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Purpose This study is to investigate the adoption and current trends of Lutetium-177 PSMA RLT for mCRPC in Germany. Methods We analyzed data from the reimbursement.INFO tool based on German hospitals’ quality reports for Lutetium-177 PSMA RLT from 2016 to 2020 and from the nationwide German hospital billing database (Destatis) for general therapy with open radionuclides in combination with prostate cancer from 2006 to 2020. For validation of these billing data, we included the 177Lu-PSMA RLT cycles from two participating institutions from 2016 to 2020. For detection of trends over time we applied linear regression models. Results General therapy with open radionuclides increased from 2006 to 2020. We identified a total of 12,553 177Lu-PSMA RLT cycles. The number of 177Lu-PSMA RLTs steadily increased from a total of 1026 therapies in 2016 to 3328 therapies in 2020 (+ 576 RLT/year; p 177Lu-PSMA RLTs, which increased to 36% (16/44) in 2020 (p 177Lu-PSMA RLT increased from 78% in 2016 to 81% in 2020. Conclusion Treatment of mCRPC with 177Lu-PSMA RLT has been rapidly increasing in Germany in the recent years providing an additional therapy option. This development is remarkable, because of outstanding formal EMA approval.

Introduction The present study aims to evaluate the clinical diagnostic value of FDG-PET/CT in patients with inflammation of unknown origin. Material and methods We retrospectively analyzed data of 130 patients who presented general inflammatory symptoms and/or elevated level of CRP and underwent FDG-PET/CT for the purpose of identifying unknown foci of inflammation. The accuracy of PET/CT findings was assessed against the standard of eventual clinical diagnosis e.g. results of pathology, microbiology or other imaging methods. Results In 99/130 patients (76 %) a final diagnosis was established, FDG-PET/CT showed a sensitivity and specificity of each 93 %. A decreased pseudocholinesterase is associated with a higher SUVmax value and with a higher CRP value whereas no significant relationship was found between elevated CRP values and the SUVmax, although higher CRP values are associated significantly with a true positive PET/CT result. Conclusion FDG-PET/CT is a highly sensitive, specific and accurate method for the detection of foci of inflammation of unknown origin. The combination of decreased pseudocholinesterase and increased CRP levels may be a useful tool to select patients for FDG PET/CT.

ZUSAMMENFASSUNG Hintergrund Die Skelettszintigrafie ist eine sensitive Methode für die Darstellung von Knochenmetastasen. Trotz der festen Etablierung in die klinische Routine gibt es kaum Daten aus größeren homogenen Kollektiven zur Wertigkeit der Skelettszintigrafie im Rahmen des Stagings. Ziel Ziel unserer Arbeit war die Evaluierung der Real-Life-Performance der Skelettszintigrafie als Staginguntersuchung bei Patientinnen mit der Erstdiagnose eines Mammakarzinoms. Patienten und Methoden Wir werteten retrospektiv die Daten der im Jahr 2015 in unserer Klinik mittels Skelettszintigrafie untersuchten Patientinnen aus. Zusätzlich wurde über einen Zeitraum von 30 Monaten evaluiert, ob sich im Verlauf diese Ergebnisse bestätigten; hierzu wurden anschließende Untersuchungen ausgewertet. Ergebnisse 207/258 Patientinnen zeigten in der initialen Skelettszintigrafie keine verdächtigen Befunde, bei 48 zeigte sich ein unklarer Befund, weshalb bei 42 Patientinnen weitere Diagnostik angeschlossen wurde. Im Follow-up wurden bei 4 Patientinnen neue Skelettmetastasen gefunden, diese hatten alle in der Primärdiagnostik Szintigrafiebefunde, die als „unklar“ gewertet wurden. Es ergab sich je nach Wertung des Ereignisses (metastasenverdächtig/metastasenverdächtig und unklar) eine Sensitivität von 37,5 %/100 %, eine Spezifität von 100 %/80 %, ein positiv prädiktiver Wert von 100 %/15,7 % und ein negativ prädiktiver Wert von 98 %/100 %. Schlussfolgerung Mittels der Skelettszintigrafie und weiterer Abklärung konnte in 99,2 % der vollständig untersuchten Patientinnen ein klinisch aussagekräftiger Befund erhoben werden, welcher sich im F17808378ollow-up bestätigte. Dieses Ergebnis zeigt die gute Real-Life-Performance der Skelettszintigrafie als Staginguntersuchung bei Patientinnen mit erstdiagnostiziertem Mammakarzinom.

