[Oncologic aspects in treatment of pathologic fractures]. / Onkologische Aspekte der Behandlung pathologischer Frakturen.

BACKGROUND: Pathological fractures are not only incisive events for tumor patients often with the need of surgical treatment but also often represent a relevant challenge in the overall concept of oncological treatment. OBJECTIVE: The aim of this article is to illustrate the necessity of a pre-interventional interdisciplinary consideration of disease-specific and patient-specific characteristics. MATERIAL AND METHODS: A literature search and evaluation of existing guidelines were carried out including the keywords "bone metastases" and "pathological fractures" with respect to the oncological and radiotherapeutic treatment. RESULTS: An essential classification of the surgical and other needs for treatment is carried out by the identification of the underlying disease and dissemination situation. For tumor-related pathological fractures a palliative treatment situation is present in most cases. Nevertheless, a possible oligometastasis and an increasing number of effective systemic treatment methods must be taken into consideration when planning the surgical treatment. In addition to the therapeutic emergency indications in spinal compression or symptomatic hypercalcemia, both additive radiotherapy and supplementary pharmaceutical osteoprotection have to be addressed in this context. Radiotherapy in particular represents an effective alternative option for symptom and tumor control. CONCLUSION: The work-up of the multifaceted oncological treatment concept represents an interdisciplinary challenge, which ideally defines the further treatment procedure, including fracture treatment, in an interdisciplinary tumor board within an overall oncological concept.

Association of proton density fat fraction in adipose tissue with imaging-based and anthropometric obesity markers in adults.

BACKGROUND/OBJECTIVES: The purpose of this study was to examine the relationship of the proton density fat fraction (PDFF), measured by magnetic resonance imaging (MRI), of supraclavicular and gluteal adipose tissue with subcutaneous and visceral adipose tissue (SAT and VAT) volumes, liver fat fraction and anthropometric obesity markers. The supraclavicular fossa was selected as a typical location where brown adipocytes may be present in humans and the gluteal region was selected as a typical location enclosing primarily white adipocytes. SUBJECTS/METHODS: In this cross-sectional study, 61 adults (44 women, median age 29.3 years, range 21-68 years) underwent an MRI examination of the neck and the abdomen/pelvis (3T, Ingenia, Philips Healthcare). PDFF maps of the supraclavicular and gluteal adipose tissue and the liver were generated. Volumes of SAT and VAT were calculated and supraclavicular and subcutaneous fat were segmented using custom-built post-processing algorithms. Body mass index (BMI), waist circumference and waist-to-height ratio were recorded. Statistical analysis was conducted using the Student's t-test and Pearson correlation analysis. RESULTS: Mean supraclavicular PDFF was 75.3±4.7% (range 65.4-83.8%) and mean gluteal PDFF was 89.7±2.9% (range 82.2-94%), resulting in a significant difference (P<0.0001). Supraclavicular PDFF was positively correlated with VAT (r=0.76, P<0.0001), SAT (r=0.73, P<0.0001), liver PDFF (r=0.42, P=0.0008) and all measured anthropometric obesity markers. Gluteal subcutaneous PDFF also correlated with VAT (r=0.59, P<0.0001), SAT (r=0.63, P<0.0001), liver PDFF (r=0.3, P=0.02) and anthropometric obesity markers. CONCLUSIONS: The positive correlations between adipose tissue PDFF and imaging, as well as anthropometric obesity markers suggest that adipose tissue PDFF may be useful as a biomarker for improving the characterization of the obese phenotype, for risk stratification and for selection of appropriate treatment strategies.

Toward individualized SAR models and in vivo validation.

The specific absorption rate (SAR) is a limiting constraint in sequence design for high-field MRI. SAR estimation is typically performed by numerical simulations using generic human body models. This entails an intrinsic uncertainty in present SAR prediction. This study first investigates the required detail of human body models in terms of spatial resolution and the number of soft tissue classes required, based on finite-differences time-domain simulations of a 3 T body coil. The numerical results indicate that a resolution of 5 mm is sufficient for local SAR estimation. Moreover, a differentiation between fatty tissues, water-rich tissues, and the lungs was found to be essential to represent eddy current paths inside the human body. This study then proposes a novel approach for generating individualized body models from whole-body water-fat-separated MR data and applies it to volunteers. The SAR hotspots consistently occurred in the arms due to proximity to the body coil as well as in narrow regions of the muscles. An initial in vivo validation of the simulated fields in comparison with measured B(1)-field maps showed good qualitative and quantitative agreement.

