[Adequate supportive treatment in therapeutic use of "biologicals" for GI tumours in oncosurgery--what does the surgeon need to know?]. / Adäquate Supportivtherapie im therapeutischen Einsatz von "Biologicals" bei gastrointestinalen(GI) Tumoren in der Onkochirurgie--Was muss der Chirurg wissen?

BACKGROUND: Along with the increasing use and inauguration of novel antineoplastic substances (inhibitors, antibodies [Ab]) at various levels of the tumour cell-specific intracellular signalling (transduction cascade) on the cell surface and within the cell as well as messengers ["biologicals", "targeted therapy"]), a new quality, intensity and complexity of adverse effects was simultaneously developed, which have become more and more relevant even to oncosurgeons. AIM: A summary is given of clinically obtained expertise including recommendations for a competent approach, management and use of biologicals for targeted therapy in case of abnormal or adverse effects as well as toxic reactions, which are compared with available data from the literature and provided as systematic short review on the clinically used substances and drugs in GI tumour lesions. METHODS: The compact overview is based on the authors' daily clinical experiences including a selective and comparative literature search in PubMed (searching strategy using the following terms: "supportive treatment/therapy", "biological[s]"). RESULTS: The discussed profile of biologicals comprises: Herceptin®/Trastuzumab (Her2 neu-AK), Erbitux®/Cetuximab (EGFR-AK), Glivec®/Imatinib, Sutent®/Sunitinib and Nexavar®/Sorafenib (multikinase inhibitors)--reference to haematological and oncological literature for MabThera®/Rituximab and Sprycel®/Dasatinib; Tasigna®/Nilotinib. All of them induce more or less severe, partially single or combined, known (haematological, gastroenterological, neurological and dermatological [according to the WHO classification]) or completely novel (GI perforation in case of Avastin®; apparent predominance of neurological and dermatological) adverse effects, which show (in the majority of cases) substance- and/or drug-specific properties in the spectrum of adverse effects, which can be sufficiently managed. These circumstances increase the requirements for the expertise of today's responsible oncologists/oncosurgeons. DISCUSSION: The management of "biologicals"-associated adverse effects can be considered a novel aspect in the overall concept of oncological care, which shows a partially known as well as novel phenomenology and, thus, requires adapted therapeutic approaches.

Synergistic immunosuppressive effects of the mTOR inhibitor sirolimus and the phytochemical curcumin.

The immunosuppressant sirolimus and curcumin, the main principle of the turmeric spice, have shown antiproliferative effects on many human and not-human cell lines. Whereas the antiproliferative effect of sirolimus is mainly mediated by inhibition of mTOR, curcumin is described to affect many molecular targets which makes it unpredictable to appraise if the effects of these both substances on cell proliferation and especially on immunosuppression are additive or synergistic. To answer this question we investigated the interaction of both these substances on OKT3-induced human peripheral blood mononuclear cell (PBMC) proliferation. OKT3-induced human PBMC proliferation was determined by measuring (3)H-thymidine incorporation. Influence of curcumin on interleukin-2 (IL-2) release and IκB-phosphorylation in PBMC was determined by ELISA and western blot, respectively. Curcumin-induced apoptosis and necrosis was analyzed by FACS analysis. Whereas curcumin completely inhibited OKT3-induced PBMC proliferation in a dose-dependent manner with an IC(50) of 2.8 µM, sirolimus could reduce PBMC proliferation dose-dependently only to a minimum of 28% at a concentration of 5 ng/ml (IC(50) 1.1 ng/ml). When curcumin was combined at concentrations of 1.25-2.5 µM with sirolimus at concentrations from 0.63 to 1.25 ng/ml the effects were synergistic. Combination of curcumin (1.25-2.5 µM) with sirolimus (5 ng/ml) showed additive effects. The effects after combination of curcumin at 5 µM with each sirolimus concentration and sirolimus at 10 ng/ml with each curcumin concentration were presumably antagonistic. We conclude that the immunosuppressive effects of curcumin and sirolimus in low concentrations are synergistic in OKT3-activated PBMC. Whether curcumin and sirolimus have also synergistic antiproliferative effects in tumor cells has to be shown in further experiments including animal models.

Geometric multigrid to accelerate the solution of the quasi-static electric field problem by tetrahedral finite elements.