Purpose The interdisciplinary “Martinique-Principles” of four international professional societies concerned with the patient management of differentiated thyroid cancer (DTC) patients were agreed upon. Differences in perioperative diagnostics can lead to differences in clinical decision founding regarding the treatment of thyroid carcinoma. Our aim was to analyze the perioperative diagnostics of patients referred for postoperative I-131 therapy of DTC. Methods We retrospectively examined the data of 142 patients who were referred to our center for the first course of postsurgical I-131 therapy. We extracted data on perioperative diagnostics. Results Fine-needle biopsy (FNB) was performed in 27/142 patients. In 17 patients, FNB yielded findings suspicious of malignancy, in 3 patients a follicular lesion was reported. An intraoperative frozen section analysis was performed in 79/142 patients. 5/63 patients showed already a cytologically proven malignancy. In 10/79 patients, the frozen section had a nonmalignant result, although DTC was found on final assessment. In 2/79 patients, frozen section analysis was indecisive, although the final report confirmed DTC. In the remaining 67 patients, frozen section yielded DTC. Conclusions There is room for improvement in perioperative diagnostics surrounding thyroid surgery, currently many procedures are performed without adequate information on potential presence of thyroid cancer. More frequent use of FNB might be able to decrease the number of unnecessary thyroid surgeries, increased use of frozen section might decrease the number of second operations and might contribute to less discordance between experts in the field of DTC treatment.

Bone scintigraphy is a sensitive method for imaging bone metastases in patients with breast cancer. Despite its firm establishment in clinical routine, there are hardly any reliable data from larger homogeneous collectives on the value of bone scintigraphy in the context of staging of first diagnosed breast cancer patients.The aim of our work was to evaluate the real-life performance of bone scintigraphy as a staging examination in female patients with the initial diagnosis of breast cancer.We retrospectively evaluated the data of the patients examined in the year 2015 with the first diagnosis of breast cancer at the University Hospital Marburg by bone scintigraphy. In addition a follow-up over a period of 30 months after the first bone scintigraphy was performed. For this purpose we evaluated whether the results of this initial diagnostic could be confirmed in following diagnostic.207/258 patients showed no suspicious findings in the initial bone scintigraphy, 48 had an unclear finding, which is why 42 patients received further diagnostics. In follow-up, new bone metastases were found in 4 patients, all of these had scintigraphic findings in the primary diagnosis, which were considered "unclear". Depending on the evaluation of the event (suspicious for metastasis/suspicious for metastasis and unclear), the sensitivity was 37.5%/100%, the specificity 100%/80%, the positive predictive value 100%/15.7% and the negative predictive value 98%/100%.By using bone scintigraphy and, if necessary, subsequent further imaging or histological clarification, a clinically significant diagnosis was obtained in 99,2% of the examined patients and confirmed in the follow-up. This result shows the good real-life performance of bone scintigraphy as a staging examination in patients with first diagnosed breast carcinomas.Die Skelettszintigrafie ist eine sensitive Methode für die Darstellung von Knochenmetastasen. Trotz der festen Etablierung in die klinische Routine gibt es kaum Daten aus größeren homogenen Kollektiven zur Wertigkeit der Skelettszintigrafie im Rahmen des Stagings. ZIEL: Ziel unserer Arbeit war die Evaluierung der Real-Life-Performance der Skelettszintigrafie als Staginguntersuchung bei Patientinnen mit der Erstdiagnose eines Mammakarzinoms.Wir werteten retrospektiv die Daten der im Jahr 2015 in unserer Klinik mittels Skelettszintigrafie untersuchten Patientinnen aus. Zusätzlich wurde über einen Zeitraum von 30 Monaten evaluiert, ob sich im Verlauf diese Ergebnisse bestätigten; hierzu wurden anschließende Untersuchungen ausgewertet.207/258 Patientinnen zeigten in der initialen Skelettszintigrafie keine verdächtigen Befunde, bei 48 zeigte sich ein unklarer Befund, weshalb bei 42 Patientinnen weitere Diagnostik angeschlossen wurde. Im Follow-up wurden bei 4 Patientinnen neue Skelettmetastasen gefunden, diese hatten alle in der Primärdiagnostik Szintigrafiebefunde, die als „unklar“ gewertet wurden. Es ergab sich je nach Wertung des Ereignisses (metastasenverdächtig/metastasenverdächtig und unklar) eine Sensitivität von 37,5%/100%, eine Spezifität von 100%/80%, ein positiv prädiktiver Wert von 100%/15,7% und ein negativ prädiktiver Wert von 98%/100%.Mittels der Skelettszintigrafie und weiterer Abklärung konnte in 99,2% der vollständig untersuchten Patientinnen ein klinisch aussagekräftiger Befund erhoben werden, welcher sich im Follow-up bestätigte. Dieses Ergebnis zeigt die gute Real-Life-Performance der Skelettszintigrafie als Staginguntersuchung bei Patientinnen mit erstdiagnostiziertem Mammakarzinom.