Successful treatment of enterovirus-infected mice by 2-(alpha-hydroxybenzyl)-benzimidazole and guanidine.

Echo virus 9- or Coxsackie A 9-infected newborn mice are protected from paralysis and death by combined treatment with nontoxic concentrations of HBB plus guanidine. HBB alone also protects Coxsackie A 9, but not echo virus 9-infected animals, whereas guanidine alone is ineffective in either case. Protection is due to inhibition of virus multiplication via the antiviral activity of these selective inhibitors. Treatment must be begun at the latest 48 h after virus inoculation. 3 days of treatment are sufficient if started at the time of virus inoculation. Failure of protection after treatment with one compound alone is not due to rapid development of drug-resistant virus mutants. Infected, successfully treated mice may develop a solid immunity.

Inhibition of release of vaccinia virus by N1-isonicotinoly-N2-3-methyl-4-chlorobenzoylhydrazine.

N(1)-isonicotinoyl-N(2)-3-methyl-4-chlorobenzoylhydrazine (IMCBH) is a selective inhibitor of vaccinia virus multiplication. In concentrations up to 50 microg/ml, IMCBH causes neither toxic morphologic changes, nor does it inhibit the multiplication of cells. Viruses other than vaccinia are not affected by IMCBH. The virus-inhibitory effect of IMCBH is dependent on the type of host cell used, i.e., the compound is effective in chick embryo fibroblasts and monkey kidney cells but not in L cells. IMCBH does not exhibit any protecting effect on vaccinia virus-infected mice or rabbits. IMCBH interferes with virus release: in single cycle experiments in chick embryo fibroblasts, IMCBH strongly blocks the release of vaccinia virus at concentrations as low as 3 microg/ml, while intracellular virus synthesis is hardly affected. Viral cytopathic changes are completely suppressed by IMCBH within the span of a single cycle infection, although extensive changes eventually occur. By inhibiting virus release from initially infected cells, IMCBH markedly inhibits the multiplication of vaccinia virus in cell cultures infected at low virus/ cell multiplicities. IMCBH does not inhibit the early toxic cytopathic changes induced by large inocula of vaccinia virus in BHK21 cells.

Whole-heart imaging using undersampled radial phase encoding (RPE) and iterative sensitivity encoding (SENSE) reconstruction.

Whole-heart isotropic nonangulated cardiac magnetic resonance (CMR) is becoming an important protocol in simplifying MRI, since it reduces the need of cumbersome planning of angulations. However the acquisition times of whole-heart MRI are prohibitive due to the large fields of view (FOVs) and the high spatial resolution required for depicting small structures and vessels. To address this problem, we propose a three-dimensional (3D) acquisition scheme that combines Cartesian sampling in the readout direction with an undersampled radial scheme in the phase-encoding plane. Different undersampling patterns were investigated in combination with an iterative sensitivity encoding (SENSE) reconstruction and a 32-channel cardiac coil. Noise amplification maps were calculated to compare the performance of the different patterns using iterative SENSE reconstruction. The radial phase-encoding (RPE) scheme was implemented on a clinical MR scanner and tested on phantoms and healthy volunteers. The proposed method exhibits better image quality even for high acceleration factors (up to 12) in comparison to Cartesian acquisitions.

Physiological basis of anisometropic amblyopia.

In the visual cortex of kittens that have received their only visual experience while wearing a high-power lens before one eye, most neurons are dominated by input from the normal eye. Moreover, contrast sensitivity and resolving power are lower for stimulation through the originally defocused eye, mimicking psychophysical results from human anisometropic amblyopes.

Rhodanine: a selective inhibitor of the multiplication of echovirus 12.

A search for compounds which have previously unrecognized antiviral activity led to the discovery that rhodanine inhibits the multiplication of echovirus 12 and also the development of virus-induced morphologic changes. Eighteen derivatives and analogs of rhodanine were synthesized and tested against echovirus 12. These compounds were considerably less active than rhodanine or were inactive, and some of them were more toxic to the host cells than rhodanine.

Intratumoral expression of programmed death ligand 1 (PD-L1) in patients with clear cell renal cell carcinoma (ccRCC).