The acceleration of the solution of the quasi-static electric field problem considering anisotropic complex conductivity simulated by tetrahedral finite elements of first order is investigated by geometric multigrid.

Assessing abdominal fatness with local bioimpedance analysis: basics and experimental findings.

OBJECTIVE: Abdominal fat is of major importance in terms of body fat distribution but is poorly reflected in conventional body impedance measurements. We developed a new technique for assessing the abdominal subcutaneous fat layer thickness (SFL) with single-frequency determination of the electrical impedance across the waist (SAI). SUBJECTS AND MEASUREMENTS: The method uses a tetrapolar arrangement of surface electrodes which are placed symmetrically to the umbilicus in a plane perpendicular to the body axis. Twenty-four test subjects (12 male, 12 female) underwent SAI and abdominal magnetic resonance imaging (MRI). The SFL below the sensing electrodes was determined from MRI and correlated with the SAI data at four different frequencies (5, 20, 50 and 204 kHz). RESULTS: A highly significant linear correlation (r2=0.99) between SFL and SAI over a wide range of the abdominal SFL was found. Separate regression models for female and male subjects did not differ significantly, except at 50 kHz. CONCLUSION: SAI represents a good predictor of the SFL and provides an excellent tool for the assessment of central obesity.

In vivo determination of tumor optical parameters in esophageal carcinoma.

BACKGROUND AND OBJECTIVE: Dose dependence of light cannot be discussed on the basis of dose alone. On a more fundamental scientific level, the propagation of light in tissue depends on optical parameters of treated tumor tissue. In a prospective, nonrandomized study, in vivo optical parameters of esophageal carcinoma were studied. STUDY DESIGN/MATERIALS AND METHODS: Nineteen intraoperative measurements of tumor optical parameters in six patients with esophageal carcinoma were performed. After diagnostic work-up and clinical staging, right-sided, posterolateral thoracotomy, and dissection of the esophagus were carried out. The tumor site was exposed and continuous endoluminal irradiation was started during determination of light penetration at the level of the adventitia of the esophagus. The tumors were located exactly between the endoluminal irradiation source and measurement probe in the thoracic cavity. Measurements were performed on tumors having different diameters to show the relationship between tumor diameter, extinction coefficient, and light penetration depth. RESULTS: The endoluminal incident intensity was 18.5 mW/cm(2). At a tumor diameter of 4, 6, 8, and 9 mm measured intensity of 5.12, 2.28, 0.88 and 0.65 mW/cm(2), an extinction coefficient of 0.321, 0.349, 0.381, and 0.373, as well as penetration depth of 3.21, 2.87, 2.62, and 2. 68 mm, respectively, could be measured. The correlation of tumor optical parameters, tumor diameter, penetration depth, and treatment time were expressed by the relative correction factor for different tumor diameters. CONCLUSION: The knowledge of tumor optical properties seems to be necessary to adapt dosimetry to the individual situation and manage optimal results of PDT in esophageal cancer.

[New methods for noninvasive and continuous determination of dynamic compliance of the carotid artery]. / Neues Verfahren zur nichtinvasiven und kontinuierlichen Bestimmung der dynamischen Compliance der A. carotis.

A new method for the noninvasive, continuous determination of the compliance of the carotid artery wall has been developed and, in an initial study, validated. Measurements of pulsatile changes in the diameter of the carotid artery are accomplished with the 4-electrode impedance method, and the intravascular blood pressure is measured using an applanation tonometer developed during this project. The method has been employed for measurements in 12 individuals with no vascular disease, and in one patient with carotid artery stenosis before, during and after successful dilatation. With the pressure-volume curves recorded during the cardiac cycle, it is possible to calculate dynamic compliance and the non-elastic deformation work. While initial results are very promising, further validation by a large-scale clinical study is required.

Non-invasive cardiac allograft monitoring: the graz experience.

