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.

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.

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.

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.

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.

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.

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.

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.

[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.

[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.

Electron microscopic findings in a case of systemic mastocytosis.

For several decades urticaria pigmentosa had been considered to be a benign and purely cutaneous disease, caused by infiltrations of tissue mast cells in the skin. Yet until 1962 at least 24 cases of systemic mastocytosis had been published. Sagher estimated the incidence of systemic mastocytosis as being in the region of about 10% of all cases of urticaria pigmentosa. A case of systemic mastocytosis in a 4-year-old child is described. Biopsy specimens were examined by electron microscopy to study the process of degranulation of tissue mast cells during which histamine and heparin are released.

[T- and B-lymphocyte determination in infectious mononucleosis]. / T- und B-Lymphozyten-Bestimmung bei Mononucleosis infectiosa.

In 12 children with infectious mononucleosis the peripheral blood T- and B-lymphocytes were studied and compared to a control group of 26 children, aged 2 to 13 years, without any infection. Spontaneous sheep red blood cell rosettes were used as a T-cell marker, demonstration of surface immunoglobulins by immunofluorescence technique was used as a B-cell marker. Patients with infectious mononucleosis showed a marked increase of T-lymphocytes (percentage and absolute numbers) in comparison with the control group; the difference was statistically significant. Since only B-lymphocytes are the target cells fo Epstein-Barr virus, the increase of T-lymphocytes in infectious mononucleosis probably represents the response of cell mediated immunity against B-lymphocytes which are altered in their antigenic properties by Epstein-Barr virus.

[Tertiary malaria with acute lung edema in a Turkish child]. / Malaria tertiana mit akutem Lungenödem bei einem türkischen Kind.

In the past 10-15 years there has been a continuous increase of imported cases of malaria in the Federal Republic of Germany. The case of a two-year-old child of a Turkish foreign worker with severe tertian malaria complicated by pulmonary edema is described. In general tertian malaria is rarely fatal to adults, but in children the primary attack can be life threatening.

[Improved prognosis of Ewing-sarcoma by combined irradiation and chemotherapy (author's transl)]. / Bessere Prognose in der Behandlung des Ewing-Sarkoms durch kombinierte Strahlen- und Chemotherapie

Until recently Ewing's sarcoma has been considered the most lethal malignant bone tumor with the poorest prognosis. An 8-year-old girl with Ewing's sarcoma is described who survived without recurrent disease for nearly 5 years now. 5-year-survival rates among large groups in the literature are reported, and different kinds of therapy compared. There are indications for a tendency that combined radio- and chemotherapy probably have the best results, since in most cases at the time of diagnosis the tumor already has metastasized or, like Lichtenstein believes, Ewing's sarcoma, primarily is of multicentric origin.

[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.

[Wilms tumor in hemihypertrophy]. / Wilms-Tumor bei Hemihypertrophie

The case of a 4-year-old boy with Wilms' tumor and hemihypertrophy is described. Wilms' tumors are frequently associated with congenital malformations of the urinary tract, with aniridia and hemihypertrophy. Hemihypertrophy is a relatively rare malformation (1:14000) in the common population, but in patients with Wilms' tumors its frequency is about 1:49. Besides Wilms' tumors tumors of the adrenal cortex and hepatoblastomas are frequently observed together with hemihypertrophy.

[Dubowitz syndrome with immunodeficiency and solid malignant tumor in two siblings (author's transl)]. / Dubowitz-Syndrom mit Immundefizienz und malignem Neoplasma bei zwei Geschwistern.

The main features of Dubowiz syndrome are bird headed dwarfism and a typical facial configuration. Including two own patients 13 cases among 8 siblings are known in the literature. Two own cases of Dubowitz syndrome in two sisters are described, one of them with hypogammaglobulinemia and neuroblastoma, the other one with complete Ig A deficiency and malignant lymphoma. A propable relationship between immundeficiency and malignancies is discussed. Until 1973 151 malignant tumors with primary immundeficiency had been registrated. This paper is the first description of two cases of Dubowitz syndrome with immunodeficiency and malignant neoplasms.