The immunological checkpoints of programmed death 1 and its ligand (PD-L1) are currently in focus as novel therapeutic targets in renal cell carcinoma (RCC). The aim of this study was to evaluate the prognostic association of PD-L1 expression in clear cell (cc) RCC with clinical parameters, tumor aggressiveness and overall survival (OS). Patients who underwent renal surgery due to RCC between 1994 and 2003 were retrospectively evaluated. Tumor specimens were analyzed for PD-L1 expression by immunohistochemistry. One hundred and seventy-seven ccRCC patients were eligible for analysis, in which 140 (79.1 %) were negative and 37 (20.9 %) were positive for PD-L1 expression. PD-L1 positivity was associated with female gender (p = 0.001), lymph node metastasis (p = 0.004), distant metastasis (p = 0.002), higher AJCC stage (p = 0.004), as well as advanced disease (pT3/4 and/or N+ and/or M1) (p < 0.001). Kaplan-Meier analysis revealed a significantly diminished 5- and 10-year overall survival of 46.7 and 28.3 % for PD-L1(+) compared to PD-L1(-) tumors with 66 and 53.4 % (p = 0.005), respectively. Univariate analysis showed a significant negative association of OS with PD-L1 positivity [p = 0.005; HR: 2 (95 % CI 1.2-3.3)], even though PD-L1 positivity only tends to predict independently the OS using multivariate analyses [p = 0.066; HR: 1.6 (95 % CI 0.98-2.7)]. PD-L1 expression in ccRCC is associated with parameters of aggressiveness, as well as with poor OS, even though PD-L1 status was not identified as a significant independent prognostic parameter. However, further studies in larger cohorts are warranted.

Disposition kinetics of moclobemide, a monoamine oxidase-A enzyme inhibitor: single and multiple dosing in normal subjects.

The absorption and disposition kinetics of moclobemide (Ro 11-1163), a new reversible and preferential monoamine oxidase-A enzyme inhibitor, were examined in 12 normal male subjects. An intravenous infusion was administered before and after a 15-day multiple oral dosing regimen (100 mg t.i.d.). Plasma concentration-time data were obtained after each intravenous infusion, after the first oral dose, during two dosing intervals at steady state, and before the second daily dose on several days. The disposition values (percent coefficient of variation in parentheses) after the first and second intravenous infusions, respectively, were: clearance, 39.4 (15%) and 29.1 (12%) L/hr; elimination half-life, 1.60 (15%) and 2.00 (18%) hours; and volume of distribution at steady state, 84.3 (11%) and 80.7 (15%) L. The absolute oral bioavailability increased from 0.56 after the first oral dose to 0.86 and 0.90 after the first and second weeks of administration, respectively. The reduced metabolic, presumably hepatic, clearance may be the result of self-inhibition or metabolite inhibition of moclobemide clearance.

Cimetidine alters the disposition kinetics of the monoamine oxidase-A inhibitor moclobemide.

The influence of cimetidine on the absorption and disposition of moclobemide was examined in eight healthy male subjects. A single 100 mg intravenous and 100 mg oral dose of moclobemide was administered before and after 2 weeks of cimetidine administration (200 mg five times a day). The data on intravenous administration indicated that cimetidine produced a statistically significant alteration in the following disposition parameters (mean values for control versus cimetidine): systemic clearance, 46.6 versus 28.3 L/hr; mean residence time, 2.1 versus 3.2 hours; elimination half-life, 1.6 versus 2.3 hours. There was no significant difference in the steady-state volume of distribution. The absolute oral bioavailability of moclobemide increased significantly after cimetidine administration (54% versus 68%), as did the maximum plasma concentration after a single oral dose (575 versus 787 ng/ml). There were no differences in the mean absorption time or time to achieve maximum concentration. The values of systemic and apparent oral clearances of moclobemide after cimetidine administration were directly related to the corresponding control values before cimetidine. In contrast, the percentage change in clearance was essentially independent of the corresponding initial control clearance value.

Detection of DNA-protein binding in western blots by phosphorus-labeled and biotinylated DNA probes.

Eukaryotic DNA-binding proteins can be detected by a filter binding assay combining protein blotting on nitrocellulose, incubation with DNA by filtration, and the application of radioactively or nonradioactively labeled DNA probes. Basic nuclear and non-nuclear standard proteins are assayed in dot blots as well as in Western blots from sodium dodecyl sulfate gels. The DNA-binding ability of fractionated proteins is compared employing two different blotting techniques, conventional electro-transfer and protein-renaturating capillary transfer. Biotinylated DNA probes exhibit high sensitivity and a distinct discrimination of detection signals corresponding only to defined DNA-binding proteins. In contrast, phosphorus-labeled DNA probes show higher sensitivity, but less effective resolving power, especially for bands localized close to each other. Using the DNA-incubation procedure described, biotinylated DNA probes are preferable to radioactively-labeled probes for screening DNA-binding proteins in complex protein fractions.

