The Strength of Alpha Oscillations in the Electroencephalogram Differently Affects Algorithms Used for Anesthesia Monitoring.

BACKGROUND: Intraoperative patient monitoring using the electroencephalogram (EEG) can help to adequately adjust the anesthetic level. Therefore, the processed EEG (pEEG) provides the anesthesiologist with the estimated anesthesia level. The commonly used approaches track the changes from a fast- and a low-amplitude EEG during wakefulness to a slow- and a high-amplitude EEG under general anesthesia. However, besides these changes, another EEG feature, a strong oscillatory activity in the alpha band (8-12 Hz), develops in the frontal EEG. Strong alpha-band activity during general anesthesia seems to reflect an appropriate anesthetic level for certain anesthetics, but the way the common pEEG approaches react to changes in the alpha-band activity is not well explained. Hence, we investigated the impact of an artificial alpha-band modulation on pEEG approaches used in anesthesia research. METHODS: We performed our analyses based on 30 seconds of simulated sedation (n = 25) EEG, simulated anesthesia (n = 25) EEG, and EEG episodes from 20 patients extracted from a steady state that showed a clearly identifiable alpha peak in the density spectral array (DSA) and a state entropy (GE Healthcare) around 50, indicative of adequate anesthesia. From these traces, we isolated the alpha activity by band-pass filtering (8-12 Hz) and added this alpha activity to or subtracted it from the signals in a stepwise manner. For each of the original and modified signals, the following pEEG values were calculated: (1) spectral edge frequency (SEF95), (2) beta ratio, (3) spectral entropy (SpEntr), (4) approximate entropy (ApEn), and (5) permutation entropy (PeEn). RESULTS: The pEEG approaches showed different reactions to the alpha-band modification that depended on the data set and the amplification step. The beta ratio and PeEn decreased with increasing alpha activity for all data sets, indicating a deepening of anesthesia. The other pEEG approaches behaved nonuniformly. SEF95, SpEntr, and ApEn decreased with increasing alpha for the simulated anesthesia data (arousal) but decreased for simulated sedation. For the patient EEG, ApEn indicated an arousal, and SEF95 and SpEntr showed a nonuniform change. CONCLUSIONS: Changes in the alpha-band activity lead to different reactions for different pEEG approaches. Hence, the presence of strong oscillatory alpha activity that reflects an adequate level of anesthesia may be interpreted differently, by an either increasing (arousal) or decreasing (deepening) pEEG value. This could complicate anesthesia navigation and prevent the adjustment to an adequate, alpha-dominant anesthesia level, when titrating by the pEEG values.

Targeted Natural Killer Cell-Based Adoptive Immunotherapy for the Treatment of Patients with NSCLC after Radiochemotherapy: A Randomized Phase II Clinical Trial.

PURPOSE: Non-small cell lung cancer (NSCLC) is a fatal disease with poor prognosis. A membrane-bound form of Hsp70 (mHsp70) which is selectively expressed on high-risk tumors serves as a target for mHsp70-targeting natural killer (NK) cells. Patients with advanced mHsp70-positive NSCLC may therefore benefit from a therapeutic intervention involving mHsp70-targeting NK cells. The randomized phase II clinical trial (EudraCT2008-002130-30) explores tolerability and efficacy of ex vivo-activated NK cells in patients with NSCLC after radiochemotherapy (RCT). PATIENTS AND METHODS: Patients with unresectable, mHsp70-positive NSCLC (stage IIIa/b) received 4 cycles of autologous NK cells activated ex vivo with TKD/IL2 [interventional arm (INT)] after RCT (60-70 Gy, platinum-based chemotherapy) or RCT alone [control arm (CTRL)]. The primary objective was progression-free survival (PFS), and secondary objectives were the assessment of quality of life (QoL, QLQ-LC13), toxicity, and immunobiological responses. RESULTS: The NK-cell therapy after RCT was well tolerated, and no differences in QoL parameters between the two study arms were detected. Estimated 1-year probabilities for PFS were 67% [95% confidence interval (CI), 19%-90%] for the INT arm and 33% (95% CI, 5%-68%) for the CTRL arm (P = 0.36, 1-sided log-rank test). Clinical responses in the INT group were associated with an increase in the prevalence of activated NK cells in their peripheral blood. CONCLUSIONS: Ex vivo TKD/IL2-activated, autologous NK cells are well tolerated and deliver positive clinical responses in patients with advanced NSCLC after RCT.

