Definition of stereotactic body radiotherapy: principles and practice for the treatment of stage I non-small cell lung cancer.

This report from the Stereotactic Radiotherapy Working Group of the German Society of Radiation Oncology (Deutschen Gesellschaft für Radioonkologie, DEGRO) provides a definition of stereotactic body radiotherapy (SBRT) that agrees with that of other international societies. SBRT is defined as a method of external beam radiotherapy (EBRT) that accurately delivers a high irradiation dose to an extracranial target in one or few treatment fractions. Detailed recommendations concerning the principles and practice of SBRT for early stage non-small cell lung cancer (NSCLC) are given. These cover the entire treatment process; from patient selection, staging, treatment planning and delivery to follow-up. SBRT was identified as the method of choice when compared to best supportive care (BSC), conventionally fractionated radiotherapy and radiofrequency ablation. Based on current evidence, SBRT appears to be on a par with sublobar resection and is an effective treatment option in operable patients who refuse lobectomy.

Experiences of a poison center with metformin-associated lactic acidosis.

Metformin is widely used in the treatment of type 2 diabetes, though it is recognized to be associated with the risk of lactic acidosis. A case of pronounced lactic acidosis with cardiac arrest (pH 6.60, lactate 17.5 mmol/l, base excess - 30, standard bicarbonate 2.5 mmol/l, core body temperature 27.8 degrees C) is presented in a 61-year-old woman under metformin therapy. The key laboratory abnormalities observed during the intensive care treatment including repeated hemodialysis are described. The patient showed a complete recovery with residually reduced mental capabilities. Furthermore, an explorative data analysis of our poison center database from 1995 until 2003 concerning metformin was performed. In 109 inquiries for metformin a lactic acidosis (mean pH 6.87 +/- 0.11, mean lactate 20.9 +/- 8.1 mmol/l) was present in 14 cases (9 female, 5 male, average age 57.7 years) with 8 patients under regular metformin therapy and 6 patients who ingested large amounts of metformin to attempt suicide. 4 patients did not survive the severe metabolic disturbance. The present report demonstrates that metformin-associated lactic acidosis is a rare but critical complication of metformin therapy of type 2 diabetes as well as in acute suicidal ingestion of metformin. Early diagnosis and rapid correction of the metabolic acidosis using hemodialysis provides the possibility of a positive outcome even in severe cases. If metformin-associated lactic acidosis is suspected we recommend early involvement of a poison center.

[Fulminant pulmonary edema in falciparum malaria [corrected]]. / Fulminantes Lungenödembei Malaria tropica.

HISTORY AND ADMISSION FINDINGS: A 54-year-old man was admitted because of intermittent fever for 2 days. Ten days earlier he had returned from Kenya. He had not taken any antimalarial drugs prophylactically. INVESTIGATIONS: Initial blood smears showed Plasmodium falciparum in 10.4% of erythrocytes. Laboratory tests indicated hyponatremia and disseminated intravascular coagulation. Also, laboratory markers of infection and hemolysis were clearly positive and accompanied by a low-grade normocyticanaemia. Chest radiograph showed the heart size to be at the upper limit of normal and no signs of congestion, pleural effusion or inflammatory infiltrates. Sonography demonstrated hepatosplenomegaly with diffusely increased echogenicity of the liver. TREATMENT AND COURSE: Falciparum malaria [corrected] with quartan fever was diagnosed and treatment with quinine and doxycycline was initiated. Despite the successful elimination of parasites and a negative fluid balance the patient died two days after admission from pulmonary edema and heart failure. CONCLUSIONS: A negative fluid balance failed to prevent acute pulmonary edema in this case of severe malaria,supporting the view that fluid imbalance is not an essential feature in malaria-induced lung injury and that cytokines play and important role.

[A simple dose-effect model for the optimization of IMRT]. / Einfache Dosis-Effekt-Modelle für die Optimierung in der IMRT.

Optimization of percutaneous photon beams with intensity modulation was investigated in terms of the influence of different dose-effect functions for lung tissue on the resulting dose distributions. The fluence profiles were optimized for a cylindrical phantom with a L-shaped target, the spinal cord and lung presenting the critical organs. Concurrent criteria were a minimum dose constraint for the target and a maximum dose constraint for the spinal cord. The dose effect in the lung was minimized using different approaches. All tested approaches were able to control the dose distribution in the lung. The mean dose remained constant, where as the volume of low dose could be changed. Due to the simplicity of functions and parameters, these models are suitable for clinical implementation.

Application of constrained optimization to radiotherapy planning.

