Thomas Auer

Prediction model to estimate presence of coronary artery disease: Retrospective pooled analysis of existing cohorts

Objectives To develop prediction models that better estimate the pretest probability of coronary artery disease in low prevalence populations. Design Retrospective pooled analysis of individual patient data. Setting 18 hospitals in Europe and the United States. Participants Patients with stable chest pain without evidence for previous coronary artery disease, if they were referred for computed tomography (CT) based coronary angiography or catheter based coronary angiography (indicated as low and high prevalence settings, respectively). Main outcome measures Obstructive coronary artery disease (≥50% diameter stenosis in at least one vessel found on catheter based coronary angiography). Multiple imputation accounted for missing predictors and outcomes, exploiting strong correlation between the two angiography procedures. Predictive models included a basic model (age, sex, symptoms, and setting), clinical model (basic model factors and diabetes, hypertension, dyslipidaemia, and smoking), and extended model (clinical model factors and use of the CT based coronary calcium score). We assessed discrimination (c statistic), calibration, and continuous net reclassification improvement by cross validation for the four largest low prevalence datasets separately and the smaller remaining low prevalence datasets combined. Results We included 5677 patients (3283 men, 2394 women), of whom 1634 had obstructive coronary artery disease found on catheter based coronary angiography. All potential predictors were significantly associated with the presence of disease in univariable and multivariable analyses. The clinical model improved the prediction, compared with the basic model (cross validated c statistic improvement from 0.77 to 0.79, net reclassification improvement 35%); the coronary calcium score in the extended model was a major predictor (0.79 to 0.88, 102%). Calibration for low prevalence datasets was satisfactory. Conclusions Updated prediction models including age, sex, symptoms, and cardiovascular risk factors allow for accurate estimation of the pretest probability of coronary artery disease in low prevalence populations. Addition of coronary calcium scores to the prediction models improves the estimates.

Repositioning Accuracy: Comparison of a Noninvasive Head Holder with Thermoplastic Mask for Fractionated Radiotherapy and a Case Report

PURPOSE To compare accuracy, clinical feasibility, and subjective patient impression between a noninvasive head holder (Vogele Bale Hohner [VBH]; Wellhoefer Dosimetry, Schwarzenbruck, Germany) developed at the University of Innsbruck and the thermoplastic mask fixation system for use in fractionated external radiotherapy. We present a case report of an actual patient fixated in the VBH head holder during radiation therapy. MATERIALS AND METHODS The VBH head holder consists of an individualized vacuum dental cast connected to a head plate via two hydraulic arms allowing noninvasive, reproducible head fixation of even uncooperative patients. Accuracy was tested and compared with that of the thermoplastic mask using the Phillips EasyGuide navigation system on five volunteers. Specific external registration points served as landmarks and their positions were compared after each repositioning. System and operator inaccuracy were also taken into account. The times taken for production and repositioning of the respective fixation devices were compared, and subjective impressions were noted. RESULTS Mean VBH head holder repositioning accuracy was 1.02 mm while that of the thermoplastic mask was 3.05 mm. 69% of mask repositionings showed a deviation > 2 mm and 41% > 3 mm (as opposed to 8% and 1% respectively for the VBH head holder) Those points located farthest away from the respective plane of fixation showed the largest deviations. Both production and repositioning times were similar between the systems; depending upon the patient, the VBH head holder was generally better tolerated than the mask system. CONCLUSION Due to its significantly better repositioning accuracy compared to that of the thermoplastic mask, the VBH head holder is especially suited for external radiation requiring precise repositioning due to critical tissues in immediate surrounding of the area to be irradiated.

AKR1B10 expression is associated with less aggressive hepatocellular carcinoma: a clinicopathological study of 168 cases

Background/Aims: The detoxification enzyme AKR1B10, a member of the aldo‐keto reductase superfamily, is discussed as a new biomarker candidate for hepatocellular carcinoma (HCC). Only rare clinicopathological data on AKRB1B10 in HCC exist. This retrospective study determines the diagnostic and prognostic relevance of AKR1B10 expression in HCC and its relationship to a series of clinicopathological parameters including underlying aetiological factors.