Monitoring depth of sedation: evaluating the agreement between the Bispectral Index, qCON and the Entropy Module's State Entropy during flexible bronchoscopy.

BACKGROUND: We investigated the correlation and agreement of three depth of anesthesia indices, Bispectral Index (BIS), qCON and state entropy (SE) during propofol sedation, because there is extensive literature that deals with the comparability of these indices during general anesthesia, but not during sedation. METHODS: We recorded electroencephalogram (EEG) and SE trend data, using the Entropy Module from 21 patients who underwent elective bronchoscopy with target-controlled infusion of propofol. EEG data were replayed to BIS and qCON with an EEG player. We calculated the Spearman correlation to evaluate similarities in index trend behavior and estimated the general index agreement of displaying the same anesthetic level, i.e., wakefulness, sedation and anesthesia. We used coughing episodes and the bronchoscope placement to investigate the index for possible arousal reactions. RESULTS: We found a high to very high correlation of the indices' trend during the procedure. Furthermore, qCON was significantly lower than BIS and SE. All indices increased significantly after bronchoscope placement and coughing. The agreement of BIS/SE was 68% and around 50% for BIS/qCON and qCON/SE. The median duration of disagreement by >10 points was 39 s for BIS/SE and around 75 s for qCON with BIS and SE. CONCLUSIONS: The results indicate a high probability of similar index performance between SE, BIS and qCON with the caveat of a different index scaling for qCON. These results can help the user of these monitoring devices to translate findings from one index to the other.

Heat Shock Protein 70 (Hsp70) Peptide Activated Natural Killer (NK) Cells for the Treatment of Patients with Non-Small Cell Lung Cancer (NSCLC) after Radiochemotherapy (RCTx) - From Preclinical Studies to a Clinical Phase II Trial.

Heat shock protein 70 (Hsp70) is frequently overexpressed in tumor cells. An unusual cell surface localization could be demonstrated on a large variety of solid tumors including lung, colorectal, breast, squamous cell carcinomas of the head and neck, prostate and pancreatic carcinomas, glioblastomas, sarcomas and hematological malignancies, but not on corresponding normal tissues. A membrane (m)Hsp70-positive phenotype can be determined either directly on single cell suspensions of tumor biopsies by flow cytometry using cmHsp70.1 monoclonal antibody or indirectly in the serum of patients using a novel lipHsp70 ELISA. A mHsp70-positive tumor phenotype has been associated with highly aggressive tumors, causing invasion and metastases and resistance to cell death. However, natural killer (NK), but not T cells were found to kill mHsp70-positive tumor cells after activation with a naturally occurring Hsp70 peptide (TKD) plus low dose IL-2 (TKD/IL-2). Safety and tolerability of ex vivo TKD/IL-2 stimulated, autologous NK cells has been demonstrated in patients with metastasized colorectal and non-small cell lung cancer (NSCLC) in a phase I clinical trial. Based on promising clinical results of the previous study, a phase II randomized clinical study was initiated in 2014. The primary objective of this multicenter proof-of-concept trial is to examine whether an adjuvant treatment of NSCLC patients after platinum-based radiochemotherapy (RCTx) with TKD/IL-2 activated, autologous NK cells is clinically effective. As a mHsp70-positive tumor phenotype is associated with poor clinical outcome only mHsp70-positive tumor patients will be recruited into the trial. The primary endpoint of this study will be the comparison of the progression-free survival of patients treated with ex vivo activated NK cells compared to patients who were treated with RCTx alone. As secondary endpoints overall survival, toxicity, quality-of-life, and biological responses will be determined in both study groups.

Hybrid electromagnetic and image-based tracking of endoscopes with guaranteed smooth output.

PURPOSE: Flexible fiber-optic bronchoscopy is a widespread medical procedure for the diagnosis and treatment of lung diseases. Navigation systems are needed to track the flexible endoscope within the bronchial tree. Electromagnetic (EM) tracking is currently the only technology used clinically for this purpose. The registration between EM tracking and patient anatomy may become inaccurate due to breathing motion, so the addition of image-based tracking has been proposed as a hybrid EM-image-based system. METHODS: When EM tracking is used as an initialization for image registration, small changes in the initialization may lead to different local minima and noise is amplified by hybrid tracking. The tracking output is modeled as continuous and uses splines for interpolation, thus smoothness is greatly improved. The bronchoscope pose relative to computed tomography data is interpolated using Catmull-Rom splines for position and spherical linear interpolation (SLERP) for orientation. RESULTS: The hybrid method was evaluated using ground truth poses manually selected by experts, where mean inter-expert agreement was determined as 1.26 mm. Using four dynamic phantom data sets, the accuracy was 4.91 mm, which is equivalent to previous methods. Compared to state-of-art methods, inter-frame smoothness was improved from 2.77-3.72 to 1.24 mm. CONCLUSIONS: Hybrid image and electromagnetic endoscope guidance provides a more realistic and physically plausible solution with significantly less jitter. This quantitative result is confirmed by visual comparison of real and virtual video, where the virtual video output is much more consistent and robust, with fewer occasions of tracking loss or unexpected movement compared with previous methods.