Essential for the calculation of photon fluence distributions for intensity modulated radiotherapy (IMRT) is the use of a suitable objective function. The objective function should reflect the clinical aims of tumor control and low side effect probability. Individual radiobiological parameters for patient organs are not yet available with sufficient accuracy. Some of the major drawbacks of some current optimization methods include an inability to converge to a solution for arbitrary input parameters, and/or a need for intensive user input in order to guide the optimization. In this work, a constrained optimization method was implemented and tested. It is closely related to the demanded clinical aims, avoiding the drawbacks mentioned above. In a prototype treatment planning system for IMRT, tumor control was guaranteed by setting a lower boundary for target dose. The aim of low complication is fulfilled by minimizing the dose to organs at risk. If only one type of tissue is involved, there is no absolute need for radiobiological parameters. For different organs, threshold dose, relative seriality of the organs or an upper dose limit could be set. All parameters, however, were optional, and could be omitted. Dose-volume constraints were not used, avoiding the possibility of local minima in the objective function. The approach was benchmarked through the simulation of both a head and neck and a lung case. A cylinder phantom with precalculated dose distributions of individual pencil beams was used. The dose to regions at risk could be significantly reduced using at least seven ports of beam incidence. Increasing the number of ports beyond seven produced only minor further gain. The relative seriality of organs was modeled through the use of an added exponent to the dose. This approach however increased calculation time significantly. The alternative of setting an upper limit is much faster and allows direct control of the maximum dose. Constrained optimization guarantees high tumor control probability, it is computationally more efficient than adding penalty terms to the objective function, and the input parameters are dose limits known in clinical practice.

A simple model for examining issues in radiotherapy optimization.

Convolution/superposition software has been used to produce a library of photon pencil beam dose matrices. This library of pencil beams is designed to serve as a tool for both education and investigation in the field of radiotherapy optimization. The elegance of this pencil beam model stems from its cylindrical symmetry. Because of the symmetry, the dose distribution for a pencil beam from any arbitrary angle can be determined through a simple rotation of a pre-computed dose matrix. Rapid dose calculations can thus be performed while maintaining the accuracy of a convolution/superposition based dose computation. The pencil beam data sets have been made publicly available. It is hoped that the data sets will facilitate a comparison of a variety of optimization and delivery approaches. This paper will present a number of studies designed to demonstrate the usefulness of the pencil beam data sets. These studies include an examination of the extent to which a treatment plan can be improved through either an increase in the number of beam angles and/or a decrease in the collimator size. A few insights into the significance of heterogeneity corrections for treatment planning for intensity modulated radiotherapy will also be presented.

In vitro and in vivo porphyrin accumulation by C6 glioma cells after exposure to 5-aminolevulinic acid.

Several malignant tissues synthesize endogenous porphyrins after exposure to 5-aminolevulinic acid (5-ALA). The present experiments have been designed to elucidate whether the C6 glioma cell, a model cell for human malignant glioma, similarly synthesizes porphyrins when exposed to 5-ALA, and whether specific synthesis occurs when C6 cells are inoculated into rat brains to form a tumor. In this situation the blood-brain barrier may interfere with 5-ALA availability, and spreading of porphyrins with edema outside the tumor may occur. Flow cytometry is used to determine the course of cell volume and porphyrin fluorescence intensities in cultured C6 cells which are incubated in 1 mM 5-ALA. For the induction of experimental brain tumors, 10(4) untreated C6 cells are inoculated into the brains of rats. After 9 days animals receive 100 mg 5-ALA/kg body weight. Brains are removed after 3, 6, or 9 h and frozen coronal sections obtained for H/E staining or fluorescence spectography. Cultured C6 cells show a linear increase of protoporphyrin IX fluorescence after exposure to 5-ALA, which begins to plateau after 85 min. Marked fluorescence is also observed in solid and infiltrating experimental tumor. However, faint fluorescence also occurs in normal tissue, basal pia, choroid plexus, and, more obviously, in white-matter tracts bordering the tumor (maximal distance: 1.5 +/- 0.7 mm). The observations demonstrate that C6 cells synthesize protoporphyrin IX after exposure to 5-ALA in vitro and in vivo. However, when utilizing 5-ALA for fluorescence detection or photodynamic therapy of brain tumors, attention should be paid to the possibility of protoporphyrin IX occurring outside the tumor.

High-resolution native and complex structures of thermostable beta-mannanase from Thermomonospora fusca - substrate specificity in glycosyl hydrolase family 5.