Proteomic identification of aldo-keto reductase AKR1B10 induction after treatment of colorectal cancer cells with the proteasome inhibitor bortezomib

Targeting the ubiquitin-proteasome pathway with the proteasome inhibitor bortezomib has emerged as a promising approach for the treatment of several malignancies. The cellular and molecular effects of this agent on colorectal cancer cells are poorly characterized. This study investigated the antiproliferative effect of bortezomib on colorectal cancer cell lines (Caco-2 and HRT-18). In order to define the proteins potentially involved in the mechanisms of action, proteome profiling was applied to detect the proteins altered by bortezomib. The in vitro efficacy of bortezomib as a single agent in colorectal cancer cell lines was confirmed. Proteome profiling with two-dimensional PAGE followed by mass spectrometry revealed the up-regulation of the major inducible isoform of heat shock protein 70 (hsp72) and lactate dehydrogenase B in both cell lines, as well as the induction of aldo-keto reductase family 1 member B10 (AKR1B10) in HRT-18 cells. Both AKR1B10 and hsp72 exert cell-protective functions. This study shows for the first time a bortezomib-induced up-regulation of AKR1B10. Small interfering RNA–mediated inhibition of this enzyme with known intracellular detoxification function sensitized HRT-18 cells to therapy with the proteasome inhibitor. To further characterize the relevance of AKR1B10 for colorectal tumors, immunohistochemical expression was shown in 23.2% of 125 tumor specimens. These findings indicate that AKR1B10 might be a target for combination therapy with bortezomib. [Mol Cancer Ther 2009;8(7):1995–2006]

Erste Erfahrungen mit computerunterstützter stereotaktischer interstitieller Brachytherapie