The management of differentiated thyroid carcinoma has shown considerable changes in recent years, moving away from a fixed therapy regimen towards individual treatment strategies. The aim of our work (literature research) is to present current developments in the follow-up of differentiated thyroid cancer. For the management of individual follow-up, an initial evaluation and, at later time points, the re-evaluation of the risk of recurrence is crucial. The performance of I-131-diagnostics after radioiodine therapy can provide essential information and can be seen as a survey of a new baseline situation, in order to be able to draw a comparison in case of a rising Thyreoglobulin (Tg). The measurement of Tg with a highly sensitive assays shows a high negative predictive value. Negative Tg measurements with these assays seem to indicate complete remission even with Tg antibodies being present. An increasing Tg value in follow-up implies further diagnostic work-up, primarily neck ultrasonography. Sonographically suspicious findings should be subjected to fine needle biopsy, whereby in addition to cytological processing, determination of Tg from the sample can be recommended. If the suspicious lesion cannot be displayed sonographically and Tg values keep rising, computed tomography (CT) and magnetic resonance imaging (MRI) of the neck region can provide further information. FDG-PET/CT has also shown an excellent performance in this setting. The previously fixed therapy regimen has been realigned towards an individual treatment management. Current studies and guidelines lead to a repetitive recurrence risk evaluation and the adjustment of the aftercare planning to the individual risks with appropriately selected examination methods and personalized intervals of assessment.

146 Background: Our purpose was to investigate the adoption and current trends of Lutetium-177 PSMA radioligand therapy (RLT) for metastatic castration-resistant prostate cancer (mCRPC) in Germany. Methods: We analyzed the nationwide German hospital billing database (Destatis) and the hospitals’ quality reports for 177Lutetium PSMA RLT from 2016 to 2020 using the reimbursement.INFO tool. For detection of trends over time we applied linear regression models. For validation of these billing data, we included a total of 1239 177Lu-PSMA RLT cycles from 392 patients within the WARMTH multicenter study from 2016 to 2018. Additionally, we included the 177Lu-PSMA RLT cycles from two participating institutions from 2016 to 2020 for further validation. Results: We identified 12553 cases which were treated with 177Lu-PSMA RLT. The number of 177Lu-PSMA RLTs steadily increased from 1077 to 3640 therapies during the study period (+641 RLT/year; p177Lu-PSMA RLTs, which increased to 36% (16/44) in 2020 (p177Lu-PSMA RLTs were performed at a university hospital, which decreased to 70% (31/44) in 2020. The proportion of patients older than 65 years receiving 177Lu-PSMA RLT increased from 78% in 2016 to 81% in 2020. Conclusions: Treatment of mCRPC with 177Lu-PSMA RLT has been rapidly increasing in Germany in the recent years providing an additional therapy option. Most of the therapies are performed at academic hospitals.

Simple Summary Prostate-specific membrane antigen (PSMA)-targeted therapy represents a promising therapeutic option for the treatment of advanced carcinoma, but data on the relevance of PSMA-targeted diagnostics and therapy for anaplastic (ATC) and poorly differentiated (PDTC) thyroid carcinoma are still lacking. Due to the limited therapeutic options for these entities, the aim of this study was to evaluate to what extent Gallium-68 (68Ga)-PSMA-positron emission tomography/computed tomography (PET/CT) is superior to F-18-Fluordeoxyglucose (18F-FDG)-PET/CT in the diagnostic of ATC/PDTC and could represent a new therapeutic option in terms of theranostic. The findings of this study confirm the high diagnostic sensitivity and superiority of 18F-FDG-PET/CT in comparison to 68Ga-PSMA-PET/CT in the diagnosis of ATC and PDTC. However, it can be suggested that 68Ga-PMSA-PET/CT can be considered as a beneficial adjunct to the well-established 18F-FDG-PET/CT for a few individual selected patients with ATC and PDTC to detect lesions not discovered by 18F-FDG-PET/CT and to determine patients’ eligibility for a radioligand therapy. With regard to our results, radiolabelled PSMA-ligands with Lutetium-177 (177Lu)-PSMA may, in the future, represent a theranostic approach with only minor side effects for a few individual selected patients with ATC and PDTC who need alternative treatment options in case of progression when established therapies are no longer effective. Abstract Several studies have demonstrated an expression of the prostate-specific membrane antigen (PSMA) in the cancer-related neovasculature of thyroid malignancies. Due to the poor prognosis and limited therapeutic options for patients with anaplastic (ATC) and poorly differentiated (PDTC) thyroid carcinoma, the aim of our study was to investigate the theranostic approach of PSMA expression in these patients. The PSMA uptake on Gallium-68 (68Ga)-PSMA-positron emission tomography/computed tomography (PET/CT) and glucose uptake on F-18-Fluordeoxyglucose (18F-FDG)-PET/CTs were analysed in two ATC and six PDTC patients. The PSMA expression in corresponding patients’ tissue samples was detected by immunohistochemistry. In addition, various tissue sections from 22 ATC and six PDTC patients were examined concerning PSMA expression. 68Ga-PSMA-PET/CT showed heterogeneous PSMA expression among patients and lesions. Six of the eight analyzed patients (two ATC, four PDTC) showed increased glucose metabolism without increased PSMA uptake after PET/CT. In one patient (PDTC), 18F-FDG-PET/CT tracer uptake was positive and 68Ga-PSMA-PET/CT showed heterogeneous results. Another patient (PDTC) evidenced only PSMA-positive lesions and received two cycles of Lutetium-177 (177Lu)-PSMA therapy, which kept his disease stable for seven months. There was a correlation between immunohistochemical PSMA expression and uptake on 68Ga-PMSA-PET/CT in three of the examined patients. Twenty-seven of the analyzed 39 ATC and 13 of the analyzed 22 PDTC tissue sections showed a strong PSMA expression. Considering the rarity of PDTC and ATC, which is the reason for the small patient population we studied, the findings of this study confirm the high diagnostic sensitivity and superiority of 18F-FDG-PET/CT in comparison to 68Ga-PSMA-PET/CT in the diagnosis of ATC and PDTC. However, it can be suggested that 68Ga-PMSA-PET/CT can be considered as a beneficial adjunct to the well-established 18F-FDG-PET/CT for a few individual selected patients with ATC and PDTC to detect lesions not discovered by 18F-FDG-PET/CT and to determine patients’ eligibility for a radioligand therapy. Radiolabelled PSMA-ligands may, in the future, represent a theranostic approach with only minor side effects for a few individual selected patients with ATC and PDTC who need alternative treatment options in case of progression when established therapies are no longer effective. However, due to the small sample size of our collective, larger studies are needed to allow for a final evaluation on the significance of PSMA-targeted diagnostic and therapy for ATC and PDTC.