In situ hybridization with digoxigenin-labeled DNA of human papillomaviruses (HPV 16/18) in HeLa and SiHa cells.

To establish a nonradioactive method for demonstrating HPV DNA in routinely treated smears of the uterine cervix (alcohol fixation, staining according to Papanicolaou, preservation), in situ hybridizations were carried out in HeLa and SiHa cells grown on slides. After detailed investigations, the sensitivity and specificity of the biotin-avidin method (10) initially used proved to be inadequate for this purpose. Demonstration of HPV 16 DNA in SiHa cells (SiHa cells only contain 1-2 HPV genome copies) was possible only by use of digoxigenin-labeled HPV 16 gene probes, as well as an improved purification of the sample DNA from vector contaminations. Thus, for the first time a protocol for correlation of the results of an in situ hybridization with the cytological appraisal in the very same smear preparation has been developed for routine diagnostics.

Natural strabismus in monkeys. Convergence errors assessed by cover test and photographic methods.

A standard set of clinical prism and cover tests and a recently developed photographic method were used to assess binocular alignment in ten monkeys that previously were determined to have a naturally occurring infantile strabismus. Extensive measurements of the alignment state were made for fixation attempts throughout the field of gaze. Patterns of alignment errors were examined in an attempt to compared the strabismus found in individual monkeys with common syndromes of human infantile strabismus. Two monkeys showed patterns consistent with the syndrome of essential infantile esotropia. Five monkeys had patterns consistent with accommodative esotropia. One monkey that had bilateral anterior chamber hemorrhage at birth had a constant-angle esotropia. One monkey that previously had been shown to have a large-angle esotropia during development exhibited only exophoria, and in a final monkey in which large-angle esotropia was found during development, the strabismus had resolved. These results demonstrate that naturally occurring strabismus in monkeys might be related to syndromes seen in children. In addition, they provide extensive information about other characteristics of strabismus that have not been examined previously. These include a characterization of the magnitude of the misalignment in terms of error surface plots of bias and a detailed analysis of scatter in the measurements that show coupling relationships between the two eyes.

Postnatal axial eye elongation in normal and visually deprived rhesus monkeys.

The influence of anomalous visual experience on the postnatal regulation of axial eye elongation was explored by raising newborn rhesus monkeys under different types of monocular and binocular deprivation and comparing their eye growth pattern with that of age-matched normal monkeys. Monocular manipulations included eyelid suture to eliminate pattern vision; continuous occlusion with an opaque lens to prevent visual experience; surgical removal of the natural lens to induce continuous blur; and correction of surgically induced aphakia with extended-wear contact lenses (EWCLs) to provide a focused image of near objects. Binocular manipulations involved correction of aphakia with an EWCL in one eye and continuous or partial occlusion of the phakic fellow eye. After monocular eyelid suture or occlusion, the deprived eyes were longer than the unmanipulated fellow eyes. Aphakic eyes, however, were shorter than their unmanipulated fellow eyes. The unmanipulated eyes followed the eye elongation pattern of age-matched normal monkeys. Binocular manipulations also resulted in differences in axial length between the two eyes. Aphakic eyes were shorter, and continuously occluded eyes were longer, than eyes of age-matched controls. After partial occlusion, however, the axial length of occluded eyes was similar to that of normal eyes. The finding that lid-sutured and occluded eyes become longer while aphakic eyes remain shorter than normal eyes suggests that additional factors besides retinal image quality control postnatal eye growth.

Neonatal lensectomy and intraocular lens implantation: effects in rhesus monkeys.