PURPOSE To reach an optimal treatment result and to avoid damage to critical structures a homogeneous dose distribution in the tumor volume with a rapid decreasing dose to the surrounding structures is necessary. Fractionated interstitial brachytherapy of tumors in the ENT region employing needles depends on exact localization of the target volume during all fractions. Therefore reproducibility of positioning of the needle(s) plays an important role. MATERIAL AND METHODS We used the ISG Viewing Wand system in combination with the Vogele-Bale-Hohner (VBH) head holder and a new targeting device. Point of entrance, pathway, and target point of the needle were planned and insertion of the needle simulated in advance. To date we have treated 7 patients with inoperable tumors in the ENT region. The actual position of the needle in the control CT was compared to the planned position. RESULTS The accuracy of positioning of the needle depended on the location of the tumor. In a patient with a recurrent retroorbital adenocarcinoma the mean accuracy was 1 mm. Due to soft tissue displacement in the neck region and the resulting necessity to readjust the targeting device the needle was placed with a mean deviation of 15 mm between the planned and the actual position. CONCLUSIONS Computer-assisted frameless stereotactic interstitial brachytherapy allows for precise, reproducible and preplanned insertion of hollow needles into target structures closely adherent to the surrounding tissue, thus avoiding damage of neighbouring structures. This technique is of great advantage in treating deeply seated tumors which are fixed to bony structures, especially at the skull base. Inaccuracy in the neck region caused by soft tissue shift requires improvement of the immobilization in this region.ZusammenfassungFragestellungDie fraktionierte interstitielle Brachytherapie mit Nadeln von Tumoren im HNO-Bereich erfordert eine exakte Lokalisierung des Zielgewebes bei allen Bestrahlungsfraktionen. Eine wichtige Voraussetzung hier für ist die Reproduzierbarkeit der Positionierung der Nadel(n).Material und MethodenZur Ansteuerung verwendeten wir das ISG-Viewing-Wand-Navigationssystem (ISG Technologies Inc., Mississauga, Ontario, Kanada) in Kombination mit der Vogele-Bale-Hohner-(VBH-) Kopfhalterung (Fa. Wellhöfer Dosimetrie, Schwarzenbruck, Deutschland) und einer Zielvorrichtung. Eintrittspunkt, Stichlanal und Zielpunkt werden vor der Bestrahlungssitzung geplant, und das Vorschieben der Nadel wird simuliert. Wir haben diese Methode bei sieben Patienten mit inoperablen Kopf-Hals-Tumoren angewendet und jeweils die Nadellage am Kontroll-CT mit der geplanten Lokalisation verglichen.ErgebnisseDie Abweichung der erreichten von der geplanten Position der Nadel war von der Tumorlokalisation abhängig. Bei einem intraorbitalen, retrobulbären Tumorrezidiv eines Adenokarzinoms wurde eine mittlere Genauigkeit von 1 mm erzielt. Aufgrund der Weichteilverschieblichkeit und der Notwendigkeit der Nachjustierung der Zielvorrichtung war die Positionierung im Bereich des Halses nur mit einer mittleren Genauigkeit von 15 mm möglich.SchlußfolgerungenDie computerunterstützte, rahmenlos stereotaktische interstitielle Brachytherapie erlaubt die exakte, reproduzierbare und vorgeplante Plazierung von Brachytherapiehohlnadeln in wenig verschiebliche Zielstrukturen unter Schonung benachbarten Gewebes. Sie ist daher speziell bei der Therapie von am Knochen adhärenten, tiefliegenden Tumoren, insbesondere an der Schädelbasis, von Vorteil. Die durch Weichteilverschieblichkeit bedingte Ungenauigkeit in der Halsregion erfordert die Verbesserung der Immobilisation in dieser Region.AbstractPurposeTo reach an optimal treatment result and to avoid damage to critical structures a homogenous dose distribution in the tumor volume with a rapid decreasing dose to the surrounding structures is necessary. Fractionated interstitial brachytherapy of tumors in the ENT region employing needles depends on exact localization of the target volume during all fractions. Therefore reproducibility of positioning of the needle(s) plays an important role.Material and MethodsWe used the ISG Viewing Wand system in combination with the Vogele-Bale-Hohner (VBH) head holder and a new targeting device. Point of entrance, pathway, and target point of the needle were planned and insertion of the needle simulated in advance. To date we have treated 7 patients with inoperable tumors in the ENT region. The actual position of the needle in the control CT was compared to the planned position.ResultsThe accuracy of positioning of the needle depended on the location of the tumor. In a patient with a recurrent retroorbital adenocarcinoma the mean accuracy was 1 mm. Due to soft tissue displacement in the neck region and the resulting necessity to readjust the targeting device the needle was placed with a mean deviation of 15 mm between the planned and the actual position.ConclusionsComputer-assisted frameless stereotactic interstitial brachytherapy allows for precise, reproducible and preplanned insertion of hollow needles into target structures closely adherent to the surrounding tissue, thus avoiding damage of neighbouring structures. This technique is of great advantage in treating deeply seated tumors which are fixed to bony structures, especially at the skull base. Inaccuracy in the neck region caused by soft tissue shift requires improvement of the immobilization in this region.

Nichtinvasive Kopffixation für externe Bestrahlung von Tumoren im Kopf-Hals-Bereich