The main screening parameter to monitor prostate cancer recurrence (PCR) after primary treatment is the serum concentration of prostate-specific antigen (PSA). In recent years, Ga-68-PSMA PET/CT has become an important method for additional diagnostics in patients with biochemical recurrence.While Ga-68-PSMA PET/CT performs better, it is an expensive, invasive, and time-consuming examination. Therefore, in this study, we aim to employ modern multivariate Machine Learning (ML) methods on electronic health records (EHR) of prostate cancer patients to improve the prediction of imaging confirmed PCR (IPCR).We retrospectively analyzed the clinical information of 272 patients, who were examined using Ga-68-PSMA PET/CT. The PSA values ranged from 0 ng/mL to 2270.38 ng/mL with a median PSA level at 1.79 ng/mL. We performed a descriptive analysis using Logistic Regression. Additionally, we evaluated the predictive performance of Logistic Regression, Support Vector Machine, Gradient Boosting, and Random Forest. Finally, we assessed the importance of all features using Ensemble Feature Selection (EFS).The descriptive analysis found significant associations between IPCR and logarithmic PSA values as well as between IPCR and performed hormonal therapy. Our models were able to predict IPCR with an AUC score of 0.78 ± 0.13 (mean ± standard deviation) and a sensitivity of 0.997 ± 0.01. Features such as PSA, PSA doubling time, PSA velocity, hormonal therapy, radiation treatment, and injected activity show high importance for IPCR prediction using EFS.This study demonstrates the potential of employing a multitude of parameters into multivariate ML models to improve identification of non-recurring patients compared to the current focus on the main screening parameter (PSA). We showed that ML models are able to predict IPCR, detectable by Ga-68-PSMA PET/CT, and thereby pave the way for optimized early imaging and treatment.

Background Chylothorax is a life-threatening pathological condition associated with significant morbidity and mortality. If chyle leakage does not close spontaneously with medical therapy, surgical treatment is inevitable. Herein, we reported a case of spontaneous persistent chylothorax from mediastinal seminoma that was successfully closed between the descending thoracic aorta, and the vertebral column through a left mini-thoracotomy. Case presentation A 24-year old man with mediastinal seminoma was referred to our attention for management of high output persistent chylothorax (> 800 ml/24 h for 30 days) that did not close with conservative treatment. As the leak was isolated within left upper chest cavity, we planned to close the thoracic duct via Poirier’s triangle by uniportal thoracoscopy. However, the long conservative treatment favoured the formation of multiple, tenacious, and bleeding adhesions that made unfeasible thoracoscopy. A conversion to mini-thoracotomy was performed; by the incision of the posterior parietal pleura, the thoracic duct was isolated and ligated behind the thoracic aorta, in an anatomical space delimited by the 4th and the 5th posterior intercostal arteries and the vertebral column. Conclusions Complete resolution of chylothorax was obtained the day after. Patient was discharged on post-operative day 5, and no recurrence was observed during the follow-up. Electronic supplementary material The online version of this article (10.1186/s13019-019-0917-8) contains supplementary material, which is available to authorized users.