Influence of acute exposure to high altitude on basal and postprandial plasma levels of gastroenteropancreatic peptides.

Acute mountain sickness (AMS) is characterized by headache often accompanied by gastrointestinal complaints that vary from anorexia through nausea to vomiting. The aim of this study was to investigate the influence of high altitude on plasma levels of gastroenteropancreatic (GEP) peptides and their association to AMS symptoms. Plasma levels of 6 GEP peptides were measured by radioimmunoassay in 11 subjects at 490 m (Munich, Germany) and, after rapid passive ascent to 3454 m (Jungfraujoch, Switzerland), over the course of three days. In a second study (n = 5), the same peptides and ghrelin were measured in subjects who consumed standardized liquid meals at these two elevations. AMS symptoms and oxygen saturation were monitored. In the first study, both fasting (morning 8 a.m.) and stimulated (evening 8 p.m.) plasma levels of pancreatic polypeptide (PP) and cholecystokinin (CCK) were significantly lower at high altitude as compared to baseline, whereas gastrin and motilin concentrations were significantly increased. Fasting plasma neurotensin was significantly enhanced whereas stimulated levels were reduced. Both fasting and stimulated plasma motilin levels correlated with gastrointestinal symptom severity (r = 0.294, p = 0.05, and r = 0.41, p = 0.006, respectively). Mean O(2)-saturation dropped from 96% to 88% at high altitude. In the second study, meal-stimulated integrated (= area under curve) plasma CCK, PP, and neurotensin values were significantly suppressed at high altitude, whereas integrated levels of gastrin were increased and integrated VIP and ghrelin levels were unchanged. In summary, our data show that acute exposure to a hypobaric hypoxic environment causes significant changes in fasting and stimulated plasma levels of GEP peptides over consecutive days and after a standardized meal. The changes of peptide levels were not uniform. Based on the inhibition of PP and neurotensin release a reduction of the cholinergic tone can be postulated.

Deformable registration of bronchoscopic video sequences to CT volumes with guaranteed smooth output.

We present a novel approach to tracking of flexible bronchoscopes by modeling the output as spatially continuous over time. Bronchoscopy is a widespread clinical procedure for diagnosis and treatment of lung diseases and navigation systems are highly needed. Tracking of the bronchoscope can be regarded as a deformable registration problem. In our approach we use hybrid image-based and electromagnetic tracking, and the bronchoscope pose relative to CT data is interpolated using Catmull-Rom splines for position and SLERP for orientation. We evaluate the method using ground truth poses manually selected by experts, where mean inter-expert agreement was determined as 1.26 mm. For four dynamic phantom data sets, the accuracy of our method is between 4.13 and 5.93 mm and shown to be equivalent to previous methods. We significantly improve inter-frame smoothness from 2.35-3.08 mm to 1.08-1.51 mm. Our method provides a more realistic and physically plausible solution with significantly less jitter. This quantitative result is confirmed by video output, which is much more consistent and robust, with fewer occasions of tracking loss or unexpected movement.

High diagnostic yield from transbronchial biopsy of solitary pulmonary nodules using low-dose CT-guidance.

