 deficiency leads to reduced lung metastases in a mouse breast cancer model.

Flotillin microdomains, specialized lipid raft domains in cell membranes, serve as physical platforms for many different molecules important in crucial intracellular signaling pathways. Flotillin-2 (Flot2), together with flotillin-1, is a marker for lipid raft microdomains distinct from caveolar lipid rafts, and has been implicated in the progression of cancer and metastasis formation. Based largely on studies in xenograft models, flotillin-2 has been implicated in the progression of multiple types of human tumors, including breast cancer. In our studies, we identified flotillin-2 as highly amplified in a high-throughput comparative genomic hybridization screen of human breast cancer cell lines and breast tumor samples. Short hairpin RNA-mediated reduction of flotillin-2 protein levels significantly reduced the tumorigenicity and metastatic capability of a human breast cancer cell line in vivo. We generated mice deficient for flotillin-2 and also found a reduction of flotillin-1 protein levels and complete absence of flotillin-specific membrane microdomains in these mice. To examine the role of Flot2 in mammary tumorigenesis and lung metastasis, we used an in vivo molecular genetics approach, crossing a well-characterized transgenic mouse model of breast cancer, the MMTV-PyMT (mouse mammary tumor virus-polyoma middle T antigen) mouse, with gene-targeted Flot2(-/-) mice. Flotillin-2 deficiency lead to a striking reduction in the number of lung metastasis observed, but had no influence on primary tumor formation in this model. Our results indicate, using a novel in vivo animal model approach, that Flot2 is an important regulator of mammary tumor-derived lung metastasis.

Submucous rather than myenteric neurons are activated by mucosal biopsy supernatants from irritable bowel syndrome patients.

BACKGROUND: We previously showed that colonic mucosal biopsy supernatants from patients with irritable bowel syndrome (IBS) activate neurons of the human submucous plexus, an area with densely packed immune cells. Based on the concept that mucosa-nerve signaling is altered in IBS, we tested in this study whether the nerve sensitizing effect of IBS mucosal biopsy supernatants is more prominent in the submucous than myenteric plexus. METHODS: Fast neuroimaging with the voltage-sensitive dye Di-8-ANEPPS was used to record activity of guinea-pig submucous and myenteric neurons after application of constipation (C)- and diarrhea (D)-IBS supernatants (three each) and four supernatants from healthy control subjects. Results are based on recordings from 4731 neurons. KEY RESULTS: Control supernatants did not evoke significant responses in submucous or myenteric neurons. In contrast, all IBS supernatants evoked a significant spike discharge (median 3.6 Hz) in 46% of submucous neurons. This activation was significantly stronger than in the myenteric plexus where even twice the amount of supernatants evoked a lower spike frequency (median 2.1Hz) in only 8.5% of neurons. Pharmacological studies revealed serotonin, histamine, and proteases as components mediating neuronal activation. Individual application of these components revealed that only serotonin evoked a significantly stronger activation of submucous compared with myenteric neurons. CONCLUSIONS & INFERENCES: Direct neuronal activation by IBS mucosal biopsy supernatants is primarily a feature of submucous rather than myenteric neurons. This is associated with a stronger excitation of submucous neurons by serotonin. The plexus-specific effects support the concept that altered mucosa-nerve signaling underlies disturbances in IBS.

Out-of-field dose measurements in a water phantom using different radiotherapy modalities.

This investigation focused on the characterization of the lateral dose fall-off following the irradiation of the target with photons, protons and carbon ions. A water phantom was irradiated with a rectangular field using photons, passively delivered protons as well as scanned protons and carbon ions. The lateral dose profile in the depth of the maximum dose was measured using an ion chamber, a diamond detector and thermoluminescence detectors TLD-600 and TLD-700. The yield of thermal neutrons was estimated for all radiation types while their complete spectrum was measured with bubble detectors during the irradiation with photons. The peripheral dose delivered by photons is significantly higher compared to both protons and carbon ions and exceeds the latter by up to two orders of magnitude at distances greater than 50 mm from the field. The comparison of passive and active delivery techniques for protons shows that, for the chosen rectangular target shape, the former has a sharper penumbra whereas the latter has a lower dose in the far-out-of-field region. When comparing scanning treatments, carbon ions present a sharper dose fall-off than protons close to the target but increasing peripheral dose with increasing incident energy. For photon irradiation, the contribution to the out-of-field dose of photoneutrons appears to be of the same order of magnitude as the scattered primary beam. Charged particles show a clear supremacy over x-rays in achieving a higher dose conformality around the target and in sparing the healthy tissue from unnecessary radiation exposure. The out-of-field dose for x-rays increases with increasing beam energy because of the production of biologically harmful neutrons.

[Clinical use of a micromanipulator system: preliminary clinical experience in middle ear surgery]. / Klinischer Einsatz eines Mikromanipulators : Erste Erfahrungen in der Mittelohr- und Felsenbeinchirurgie.