Solitary fibrous tumors/hemangiopericytomas (SFTs/HPCs), constitute 1% of all CNS tumors. Spinal SFTs/HPCs are extremely rare. To date, few retrospective studies and case reports of primary spinal SFTs/HPCs have been published in the literature. We report clinical and radiological presentation, surgical treatment, and post-operative outcome at three years follow-up of a rare case of primary spinal intra and extradural SFT/HPC of thoracic spine with dumbbell shaped paravertebral intrathoracic spread and multidirectional erosion of the bone. A 73-year-old female presented with progressive lower limbs weakness and hypoesthesia below the rib cage. MRI showed an irregular isointense T5-T7 dumbbell shaped tumor. Tumor resection was successfully carried out through posterior and antero-lateral approach. Histological examination showed a grade II SFT/HPC. No local recurrence nor systemic metastases were observed at three years follow-up. A literature review has been performed to describe epidemiology, radiographic features, treatment, recurrence rate and mean disease-free survival of primary spinal SFTs/HPCs. No radiographic pathognomonic findings have been reported for these tumors. Differential diagnosis must be made with meningioma, schwannoma, chordoma, aggressive hemangioma, metastases, angiosarcoma. Surgical resection is the first choice of treatment, and total resection should be attempted whenever possible in all cases. Postsurgical radiotherapy does not change significantly recurrence rate after GTR, nonetheless it increases mean disease-free survival, especially in patients with extradural SFTs/HPCs. After subtotal resection, adjuvant radiotherapy is necessary to reduce progression of disease. The efficacy of chemotherapy has yet to be determined. Pathological degree and total surgical resection are the most important predictive factors of recurrence.

The management of differentiated thyroid carcinoma has shown considerable changes in recent years, moving away from a fixed therapy regimen towards individual treatment strategies. The aim of our work (literature research) is to present current developments in the follow-up of differentiated thyroid cancer.For the management of individual follow-up, an initial evaluation and, at later time points, the re-evaluation of the risk of recurrence is crucial. The performance of I-131-diagnostics after radioiodine therapy can provide essential information and can be seen as a survey of a new baseline situation, in order to be able to draw a comparison in case of a rising Thyreoglobulin (Tg).The measurement of Tg with a highly sensitive assays shows a high negative predictive value. Negative Tg measurements with these assays seem to indicate complete remission even with Tg antibodies being present. An increasing Tg value in follow-up implies further diagnostic work-up, primarily neck ultrasonography. Sonographically suspicious findings should be subjected to fine needle biopsy, whereby in addition to cytological processing, determination of Tg from the sample can be recommended. If the suspicious lesion cannot be displayed sonographically and Tg values keep rising, computed tomography (CT) and magnetic resonance imaging (MRI) of the neck region can provide further information. FDG-PET/CT has also shown an excellent performance in this setting.The previously fixed therapy regimen has been realigned towards an individual treatment management. Current studies and guidelines lead to a repetitive recurrence risk evaluation and the adjustment of the aftercare planning to the individual risks with appropriately selected examination methods and personalized intervals of assessment.

The prevalence of focal lesions in the thyroid is high in Germany. In 2018 about 70 000 thyroid surgeries were performed, although the malignancy rate of such findings is low. For this reason it is important to conduct an adequate selection of patients for whom surgery is indicated. The aim of our work was to validate the preoperative indication for surgery of thyroid lesions based on an independent, self-developed clinical score. The patient data were evaluated retrospectively over the period 2013 to 2014. A prerequisite for inclusion was that the patients had carried out their complete treatment in domo. The multiparametic score was determined retrospectively and ranges from 3 to 15. The subjective improvement of symptoms (self-disclosure 6 months postoperatively) and the presence of malignant histology were evaluated as positive outcome parameters. From a collective of 180 patients, 36 patients could be included, in whom all score-relevant parameters had been surveyed. The score distribution was 10 % score 3, 12.5 % score 4, 25 % score 5, 25 % score 6, 12.5 % score 7, 7.5 % score 8, 5 % score 9 and 2.5 % score 10. Using ROC analysis shows an AUC of 0.903, which is a very good differentiation. With a CUT-off score of 7 or higher, 86 % of patients have benefited from surgery. Our score with the parameters clinical complaints, sonographically defined size of the thyroid and the cytological result of a fine needle biopsy can lead to an improvement of the indication for surgical treatment of thyroid nodules. Die Prävalenz von fokalen Läsionen der Schilddrüse ist in Deutschland hoch. Im Jahr 2018 wurden etwa 70 000 Schilddrüsenoperationen durchgeführt, obwohl die Malignitätsrate solcher Befunde gering ist. Aus diesem Grund ist es wichtig, eine adäquate Auswahl der Patienten zu treffen, bei denen eine Operation indiziert ist. ZIEL: Ziel unserer Arbeit war es, die präoperative Indikation zur Operation von Schilddrüsenläsionen auf der Grundlage eines unabhängigen, selbst entwickelten klinischen Scores zu validieren. Die Patientendaten wurden retrospektiv über den Zeitraum 2013 bis 2014 ausgewertet. Voraussetzung für den Einschluss war, dass die komplette Behandlung der Patienten in domo durchgeführt wurde. Der multiparametrische Score wurde retrospektiv ermittelt und reicht von 3 bis 15. Die subjektive Verbesserung der Symptome (Angabe 6 Monate postoperativ) und das Vorliegen einer malignen Histologie wurden als positive Ergebnisparameter bewertet. Aus einem Kollektiv von 180 Patienten konnten 36 Patienten eingeschlossen werden, bei denen alle Score-relevanten Parameter erhoben wurden. Die Score-Verteilung betrug 10 % Punktzahl 3, 12,5 % Punktzahl 4, 25 % Punktzahl 5, 25 % Punktzahl 6, 12,5 % Punktzahl 7, 7,5 % Punktzahl 8, 5 % Punktzahl 9 und 2,5 % Punktzahl 10. Die ROC-Analyse zeigt eine AUC von 0,903, was einer sehr guten Differenzierung entspricht. Bei einem Cut-off-Score von 7 oder höher haben 86 % der Patienten von der Operation profitiert. Unser Score mit den Parametern klinische Beschwerden, sonografische Größe der Schilddrüse und zytologisches Ergebnis einer Feinnadelbiopsie kann zu einer Verbesserung der Indikationsstellung zur chirurgischen Behandlung von Schilddrüsenknoten führen.