BACKGROUND: . beta-Mannanases hydrolyse the O-glycosidic bonds in mannan, a hemicellulose constituent of plants. These enzymes have potential use in pulp and paper production and are of significant biotechnological interest. Thermostable beta-mannanases would be particularly useful due to their high temperature optimum and broad pH tolerance. The thermophilic actinomycete Thermomonospora fusca secretes at least one beta-mannanase (molecular mass 38 kDa) with a temperature optimum of 80 degreesC. No three-dimensional structure of a mannan-degrading enzyme has been reported until now. RESULTS: . The crystal structure of the thermostable beta-mannanase from T. fusca has been determined by the multiple isomorphous replacement method and refined to 1.5 A resolution. In addition to the native enzyme, the structures of the mannotriose- and mannohexaose-bound forms of the enzyme have been determined to resolutions of 1.9 A and 1.6 A, respectively. CONCLUSIONS: . Analysis of the -1 subsite of T. fusca mannanase reveals neither a favourable interaction towards the axial HO-C(2) nor a discrimination against the equatorial hydroxyl group of gluco-configurated substrates. We propose that selectivity arises from two possible mechanisms: a hydrophobic interaction of the substrate with Val263, conserved in family 5 bacterial mannanases, which discriminates between the different conformations of the hydroxymethyl group in native mannan and cellulose; and/or a specific interaction between Asp259 and the axial hydroxyl group at the C(2) of the substrate in the -2 subsite. Compared with the catalytic clefts of family 5 cellulases, the groove of T. fusca mannanase has a strongly reduced number of aromatic residues providing platforms for stacking with the substrate. This deletion of every second platform is in good agreement with the orientation of the axial hydroxyl groups in mannan.

Calculation of dose distributions in the vicinity of high-Z interfaces for photon beams.

In the vicinity of interfaces between materials of different atomic number Z, extremes in absorbed dose occur for high-energy photon irradiations. The spatial extension of the effects is within the range of 1 cm, which may not be ignorable from the radiobiological point of view. At the front side of a high-Z slab a maximum is observed, whereas at the exit side a small buildup zone of the dose occurs, e.g., for a 5 MV beam, in front of a water/iron interface, the enhancement is about 30% of that to the homogeneous medium. The reduction at the back of the iron slab is about 16% for this energy, but vanishes with increasing energy. For high-energy photons this effect is mainly caused by the strong atomic number dependence of the scattering power for secondary electrons. The amount and extent of the scattering effects have been measured for aluminum and for iron slabs embedded in water or PMMA. The experimental data are in good agreement with Monte Carlo calculated values. Therefore the data form a reliable base to test the performance of commonly used treatment planning algorithms. The convolution or superposition method is used to calculate dose distributions. To account for the Z dependence of the scattering and the stopping power of the secondary electrons, corrections are applied to the energy deposition kernels. The boundary crossing of energy deposition kernels can be treated only in an approximate manner. However, the algorithm developed improves the accuracy of the dose calculation in the vicinity of interfaces significantly.

[The multisegmental electron irradiation of the chest wall following ablative therapy of breast cancer]. / Zur multisegmentalen Elektronenbestrahlung der Thoraxwand nach ablativer Therapie des Mammakarzinoms.

PURPOSE: The paper describes the clinical aspects of postoperative irradiation of breast cancer using electron arc technique at the chest wall. The value of the treatment is assessed by long-term results concerning the rate of local recurrences and side effects. The advantages of the procedure are described with regard to physical and technical aspects. PATIENTS AND METHODS: After mastectomy, 117 patients underwent and adjuvant radiotherapy of the chest wall by multisegmental electron rotation technique with energies between 4 and 14 MeV. The number and angular range of the segments as well as the energy of the electrons depended on the peculiar thickness of the chest wall. 25 times 2 Gy were applied within five weeks. The treatment planning is based on a patient model constructed from five CT-slices at least. RESULTS: In four cases (3.4%) a local relapse and in one case (0.9%) a relapse in supraclavicular lymphatics was found. The recurrences appeared after an average period of 32 months. The mean observation time was 70 months. In 37 women (32%) distant metastases were seen after 29 months on an average. The five-year survival rate is 73.5%. CONCLUSION: In comparison to usual techniques using photons the described method shows a more homogeneous dose distribution to the chest wall and a reduction of lung radiation exposure. The clinical result of this dose adaptation to the treatment volume is a lower rate of local relapses and of side effects, inclusive late reactions. It can be suggested that the efficiency of the procedure will be ameliorated in future using special electron compensators. This will result in a more favorable adaptation of dose distribution to the anatomical situation in regard to the cranio-caudal profile.

Reconstruction of high-energy bremsstrahlung spectra by numerical analysis of depth-dose data.

The determination of the spectral distribution of a photon beam is important for exact dosimetry and for the calculation of dose distributions. Direct measurements are not possible because of physical reasons. The approximation described uses a numerical reconstruction method based upon depth-dose data measured in water. The basic idea of the method is that a measured depth-dose curve can be thought of as a weighted superposition of monoenergetic depth-dose curves. The monoenergetic data are obtained by convolution of Monte Carlo generated energy deposition kernels. They were fitted to the measured data by means of a least squares method. Several constraints were applied to the superposition coefficients. The optimization algorithm uses the Wolfe reduced gradient method. The results were compared to Monte Carlo generated thick target spectra.