PURPOSE To fully utilize the technical capabilities of radiation diagnostics and planning, a precise and reproducible method of head fixation is a prerequisite. METHOD We have adapted the Vogele-Bale-Hohner (VBH) head holder (Wellhöfer Dosimetrie, Schwarzenbruck, Germany), originally designed for frameless stereotactic operations, to the requirements of external beam radiotherapy. A precise and reproducible head fixation is attained by an individualized vacuum upper-dental cast which is connected over 2 hydraulic arms to an adjustable head- and rigid base-plate. Radiation field and patient alignment lasers are marked on a relocatable clear PVC localization box. RESULTS The possibility of craniocaudal adjustment of the head plate on the base plate allows the system to adapt to the actual position of the patient on the radiotherapy couch granting tensionless repositioning. The VBH head holder has proven itself to be a precise yet practicable method of head fixation. Duration of mouthpiece production and daily repositioning is comparable to that of the thermoplastic mask. CONCLUSION The new head holder is in routine use at our hospital and quite suitable for external beam radiation of patients with tumors of the head and neck.ZusammenfassungHintergrundUm die Möglichkeit der Bestrahlungsplanung von Kopf-Hals-Tumoren voll ausschöpfen zu können, ist eine exakte, reproduzierbare Kopffixation Grundvoraussetzung.MethodeWir haben die für rahmenlos stereotaktische Eingriffe entwickelte Vogele-Bale-Hohner-(VBH-)Kopfhalterung den Bedürfnissen der externen Strahlentherapie angepaßt. Durch einen individuellen Vakuum-Oberkieferzahnabdruck (Wellhöfer Dosimetrie, Schwarzenbruck, Deutschland), der über hydraulische Arme auf einer Grund- bzw. Kopfplatte fixiert ist, wird eine exakte, reproduzierbare Fixation des Kopfes erreicht. Die Bestrahlungsfelder und Lagerungslaser werden auf eine repositionierbare Plexiglashaube gezeichnet.ErgebnisseDie auf der Grundplatte in kraniokaudaler Richtung verschiebliche Kopfplatte gewährleistet eine den jeweiligen Untersuchungserfordernissen angepaßte, spannungsfreie Repositionierung des Patienten. Die VBH-Kopfhalterung erlaubt eine exakte, praktikable Immobilisation ohne erhöhten Zeitaufwand im Vergleich zur thermoplastischen Maske.SchlußfolgerungDie neue Fixationsmethode hat sich für die Strahlentherapie von Patienten mit Kopf-Hals-Tumoren bewährt und wird routinemäßig angewendet.AbstractPurposeTo fully utilize the technical capabilities of radiation diagnostics and planning, a precise and reproducible method of head fixation is a prerequisite.MethodWe have adapted the Vogele-Bale-Hohner (VBH) head holder (Wellhöfer Dosimetrie, Schwarzenbruck, Germany), originally designed for frameless stereotactic operations, to the requirements of external beam radiotherapy. A precise and reproducible head fixation is attained by an individualized vacuum upper-dental cast which is connected over 2 hydraulic arms to an adjustable head- and rigid base-plate. Radiation field and patient alignment lasers are marked on a relocatable clear PVC localization box.ResultsThe possibility of craniocaudal adjustment of the head plate on the base plate allows the system to adapt to the actual position of the patient on the radiotherapy couch granting tensionless repositioning. The VBH head holder has proven itself to be a precise yet practicable method of head fixation. Duration of mouthpiece production and daily repositioning is comparable to that of the thermoplastic mask.ConclusionThe new head holder is in routine use at our hospital and quite suitable for external beam radiation of patients with tumors of the head and neck.