Reference values are the basis for an increase of standardisation and examiner independence, and thus an improvement in the inter-institutional comparability. However for renal Mercaptoacetyltriglycin (MAG3)-scintigraphy the establishment of such values however did not find its way into clinical routine despite the convincing advantages. The aim was to establish reference values for the decisive quantitative parameters of MAG3 renal scintigraphy. The reference values should help to significantly improve and facilitate the interpretation of the examination results in everyday clinical practice. We retrospectively evaluated all MAG3 renal scintigraphies performed in the Department of Nuclear Medicine, University Hospital Marburg between 01/2014 and 08/2017. The total sample of non-pathological renal scintigrafies included 247 patients aged between 25 days and 88 years. All investigtions were performed according to the present guidelines of the German Association for Nuclear Medicine. We analysed the ratio from pulse count rate after 20 minutes/Time (T) max and the Tmax separately. Reference values for the Tmax and 20 min/T(max) count ratio of the MAG3 renal scintigraphy were defined for all adults over 18 years and divided by age catogories. For children aged 0-0.5 years and 0.5-2 years reference values for Tmax were defined. The results show a high degree of consistency with the reference values screened out in previous studies. This underlines the reliability of the reference values as a diagnostic tool in clinical application. The defined values are clinically feasible and promise a simplified and improved interpretation of the MAG3 renal scintigraphy. Referenzwerte können zu einer Verbesserung der Standardisierung, der Untersucherunabhängigkeit und damit einer Verbesserung der Vergleichbarkeit zwischen verschiedenen Untersuchungen führen. Für die renale Mercaptoacetyltriglycin (MAG3)-Szintigrafie hat die Festlegung solcher Werte trotz der überzeugenden Vorteile jedoch nicht den Weg in die klinische Routine gefunden. ZIEL: Ziel war es, Referenzwerte für die entscheidenden quantitativen Parameter der MAG3-Nierenszintigrafie festzulegen. Die Referenzwerte sollen dazu beitragen, die Interpretation der Untersuchungsergebnisse im klinischen Alltag zu verbessern und zu erleichtern. Wir werteten retrospektiv alle MAG3-Nierenszintigrafien aus, die in der Klinik für Nuklearmedizin des Universitätsklinikums Marburg zwischen 01/2014 und 08/2017 durchgeführt wurden. Die Gesamtstichprobe der nichtpathologisch veränderten Nierenszintigrafien umfasste 247 Patienten im Alter zwischen 25 Tagen und 88 Jahren. Alle Untersuchungen wurden nach den Leitlinien der Deutschen Gesellschaft für Nuklearmedizin durchgeführt. Wir analysierten den Quotienten aus der Impulsfrequenz nach 20 Minuten/Time (T)max und der Tmax getrennt. Es gab einen statistisch signifikanten Unterschied zwischen den verschiedenen Alterskategorien für das Verhältnis der Impulsrate 20 min/Tmax der linken (p = 0,001) und rechten (p = 0,001) Niere sowie der Tmax der linken Niere (p = 0,006). Die Referenzwerte für die Tmax und den Quotienten der Impulsrate 20 min/Tmax der MAG3-Nierenszintigrafie wurden für alle Erwachsenen über 18 Jahre definiert und in Alterskategorien eingeteilt. Für Kinder im Alter von 0–0,5 und 0,5–2 Jahren wurden Referenzwerte für Tmax definiert. Die Ergebnisse zeigen einen hohen Grad an Übereinstimmung mit den in früheren Studien beschriebenen möglichen Referenzwerten. Dies unterstreicht die Zuverlässigkeit der Referenzwerte als diagnostisches Instrument in der klinischen Anwendung. Die definierten Werte sind klinisch integrierbar und versprechen eine vereinfachte und verbesserte Interpretation der MAG3-Szintigrafie.