BACKGROUND AND OBJECTIVE: The diagnostic yield from fluoroscopy-guided bronchoscopic transbronchial biopsy of small solitary pulmonary nodules is low. The hypothesis tested in the present study was that the diagnostic yield can be significantly increased by combining flexible bronchoscopy with CT-guidance using a dedicated low-dose protocol. METHODS: CT-guided transbronchial biopsies were performed in 15 patients with a newly diagnosed solitary peripheral pulmonary nodule and negative conventional bronchoscopic biopsies under fluoroscopic guidance. For imaging, a multi-detector helical CT unit, adjusted at 120 kV, 15 mAs/slice, 4 x 5 mm collimation, 10 mm reconstructed slice thickness and a maximal scan length of 150 mm, was used. After advancing the biopsy forceps towards the lesion, a CT scan was obtained. When the tip of the forceps reached or penetrated the lesion a biopsy was taken, otherwise the procedure was repeated with a maximum of eight attempts. The effective radiation dose was calculated. RESULTS: The average diameter of the nodules was 23 +/- 6 mm (mean +/- SD) with a maximum distance to the parietal pleura of 18 mm (mean 6.5 mm). A mean of 4.1 (range 2-8) CT scans was performed to localize the lesion. In four patients, the forceps only reached the periphery of the nodule. In one patient, the nodule was missed in all attempts. Histology was malignant in eight patients and benign in four patients. In three patients, biopsy results were false negative (benign or non-specific instead of malignant). The overall diagnostic yield was 73%. Complications consisted of two pneumothoraces, one of which necessitated a chest tube. Mean effective radiation dose was 0.55 mSv (range 0.3-1.0). CONCLUSIONS: CT-guided transbronchial biopsy can be a valuable diagnostic tool in evaluating solitary pulmonary nodules. This applies for selected patients when other diagnostic methods are either unavailable or inappropriate. The diagnostic yield is high and, when a low-dose protocol is used, radiation exposure can be kept at a minimum.

Fiducial-free registration procedure for navigated bronchoscopy.

Navigated bronchoscopy has been developed by various groups within the last decades. Systems based on CT data and electromagnetic tracking enable the visualization of the position and orientation of the bronchoscope, forceps, and biopsy tools within CT data. Therefore registration between the tracking space and the CT volume is required. Standard procedures are based on point-based registration methods that require selecting corresponding natural landmarks in both coordinate systems by the examiner. We developed a novel algorithm for a fully automatic registration procedure in navigated bronchoscopy based on the trajectory recorded during routine examination of the airways at the beginning of an intervention. The proposed system provides advantages in terms of an unchanged medical workflow and high accuracy. We compared the novel method with point-based and ICP-based registration. Experiments demonstrate that the novel method transforms up to 97% of tracking points inside the segmented airways, which was the best performance compared to the other methods.

In-vivo kinetics of inhaled 5-aminolevulinic acid-induced protoporphyrin IX fluorescence in bronchial tissue.

BACKGROUND: In the diagnosis of early-stage lung cancer photosensitizer-enhanced fluorescence bronchoscopy with inhaled 5-aminolevolinic acid (5-ALA) increases sensitivity when compared to white-light bronchoscopy. This investigation was to evaluate the in vivo tissue pharmacokinetics of inhaled 5-ALA within the bronchial mucosa in order to define the time optimum for its application prior to bronchoscopy. METHODS: Patients with known or suspected bronchial carcinoma were randomized to receive 200 mg 5-ALA via inhalation 1, 2, 3, 4 or 6 hours before flexible fluorescence bronchoscopy was performed. Macroscopically suspicious areas as well as areas with visually detected porphyrin fluorescence and normal control sites were measured spectroscopically. Biopsies for histopathology were obtained from suspicious areas as well as from adjacent normal areas. RESULTS: Fluorescence bronchoscopy performed in 19 patients reveals a sensitivity for malignant and premalignant changes (moderate dysplasia) which is almost twice as high as that of white-light bronchoscopy, whereas specificity is reduced. This is due to false-positive inflammatory lesions which also frequently show increased porphyrin fluorescence. Malignant and premalignant alterations produced fluorescence values that are up to 5 times higher than those of normal tissue. According to the pharmacokinetics of porphyrin fluorescence measured by spectroscopy, the optimum time range for 5-ALA application is 80-270 min prior to fluorescence bronchoscopy, with an optimum at 160 min. CONCLUSION: According to our results we propose inhalation of 5-ALA 160 min prior to fluorescence bronchoscopy, suggesting that this time difference provides the best tumor/normal tissue fluorescence ratio.

Electromagnetic catheter navigation during bronchoscopy: validation of a novel method by conventional fluoroscopy.