Influence of Fractionated Irradiation on Neutrophilic Granulocyte Function

Background: A recent study has demonstrated that radiation therapy with single doses of up to 32 Gy has only a minor effect on neutrophilic granulocyte function. In clinical practice, by contrast, fractionated irradiation is applied. Therefore, the aim of the current study was to verify the influence of fractionated radiation therapy on granulocyte function. Material and Methods: Density gradient-purified granulocytes of voluntary healthy donors were used for all experiments. Granulocytes were kept in RPMI 1640 without fetal calf serum, incubated for 48 h and irradiated. Their function was assessed by measuring luminol-enhanced chemiluminescence after stimulation with phorbol myristate acid (PMA). All tests were performed at least five times. Results: Relative changes (any reactive oxygen species [ROS] release before stimulation was defined as being equal to 100%) in ROS release increased after stimulation wit PMA (mean ± SD): 0 Gy: 785 ±, 462.2%; 2 Gy: 704.3 ± 388.1%; 6 Gy: 1,360.3 ± 710.5%; 12 Gy: 1,119.4 ± 581.1%; 18 Gy: 1,087.3 ± 622.4; 6 Gy (3 × 2 Gy): 279.4 ± 201.1%; 12 Gy (6 × 2 Gy): 278.8 ± 175.3%; 18 Gy (9 × 2 Gy): 84.2 ± 41.5%. Comparing relative changes in ROS release after PMA stimulation, the differences between 0, 2, 6, 12, 18 Gy, and 6 Gy (3 × 2 Gy), 12 Gy (6 × 2 Gy), 18 Gy (9 × 2 Gy), and between 6 Gy (3 × 2 Gy), 12 Gy (6 × 2 Gy) and 18 Gy (9 × 2 Gy) proved to be significant (all p < 0.005). Conclusion: The study shows, that clinically used fractionated irradiation has an impact on granulocyte function, but contrary to common assumption, it is not to total dose itself but rather the fractionation which influences granulocyte function. This could have a major clinical impact on radiation treatment schemes especially for benign diseases or anti-inflammatory treatment.Hintergrund: Kürzlich konnte gezeigt werden, dass eine Bestrahlung mit Einzeldosen bis zu 32 Gy nur einen geringen Einfluss auf die Granulozytenfunktion hat. Da die verwendeten Dosierungsschemata nur selten Anwendung in der klinischen Routine finden, war es Ziel der vorliegenden Studie, Daten über den Einfluss einer fraktionierten Bestrahlung auf die Granulozytenfunktion zu erheben. Material und Methodik: Neutrophile Granulozyten wurden in RPMI 1640 (ohne fetales Kälberserum) kultiviert, für 48 inkubiert und bestrahlt (Bestrahlungsschema s. Tabelle 1). Die Funktion (= Möglichkeit, Sauerstoffradikale [ROS] freizusetzen) der Granulozyten wurde mittels Chemilumineszenz nach Stimulation mit Phorbolmyristatacetat (PMA) gemessen. Alle Versuche wurden mindestens fünfmal wiederholt. Ergebnisse: Nach Stimulation mit PMA zeigte sich eine Zunahme der relativen ROS-Freisetzung (die ROS-Freisetzung vor Stimulation wurde definiert als 100%; MW ± SD): 0 Gy: 785 ± 462,6%; 2 Gy: 704,3 ± 388,1%; 6 Gy: 1360,3 ± 710,5%; 12 Gy: 1 119,4 ± 581,1%; 18 Gy: 1 087,4 ± 622,4%; 6 Gy (3 × 2 Gy): 279,4 ± 201,1%; 12 Gy (6 × 2 Gy): 278,8 ± 175,3%; 18 Gy (9 × 2 Gy): 84,2 ± 41,5%. Signifikante Unterschiede eraben sich im Vergleich der relativen Veränderungen in der ROS-Freisetzung zwischen 0, 2, 6, 12, 18 Gy und 6 Gy (3 × 2 Gy), 12 Gy (6 × 2 Gy), 18 Gy (9 × 2 Gy) sowie zwischen 6 Gy (3 × 2 Gy), 12 Gy (6 × 2 Gy) und 18 Gy (9 × 2 Gy; alle p < 0,005). Schlussfolgerung: Mit der vorliegenden Studie konnte gezeigt werden, dass die fraktionierte Bestrahlung einen deutlich negativen Einfluss auf die ROS-Freisetzung als Funktion von Granulozyten hat. Die Annahme, dass nur die Gesamtdosis für eine Funktionsminderung verantwortlich sei, kann mit den vorliegenden Daten nicht nachvollzogen werden. Diese Erkenntnisse könnten einen Einfluss auf die Bestrahlungsschemata speziell bei gutartigen Erkrankungen und in der Behandlung von Entzündungen haben.