Purpose: In contrast to splenomegaly, the clinical value of a small spleen (hyposplenia) is unclear. Contrast-enhanced ultrasound (CEUS) has not been investigated systematically in hyposplenia. Methods: Between February 2005 and January 2017, 43 patients with hyposplenia (< 7 × 3 cm) were examined by B-mode ultrasound (US) and CEUS. A retrospective data analysis was performed. Results: A total of 39 (91%) patients had an underlying disease (UD; allogenic stem cell transplantation, n = 16; autoimmune-diseases, n = 7; sickle cell anemia, n = 5; solid tumors, n = 5; others, n = 6). In 4 (9%) cases, hyposplenia was an incidental finding. The echogenicity of the spleen was normal (homogeneous, isoechogenic) in 17 (39.5%) and abnormal in 26 (60.5%) cases (inhomogeneous, n = 26 and hyperechoic, n = 9). In CEUS, 21 (49%) patients presented a normal isoenhancement. An abnormal enhancement was detected in 22 (51%) patients with UD (arterial/parenchymal inhomogeneous, n = 1; no [arterial, n = 3 and parenchymal, n = 6]; reduced [arterial, n = 8 and parenchymal, n = 15]). Conclusions: Hyposplenia is a rare pathologic finding and often associated with hematological/oncological and autoimmune diseases. Furthermore, altered B-mode US appearance and a pathological CEUS pattern are frequently found. However, the clinical implication, especially regarding splenic function remains obscure to date.

Routine screening is recommended for patients with multiple endocrine neoplasia type 1 (MEN1) to enable early detection and treatment of associated neuroendocrine neoplasms (NEN). GalliumBetween January 2014 and March 2016, all MEN1 patients underwent Ga-68-DOTATOC-PET-CT in addition to conventional imaging (computed tomography of the thorax, magnetic resonance imaging of the abdomen and pituitary, endoscopic ultrasonography). The diagnostic yield of conventional imaging and Ga-68-DOTATOC-PET-CT was prospectively documented and compared, and treatment changes caused by the addition of Ga-68-DOTATOC-PET-CT were recorded.Conventional imaging detected 145 NENs, mainly pancreaticoduodenal NENs (n = 117, 81%), in 31 of 33 MEN1 patients. Ga-68-DOTATOC-PET-CT detected 55 NENs in 23 of the 33 patients (p = 0.0001). Ninety (62%) NENs detected by conventional imaging were missed by DOTATOC-PET-CT. The majority of missed lesions were pNEN (n = 68; 74%). The sensitivity of Ga-68-DOTATOC-PET-CT for NENs5, 5-9, 10-19 and ≥20 mm was 0, 29, 81 and 100%, respectively. However, Ga-68-DOTATOC-PET-CT detected more liver and lymph node metastases in patients with known metastatic disease, which did not lead to a change of patients' management. In one patient (3%), Ga-68-DOTATOC-PET-CT was the only imaging modality that detected a small intestine NEN and led to potentially curative surgery.Ga-68-DOTATOC-PET-CT cannot be recommended for routine screening of MEN1 patients. It might provide important additional information in patients with suspected or known metastatic disease.