PROBLEM DESCRIPTION: Nowadays all procedures in tympanoplasty are performed using conventional instrumentation without any mechatronic based manipulators. A micromanipulator system (MMS) holds microinstruments and transmits the surgeon's hand movements to a monitor, thus, improving precision and ergonomics. MATERIALS AND METHODS: Using the Cartesian principle, a telemanipulator with three linear degrees of freedom controlled with a joystick was designed. The three axes are powered by a servomotor. The manipulator is equipped with a sterilizable instrument holder, which is placed on a sterile covered system. On this instrument holder, sterile surgical instruments can be clipped and can be easily changed during surgery. In the scope of this study, the MMS was used to perform a tympanoplasty III in 20 patients. A workflow expert protocol, a video of the surgery, and a questionnaire completed by all surgeons were evaluated. RESULTS: Clinical use of the MMS 2.0 was performed in all 20 patients as planned. A partial/total ossicular replacement prosthesis (PORP/TORP) was used in all cases with the MMS as planned. Significantly more time was necessary not only to prepare for surgery but also to prepare the equipment intraoperatively, and the incision to suture time was longer. The number of intraoperative changes of instruments decreased by 24%. The frequency of contact between the instrument and the prosthesis was significantly decreased. All questionnaires indicated that further improvement of the MMS is needed. CONCLUSION: The manipulator MMS 2.0 was successfully used in the clinical setting for the first time. The tool offers great potential for middle ear surgery (e.g., tympanoplasty III, stapes surgery and cochlear implant insertion). The principal of telemanipulation (master-slave) could be transferred to middle ear surgery. However, numerous technical improvements are still required.

MO-D-BRB-11: Out-Of-Field Dose Measurements in Radiotherapy Using Photons and Particles.

PURPOSE: Within the European project ALLEGRO (grant agreement no. 231965), the out-of-field dose delivered to a patient when treated with different radiotherapy modalities was investigated. The study compared the dose distribution during photon and particle irradiations both in a water and an anthropomorphic phantom to evaluate the risk of inducing secondary malignancies. METHODS: Two sets of experiments with standardized conditions were used for a systematic comparison. In the former, a water phantom was irradiated with a 2D squared field to characterize the lateral dose fall-off with high spatial resolution. The latter employed an anthropomorphic phantom treated for a target volume placed at the center of its head to simulate a brain tumor. The dose was measured in several planes along the phantom main axis. For both types of experiments the dose was measured with a PTW diamond detector. Additionally, the use of TLDs and bubble detectors provided some information on the secondary neutron field produced both in the accelerator structure and the target itself. In total, experiments were conducted at six facilities using photons, protons and carbon ions; the ion irradiations were performed with passive delivery and the scanning technique. RESULTS: A significant difference among the out-of-field dose profiles is observed for distances larger than 3 cm to the target. The distribution delivered by photons is a factor 10 to 400 higher than the values of charged particles. Scanning ions reduces the out-of-field dose more than passive delivery at distances larger than 10 cm. CONCLUSIONS: The study emphasizes the physical advantage of using charged particles for tumor therapy. Together with the favorable depth dose deposition, ions spare the normal tissue surrounding the target more efficiently than photons. These results imply a lower risk of long-term effects, such as the induction of secondary malignancies, following treatments with particles compared to photons. This work was funded by the European ALLEGRO project (Grant Agreement No. 231965).

[Disseminated papules in a patient with acute myeloid leukemia]. / Disseminierte Papeln bei einer Patientin mit akuter myeloischer Leukämie.

Cryptococcosis most commonly occurs in immunosuppressed patients. The pathogen is the yeast Cryptococcus neoformans. This article reports on the case of a 20-year-old female patient with acute myeloid leukemia who suddenly developed disseminated livid red papules and papulovesicles. The clinical picture and in particular the histopathology findings led to the diagnosis of cutaneous cryptococcosis, which was successfully treated with amphotericin B. For the differential diagnosis generalized herpes zoster, erythema exudativum multiforme and disseminated molluscum contagiosum must be considered. To confirm the diagnosis attempts can also be made to culture the pathogen from skin biopsy preparations. Furthermore, fungal spores can be rapidly and simply detected with the Tzanck test.

Monoclonal antibodies in the treatment of multiple sclerosis.

Multiple sclerosis (MS), a chronic demyelinating disorder, is characterized by recurrent neurological deficits or progressive impairment with a high risk of permanent disability. Since the exact pathophysiology and etiology remains still unclear, no curing therapy is currently available. However, several treatments with beneficial effect on relapse rate such as the first line therapies interferon-beta and glatiramer acetate were approved for relapsing-remitting MS. One new important tool in the therapy of MS is the use of monoclonal antibodies. Natalizumab is the first and so far only monoclonal antibody that is approved for MS treatment by the US Food and Drug Administration and the European Medicines Agency. In addition to natalizumab other monoclonal antibodies previously used in cancer and other autoimmune disorders or even newly developed for MS are now being tested in clinical trials. With their high target specificity and efficacy monoclonal antibodies are a promising treatment approach in MS. This review summarizes the present knowledge on the use, effectiveness and safety of monoclonal antibodies in MS treatment.