Value of Multiparametric US in the Assessment of Intratesticular Lesions

Purpose To evaluate the diagnostic accuracy of multiparametric ultrasonography (US) consisting of gray-scale US, color Doppler US, strain elastography, and contrast agent-enhanced US in the assessment of intratesticular lesions. Materials and Methods Institutional review board approval was obtained for this retrospective study. From January 2012 to December 2015, 55 focal testicular lesions that were indeterminate on gray-scale US scans were further characterized with color Doppler US, strain elastography, and contrast-enhanced US. Strain elastography was performed to assess tissue elasticity, and hard lesions were defined as malignant. Color Doppler US and contrast-enhanced US were performed to determine the absence or presence of vascularization. Avascular lesions were defined as benign. Histopathologic results or follow-up examinations served as reference standards. Correct classification rate, sensitivity, specificity, and likelihood ratio were calculated. Results Of 55 testicular lesions, 43 (78.2%) were benign and 12 (21.8%) were malignant. Single-modality sensitivities and specificities were 66.7% and 88.4% for color Doppler US, 100% and 76.7% for contrast-enhanced US, and 100% and 72.1% for strain elastography, respectively. Among 12 malignant lesions, color Doppler US failed to demonstrate vascularization in four (33.3%) lesions, which were positive for cancer at contrast-enhanced US. By combining strain elastography and contrast-enhanced US, a sensitivity of 100% and specificity of 93.0% were achieved in differentiating benign and malignant focal testicular lesions. Positive likelihood ratio was 5.7 for color Doppler US, 4.3 for contrast-enhanced US, 3.6 for strain elastography, 14.3 for strain elastography combined with color Doppler US, and 14.3 for strain elastography combined with contrast-enhanced US. Conclusion Multiparametric US allows for a reliable differentiation of benign and malignant intratesticular lesions and can potentially be useful in deciding whether orchiectomy can be replaced with follow-up or less invasive organ-sparing strategies.

Increase in antibody-dependent cellular cytotoxicity (ADCC) in a patient with advanced colorectal carcinoma carrying a KRAS mutation under lenalidomide therapy

The failure of EGFR inhibitors in colorectal tumors with KRAS mutations requires the development of alternative treatment strategies for this patient subgroup. Among the hallmarks of cancer the disturbed immunosurveillance and cancer immune evasion have become emerging targets for cancer therapy. Due to their pleiotropic functions immunomodulatory drugs (IMiDs) are interesting agents for combination therapies in solid tumors. However, their possible contribution and a way of monitoring their biological effects have yet to be revealed. In a heavily pretreated patient with advanced colorectal cancer carrying mutations in APC and KRAS genes, we show an early metabolic response and enhanced NK cell activity to monotherapy with lenalidomide. After subsequent lenalidomide/cetuximab combination treatment, the patient had progressive disease. At the same time a reduced performance status, complicated by febrile neutropenia, occurred, as well as a slight increase in metabolic activity. Concordantly NK cell activity dropped back to baseline. Thus, laboratory measurements and metabolic response assessment correlated with clinical conditions. This case report describes the feasibility and potential of a functional assessment of patient derived immune competent cells in combination with functional imaging for the detection of a biological response.

Gout of hand and wrist: the value of US as compared with DECT

ObjectivesThe purpose of this study was to compare findings of ultrasound (US) with dual-energy CT (DECT) in patients presenting with suspected gouty hand and wrist arthritis.MethodsThis prospective study included 180 patients (136 men and 44 women, age range, 31– 94 years; mean age, 65.9 years) with an initial clinical diagnosis of acute gouty arthritis who underwent DECT and US examination. Intra- and extra-articular findings of each modality were tabulated and calculated with DECT as gold standard.ResultsThe final diagnosis of gout was positive in 97/180 patients (53.9%) by DECT, an alternative diagnosis confirmed in 83 patients. US showed a sensitivity of 70.1% (extra-articular: 42.5%, p < 0.0001; intra-articular: 80.3%, p = 0.14) and specificity of 51%. The double contour sign (DCS) was present in 58/61 patients with a positive US study for intra-articular gout (95.1%).ConclusionsSensitivity of US for diagnosis of gouty arthritis in hand and wrist is limited, particularly with respect to extra-articular urate deposition. The DCS is the most sensitive sign for the assessment of gouty hand and wrist arthritis by US.Key points• Sensitivity of US for diagnosis of gouty arthritis in hand and wrist is limited, particularly with respect to extra-articular gouty deposits.• The double contour sign is the most sensitive finding for the assessment of gouty hand and wrist arthritis by US.• Although the sensitivity of US for diagnosis of gouty hand and wrist arthritis is limited, it can be used as a first-line imaging modality in the presence of the DCS.