[Surgical aspects of bone tumors in children]. / Chirurgische Aspekte der Knochentumoren im Kindesalter.

The combination of surgical procedures with chemotherapy and radiotherapy has improved the disease-free 3-year survival rate in children treated for malignant bone tumors, and it is now 80%. As far as the quality of life is concerned, limb-conserving technique should be preferred whenever possible. The rate of local recurrence is equal to that after amputation, while the rate of pulmonary metastasis somewhat higher, for reasons that are still unknown. It is shown that the decision for amputation or segmental resection has to be considered strictly individually for each patient.

[Accomplishments of tumor surgery in bone sarcoma in childhood]. / Leistungen der Tumorchirurgie beim Knochensarkom im Kindesalter.

Neither chemotherapy nor surgery alone provided satisfactory treatment of bone sarcomas in children. However, their combination improved the 3-year-survival rate by up to 80% in the last decade. For better life quality, limb-sparing techniques like en-bloc-resection, rotation plasty or endoprosthesis should be preferred instead of amputation, if they are possible within the demands of radical oncological surgery. The significantly higher incidence of pulmonary metastasis of en-bloc-resection compared to that of ablative surgery as shown in the COSS-80-study points out that limb-sparing surgery is still problematic and needs further technical improvement in the future.

[3-D reconstruction of the breast implants from isocentric stereoscopic x-ray images for the application monitoring and irradiation planning of a remote-controlled interstitial afterloading method]. / 3-D-Rekonstruktion von Brustimplantaten aus isozentrischen stereoskopischen Röntgenaufnahmen (ISR) zur Applikationskontrolle und Bestrahlungsplanung einer ferngesteuerten interstitiellen Nachlademethode.

An individual irradiation planning and application monitoring by ISXP is presented for a remote-controlled interstitial afterloading technique using 192Ir wires which is applied in breast-preserving radiotherapy. The errors of reconstruction of the implants are discussed. The consideration of errors for ISXP can be extended to other stereoscopic methods. In this case the quality considerations made by other authors have to be enlarged. The maximum reconstruction error was investigated for a given digitalization precision, focus size, and object blur by patient's movements in dependence on the deviation angle. The optimum deviation angle is about 45 degrees, depending on the importance given to the individual parts and almost without being influenced by the relation between the isocenter-film and the focus-isocenter distances. In case of an optimized deviation angle, a displacement of an implant point of 1 mm leads to a maximum reconstruction error of 2 mm. The dosage is made according to the Paris system. If the circumcircle radius of the application triangle is modified by 1 mm, a dosage modification of 14% will be the consequence in case of very short wires and a small side length. A verification in a phantom showed a positioning error below 0.5 mm. The dosage error is 2% due to the mutual compensation of the direction-isotropic reconstruction errors of the needles the number of which is between seven and nine.

[CT in radiotherapy. Its value in computer-supported 3D-irradiation planning for the breast]. / CT in der Strahlentherapie. Stellenwert bei der rechnerunterstützten 3D-Bestrahlungsplanung der Mamma.

The use and value of CT-directed radiation planning in three planes is discussed. Various modifications for simulation are proposed. In particular, reconstruction for the horizontal position of the sternum is considered.

Neurological and neuropathological findings in familial erythrophagocytic lymphohistiocytosis.

An infant case of erythrophagocytic lymphohistiocytosis is reported. The disease began at the age of two months with hepatosplenomegaly and intractable fever, and later developed pancytopenia. Splenectomy had to be performed at the age of six months and led to the final diagnosis. After the age of nine months the patient developed progressive neurological signs (loss of visual function convulsions, opisthotonus and CSF pleocytosis). The changes in the CT-scan of the brain were explained by the neuropathologic findings after the death of the patient at the age of 13 months. The markedly atrophic brain showed diffuse and mainly perivascular infiltration of brain and meninges with lympho- and histiocytes and extensive microscopic calcification.

[Myositis ossificans progressiva (M.o.p.)--a morphological and biochemical study (author's transl)]. / Myositis ossificans progressive (M.o.p.). Eine morphologische und biochemische Studie.

In a two-year-old girl suffering from myositis ossificans progressiva a biopsy specimen from a soft tissue tumor was examined by electron microscopy and by collagen electrophoresis (SDS-Polyacrylamide Gel Electrophoresis). Electron microscopic findings of the biopsy specimen showed that the collagen appeared to be similar to type II collagen which can be found for example in hyaline cartilage however collagen electrophoresis revealed neither any certain signs of type II collagen nor any different proportion of type I and type III collagen compared to a healthy child.