BACKGROUND: Electromagnetic navigation in bronchoscopy is a novel method for assisting in the localization of peripheral lung lesions. STUDY OBJECTIVE: To assess the usability, accuracy, and safety of electromagnetic navigation during flexible bronchoscopy in a clinical setting. DESIGN: Prospective evaluation. PATIENTS: Consecutive patients referred to the bronchoscopy unit for the diagnosis of peripheral infiltrates or solitary pulmonary nodules (SPNs). METHODS: Navigation was performed using an electromagnetic tracking system with a position sensor encapsulated in the tip of a flexible catheter that was pushed through the working channel of the bronchoscope. Real-time, multiplanar reconstruction of a previously acquired CT data set provided three-dimensional views for localization of the catheter. To match the position of the sensor with the CT scan, four anatomic landmarks were used for registration. The sensor position generated in the navigation system was controlled by fluoroscopy, and the corresponding error distances were measured. This was performed with all SPNs and at two different peripheral locations of the right upper lobe (RUL). RESULTS: Sixteen patients (10 men and 6 women; mean age, 63.7 years) were studied. Navigation prolonged bronchoscopy by 3.9 +/- 1.3 min (mean +/- SD). The navigation system identified all lesions. The position sensor achieved a direct hit in three of five SPNs. Fluoroscopy failed to recognize three SPNs (60%) and three infiltrates (38%). The mean error distances between sensor tip position and fluoroscopically verified RUL reference position were 10.4 mm (lateral position) and 12.5 mm (apical position) respectively. The mean error distances between the sensor tip and two endobronchial registration points at the end of the procedure were 4.2 mm and 5.1 mm, respectively. CONCLUSION: Electromagnetic navigation is useful, accurate, and safe in the localization of peripheral lung lesions and may help to improve the yield of diagnostic bronchoscopic procedures.

Treatment of benign and malignant tracheobronchial obstruction with metal wire stents: experience with a balloon-expandable and a self-expandable stent type.

Over the last few years various types of metal wire stents have been increasingly employed in the treatment of both malignant and benign tracheobronchial obstruction. To date, however, few studies have investigated the in vivo properties of different stent types. We implanted 26 balloon-expandable tantalum Strecker stents (18 patients) and 18 self-expandable Wallstents (16 patients) into the tracheobronchial system of 30 patients with combined stenting in 4 patients. Mean age was 51 years (range: 0.5-79 years). Malignant disease was present in 23 patients, benign disease in seven patients. Both patients and individual stents were monitored clinically and radiographically. The probability of stents remaining within the tracheobronchial system, and of their remaining undislocated and uncompressed was calculated using Kaplan-Meier analysis for both stent types. Average stent follow-up time was 112 days until explantation and 115 days until patients' death or discharge. Kaplan-Meier analysis revealed a higher probability for the Wallstent to remain within the tracheobronchial system. Dislocation and compression occurred more rarely. Explantation, however, if desired, was more difficult compared to the Strecker stent. The Wallstent also led to the formation of granulation tissue, especially at the proximal stent end, frequently requiring reintervention. Both stent types proved to be effective therapeutic options in the management of obstructive tracheobronchial disease. The mechanical properties of the Strecker stent seem to be less favorable compared to the Wallstent but removal is easy. For benign disease, however, the Wallstent reveals limitations due to significant side effects.

Kinetics of 5-aminolevulinic acid-induced fluorescence in organ cultures of bronchial epithelium and tumor.

BACKGROUND: 5-Aminolevulinic acid (5-ALA)-induced protoporphyrin IX (PPIX) fluorescence improves the differentiation of tumor and normal tissue in the bladder, skin and brain. OBJECTIVE: The kinetics of 5-ALA-induced protoporphyrin IX (PPIX) fluorescence in organ cultures of normal human bronchial epithelium and cocultures of bronchial epithelium and tumor have been studied. METHODS: Cultured biopsies of bronchial epithelium were exposed for 5 or 15 min, or continuously to 5-ALA. PPIX fluorescence was quantified for up to 300 min by spectroscopy. Cocultures of normal bronchial epithelium and a non-small-cell lung cancer cell line (EPLC-32M1) were incubated with 5-ALA. Space-resolved fluorescence microscopy was used to quantify PPIX fluorescence kinetics in the tumor and normal epithelium. RESULTS: In cultures of normal epithelium, PPIX fluorescence kinetics were shown to depend on the duration of exposure to 5-ALA. There was a trend to higher fluorescence intensities with longer exposure times. In cocultures of bronchial epithelium and tumor, increases of fluorescence intensity were significantly greater in the tumor. Best tumor/normal tissue fluorescence ratios were found between 110 and 160 min after exposure to 5-ALA. CONCLUSION: Data obtained in this coculture system of bronchial epithelium and tumor is valuable to optimize modalities of fluorescence bronchoscopy for the diagnosis of early bronchial carcinoma.