Based on previous reports by our group, initial studies on non-invasive cardiac graft monitoring have been presented recently. In this study we define new parameters to monitor rejection and infection after heart transplantation (HTX) the ventricular evoked response (VER) T-slew rate parameter is defined as the maximum negative slope in the descending part of the repolarization phase of the VER. We calculated the VER duration parameter in milliseconds and defined it as the time between the pacemaker spike and the cross-over of the baseline, with the slope line used to calculate the VER T-slew rate. During the HTX procedure, we implant wide-band telemetric pacemakers and fractally coated, epimyocardial electrodes (Physios CTM 01 and ELC 54-UP, Biotronik; Berlin, Germany). During each follow-up and on biopsy days, intramyocardial electrogram sequences were obtained and sent via the Internet to the central data-processing unit in Graz. We scored the infection status of the patients before data acquisition. The VER parameters were automatically calculated and send back within a few minutes. We prospectivly compared 1,613 follow-ups from 42 patients with biopsy (International Society of Heart and Lung Transplantation grading) and infection classification. The VER duration parameter did not change during rejection; however, we found an increase during clinically apparent infection. The VER T-slew rate parameter was lower during rejection grade 2 or higher, as well as during clinically apparent infection. The negative predictive value to rule out rejection was 99%. Our results indicate that rejection and infection cause different, reproducible effects on the electrical activity of the transplanted heart. Non-invasive cardiac graft monitoring may reduce the need for surveillance biopsies and may offer a tool to optimize immunosuppressive therapy after HTX.

[Multi-channel data collection and visualization system for intramyocardial electrograms]. / Mehrkanal-Datenerfassungs- und Visualisierungssystem für intramyokardiale Elektrogramme.

The aim of the project was to develop a multichannel data acquisition system for the recording and visualisation of intramyocardial electrograms (IEGM) from both the spontaneously beating and the artificially paced heart. Signal processing comprises multi-step amplification, filtering (0.05-800 Hz), and AD conversion (12 Bit max. 6.25 kHz). IEGMs can be obtained either in unipolar or bipolar mode. Stimulation of the heart is achieved by an incorporated programmable dual-chamber pacemaker that can be selectively switched to the input channels. A LabView-based graphical user interface permits the programming of all system parameters via a microcontroller, and supports data acquisition and visualisation. The system can be used in animal experiments to monitor the spread of excitation across the heart, to measure propagation velocity, or to measure the impact of drugs and pathological changes on the morphology of IEGMs.

[Measurement and evaluation of three-dimensional acceleration signals for rate adaptation of cardiac pacemakers]. / Messung und Auswertung dreidimensionaler Beschleunigungsgrössen zur Frequenzanpassung von Herzschrittmachern.

The aim of this study was to determine which of the one-dimensional acceleration signals best correlates with the heart rate under the conditions of daily activities, or whether such correlation is shown by three-dimensional acceleration signals. A commercially available biosignal system (ZAK, Germany) was used to record electrographic data and acceleration caused by body movements in the three directions vertical, sagittal and lateral. The evaluation was performed on 12 young healthy volunteers and 4 elderly volunteers with cardiovascular disorders but adequate chronotropic function. Informed consent was given by all participants. Activity signals and heart rate were recorded while walking under two different conditions. For analysis, the pathways were divided into segments with different gradients. All the acceleration signals were analysed statistically and temporally with regard to peak-to-peak value, root mean square value, and step frequency by means of cross correlation. Both statistical and temporal analysis showed that the correlation of heart rate and all one-dimensional acceleration signals and the three-dimensional acceleration signal was relatively low (r < or = 0.6). Walking uphill even showed a negative correlation between acceleration signals and heart rate. Despite the widespread use of activity-controlled pacemakers, the correlation between heart rate and acceleration signals is not satisfactory.

Inductively coupled wideband transceiver for bioimpedance spectroscopy (IBIS).

Most measurement devices for bioimpedance spectroscopy are coupled to the measured object (tissue) via electrodes. At frequencies > 500 kHz, they suffer from artifacts due to stray capacitances between electrode leads as well as between the ground and object. The noninvasive measurement of the brain conductivity is hardly possible with surface electrodes. These disadvantages can be obviated by inductive coupling. The aim of this work was the development of a wideband transceiver for inductive impedance spectroscopy. In order to define its specifications, a feasibility study has been carried out with a simulation model for three different coil systems above a homogeneous conducting plate. According to simulation results, all systems render it possible to resolve conductivity changes down to 10(-3) (omega m)-1 at frequencies > 50 kHz. The transceiver electronics must then provide a resolution of > or = 1 microV and an excitation current of up to 1 A. The realized receiver matches these specifications with an S/N ratio of 22 dB at 1 microV in the frequency range of 50 kHz to 5 MHz.