PURPOSE: To compare the effects of a lensectomy with and without intraocular lens (IOL) implantation on a neonatal rhesus monkey eye. METHODS: A lensectomy and anterior vitrectomy was performed on 75 monkeys during the first 16 days of life; 21 of these monkeys also had an IOL implanted into the posterior chamber. The eyes were examined at regular intervals using biomicroscopy, applanation tonometry, and ophthalmoscopy. RESULTS: The pseudophakic monkeys were studied until they were 92.5 +/- 5.8 weeks of age and the aphakic monkeys until they were 80.4 +/- 5.7 weeks of age. Pupillary membranes (100% versus 55.5%; P < 0.01) and lens regeneration into the pupillary aperture (28.6% versus 5.6%; P = 0.02) occurred more often in the pseudophakic than the aphakic eyes. As a result, the pseudophakic eyes required more reoperations than the aphakic eyes to keep the visual axis clear (P < 0.01). There was not a significant difference in the incidence of ocular hypertension between the pseudophakic and aphakic eyes (9.5% versus 12.7%; P = 0.34). Pupillary capture of the IOL optic occurred in 52% and haptic breakage in 33% of the pseudophakic eyes. All of the eyes with broken haptics had a prominent Soemmerring's ring varying in maximum thickness from 0.6 to 2 mm. Nine of the haptics from the seven eyes with broken IOLs had eroded into the iris, two into the ciliary body, and one into the anterior chamber. CONCLUSIONS: Implanting an IOL into a neonatal monkey eye after a lensectomy and anterior vitrectomy increases the likelihood of a reoperation being necessary. Haptics frequently erode into the iris and ciliary body and may break because of stress placed on the optic-haptic junction by forward movement of the IOL.

Echovirus 9 strain barty non-structural protein 2C has NTPase activity.

Non-structural protein 2C is known to play a fundamental role in the replication of picornaviruses. Sequence analyses revealed that 2C belongs to a rapidly expanding group of proteins containing a consensus sequence for nucleotide binding (NTB). We report that echovirus 9 polypeptide 2C displays NTPase activity in vitro. In our experiments, several P2 genes were expressed in Escherichia coli as fusion proteins linked to glutathione S-transferase (GST) prior to purification close to homogeneity. In contrast to GST-2B, both GST-2C and GST-2BC showed ATPase as well as GTPase activity indicating that the site for NTB binding and splitting is located in 2C.

Detection of adenovirus nucleic acid sequences in human tonsils in the absence of infectious virus.

Human tonsillar and adenoid tissues from surgical specimens and cell cultures established therefrom were screened for adenovirus type 2 (Ad2) sequences by in situ hybridization. For labeling we have utilized biotinylated DNA probes. We report detection of adenoviral sequences after hybridization with adenovirus type 2 DNA probes in tissues as well as in cell cultures from specimens without any signs of infectious virus even after long-term cultivation. In the infected tonsils only some of the cells appear to carry viral sequences. In conclusion, truly latent adenovirus infections in man seem to occur.

Complete nucleotide sequence and biological properties of an infectious clone of prototype echovirus 9.

The prototype Hill of echovirus 9, a human enterovirus, exhibits no pathogenicity for newborn mice in contrast to some other echovirus 9 strains isolated subsequently during epidemics. In this communication we report the first complete nucleotide sequence and construction of an infectious clone of echovirus 9. Aside from the 3' poly(A)-tract, the RNA genome is 7420 nucleotides (nt) in length and encodes a single polyprotein of 2193 amino acids (aa). The open reading frame extends from position 740 to position 7318 of the genome. Sequence comparisons to other enteroviruses reveal a strong overall amino acid identity to echovirus types 11 and 12 (in each case 76%). The proteolytic cleavage sites of the three major capsid proteins were determined after purification by HPLC and protein sequencing. A full-length clone coding for an infectious RNA transcript was constructed, and recombinant echovirus 9 particles could be isolated from the supernatant of transfected cell culture. It is shown that the recombinant virus, like the original prototype, is non-pathogenic for newborn mice and does not multiply in skeletal muscles.

Analysis of sequence and pathogenic properties of two variants of encephalomyocarditis virus differing in a single amino acid in VP1.

The encephalomyocarditis (EMC) virus-induced diabetes-like syndrome in mouse inbred strains was used as a model to study the insulin-dependent diabetes mellitus (IDDM). Our investigations were performed with two EMC virus variants, PV2 and PV7. After infection of SJL mice with 10(5) PFU of PV2 about 70% of the animals developed a diabetes-like syndrome, whereas the PV7 infected mice appeared healthy. Histological examination and in situ experiments revealed that the islets of Langerhans are a main target of PV2, whereas PV7 infection leads to only modest changes of the islets. Sequence analysis of both variants revealed one amino acid exchange within the capsid protein VP1. Hence, we describe the first diabetogenic and non-diabetogenic EMCV variants differing in only one single amino acid.