Ventricular evoked response in patients with hypertrophic obstructive cardiomyopathy treated with DDD pacing.

OBJECTIVE: To assess the changes in ventricular evoked responses (VER) produced by the decrease in left ventricular outflow tract gradient (LVOTG) in patients with hypertrophic obstructive cardiomyopathy (HOCM) treated with dual-chamber (DDD) pacing. METHODS: A pulse generator Physios CTM (Biotronik, Germany) was implanted in 9 patients with severe drug-refractory HOCM. After implantation, the following conditions were assessed: 1) Baseline evaluation: different AV delay (ranging from 150 ms to 50 ms) were sequentially programmed during 5 to 10 minutes, and the LVOTG (as determined by Doppler echocardiography) and VER recorded; 2) standard evaluation, when the best AV delay (resulting in the lowest LVOTG) programmed at the initial evaluation was maintained so that its effect on VER and LVOTG could be assessed during each chronic pacing evaluation. RESULTS: LVOTG decreased after DDD pacing, with a mean value of 59 +/- 24 mmHg after dual chamber pacemaker, which was significantly less than the gradient before pacing (98 + 22 mmHg). An AV delay > 100 ms produced a significantly lower decrease in VER depolarization duration (VERDD) when compared to an AV delay < or = 100 ms. Linear regression analyses showed a significant correlation between the LVOTG values and the magnitude of VER (r = 0.69; p < 0.05) in the 9 studied patients. CONCLUSION: The telemetry obtained intramyocardial electrogram is a sensitive means to assess left ventricular dynamics in patients with HOCM treated with DDD pacing.

Noninvasive rejection monitoring of cardiac transplants using high resolution intramyocardial electrograms: initial US multicenter experience.

Endomyocardial biopsy (EMB) remains the mainstay for the diagnosis of acute cellular rejection in cardiac transplant patients. A noninvasive alternative that would supplant or reduce the number of EMBs would be a highly desirable and cost-effective tool. To evaluate one potential alternative, a pacemaker with high resolution telemetry capabilities and two fractally coated epimyocardial leads were implanted in 30 patients at five transplant centers during the heart transplant procedure. Ventricular electrograms were recorded during intrinsic and paced activity and digitized to a laptop-based data acquisition device. Electrograms were recorded at frequent intervals and systematically on days when EMBs were performed. The electrogram data were then transferred via the Internet to a central data processing site. Clinical patient management was blinded to the electrogram results and varied considerably among the five centers. Using EMB together with clinical assessment of the transplant revealed 18 cases of clinically significant rejection beyond postoperative day 27 that required antirejection therapy. The normalized parameter values extracted from the electrogram recordings during pacing (the ventricular evoked response) that were associated with significant rejection were statistically lower (86% +/- 16% versus 96% +/- 22%, P < 0.005). The application of a single-threshold diagnosis model to the parameter values allowed detection of significant rejection with a negative predictive value of 98%. This analysis also showed that as many as 55% of the routine surveillance EMBs could have been eliminated had the pacemaker monitoring technique been used as a screening tool prior to EMB. A prospective study should further define the role of this technique in the detection and management of cardiac transplant patients.

Intramyocardial electrogram variability in the monitoring of graft rejection after heart transplantation.

The ventricular evoked response is a well-standardized electrophysiological signal that can be used for noninvasive, long-term cardiac transplant monitoring. Rejection-sensitive and infection-specific parameters extracted from intramyocardial electrograms correlate with clinical results. The influences of pacing rate, transition from intrinsic to paced rhythm and positional changes on the diagnostic parameters were studied. Increasing the pacing rate shortened the ventricular evoked response and directly influenced the infection specific parameter. The rejection-sensitive parameter remained stable at pacing rates between 100 and 120 beats/min. Measurements made immediately after the patient assumed a supine position and after switching to paced rhythm showed a decrease in the rejection-sensitive parameter. A change in position from supine to upright did not influence the rejection-sensitive parameter, but higher values were measured after returning to the supine position. In conclusion, noninvasive recordings of the ventricular evoked response for monitoring of cardiac allograft should be done at the same time of day, at the same pacing rate, and with the patient resting for at least 5 minutes before measurements are made.