Neuroendocrine neoplasms (NEN) are a heterogeneous group of tumors characterized by the expression of typical proteins. A wide range of morphological and functional imaging methods is required in order to adequately assess the course of the disease and to optimally treat the patient. The spectrum of indications ranges from the detection of small primary tumors to the documentation of the metastasis pattern and the assessment of the suitability for certain invasive or noninvasive therapy methods. The exact recording and quantification of findings is indispensable. This article is based on a comprehensive literature search on the different aspects of neuroendocrine neoplasm imaging. This article is intended to provide an overview of the available imaging procedures with their respective advantages and disadvantages for diagnostics and their value for the follow-up of neuroendocrine neoplasms. Recommendations for examination protocols, typical image findings, and an outlook regarding future developments are presented. · Neuroendocrine neoplasms are relatively rare and represent a complex and multiform disease group. Even in metastatic disease, long-term progression-free survival is not uncommon.. · Diagnostics in neuroendocrine neoplasms use a wide range of complementary morphological and functional imaging methods.. · Adequate selection of the imaging method, examination planning and preparation of the patient are essential for exact staging and reliable follow-up..· Figiel JH, Viniol SG, Görlach J et al. Update Regarding Imaging of Neuroendocrine Neoplasms. Fortschr Röntgenstr 2020; 192: 171 - 182. Neuroendokrine Neoplasien (NEN) sind eine sehr heterogene Gruppe von Tumoren mit Expression typischer Proteine. Es wird eine große Bandbreite radiologischer und nuklearmedizinischer Methoden benötigt, um den Krankheitsverlauf adäquat einschätzen und den Patienten optimal behandeln zu können. Das Spektrum der Fragestellungen reicht von der Detektion kleinster Primärtumoren über die Dokumentation des Metastasierungsmusters und -verlaufs bis zur Beurteilung der Eignung für bestimmte invasive bzw. nichtinvasive Therapieverfahren. Hierbei ist eine exakte Befunderfassung und -quantifizierung unerlässlich. Diese Übersicht basiert auf einer umfassenden Literaturrecherche zu den unterschiedlichen Aspekten der Bildgebung neuroendokriner Neoplasien. Dieser Artikel soll einen Überblick über die zur Verfügung stehenden bildgebenden Verfahren mit ihren jeweiligen Vor- und Nachteilen für die Diagnostik und ihre Wertigkeit für Verlaufskontrollen neuroendokriner Neoplasien geben. Dabei werden Empfehlungen für Untersuchungsprotokolle gegeben, typische Bildbefunde dargestellt und ein Ausblick auf zukünftige Entwicklungen gegeben. · Neuroendokrine Neoplasien sind relativ selten und stellen eine komplexe und vielgestaltige Erkrankungsgruppe dar. Langjährige Krankheitsverläufe sind auch im metastasierten Stadium nicht selten.. · Die Diagnostik neuroendokriner Neoplasien bedient sich eines großen Spektrums komplementärer morphologischer und funktioneller Bildgebungsmethoden.. · Eine adäquate Methodenwahl, Untersuchungsplanung und Vorbereitung des Patienten sind für ein exaktes Staging und aussagekräftige Verlaufskontrollen unerlässlich..· Figiel JH, Viniol SG, Görlach J et al. Update Regarding Imaging of Neuroendocrine Neoplasms. Fortschr Röntgenstr 2020; 192: 171 – 182.

Postoperative chylothorax is a rare but potentially life-threatening complication. Conservative treatment is usually unsuccessful in patients with high-output chylothorax, for whom early surgical thoracic duct ligation has been advocated to minimize morbidity and mortality. This report describes left uniportal thoracoscopic closure of persistent high-output chylothorax through Poirier's triangle in a patient undergoing thoracoscopic thymectomy. After resection of pleural adhesions, the mediastinal pleura was resected at the level of the aortic arch, left subclavian artery, and vertebral column, the anatomic limits of Poirier's triangle. The thoracic duct was then isolated from the esophagus and successfully clipped along its path.

Mutations of the human VCP gene, which encodes the V: alosin C: ontaining P: rotein (synonyms: p97, TER ATPase), are associated with various multi-systemic protein aggregation diseases. We report on a patient with progressive myopathy and incipient cognitive deficits. A diagnostic muscle biopsy revealed an inclusion body myopathy with protein aggregates. Magnetic resonance imaging and F18-positron-emission-tomography disclosed a fronto-temporal atrophy and glucose hypometabolism of the frontal and temporal lobes, respectively. Based on the clinical findings, a genetic analysis was performed which revealed a heterozygous c.277CT (p.Arg93Cys) mutation of the VCP gene, thus confirming the diagnosis of IBMPFD (I: nclusion B: ody M: yopathie with P: aget Disease of the Bones and F: ronto-temporal D: ementia).Mutationen des humanen VCP-Gens, welches für das Valosin-enthaltende Protein (

ZusammenfassungMutationen des humanen VCP-Gens, welches für das Valosin-enthaltende Protein (engl. Valosin Containing Protein; Synonyme: p97, TER ATPase) kodiert, sind mit verschiedenen multisystemischen Proteinaggregationserkrankungen assoziiert. Wir stellen einen Patienten vor, der an einer progressiven Myopathie und beginnenden kognitiven Defiziten leidet. In der diagnostischen Muskelbiospie zeigte sich das Bild einer Einschlusskörpermyopathie mit Proteinaggregaten. Die kraniale MRT- und F18-FDG-PET/CT Bildgebung erbrachte den Nachweis einer deutlichen fronto-temporalen Atrophie sowie einer fronto-temporalen Hypoperfusion. Basierend auf der klinischen Symptomatik des Patienten erfolgte eine molekulargenetische Diagnostik, die eine heterozygote c.277C>T (p.Arg93Cys) Mutation des VCP-Gens detektierte, so dass abschließend die Diagnose einer IBMPFD (engl. Inclusion Body Myopathie with Paget Disease of the Bones and Fronto-temporal Dementia) gestellt werden konnte.

Efficient delivery of functional nucleic acids into specific cells or tissues is still a challenge for gene therapy and largely depends on targeted delivery strategies. The folate receptor (FR) is known to be overexpressed extracellularly on a variety of human cancers and is therefore an outstanding gate for tumor-targeted Trojan horse-like delivery of therapeutics. In this study, an amphiphilic and biodegradable ternary copolymer conjugated with folate as ligand, polyethylenimine-graft-polycaprolactone-block-poly(ethylene glycol)-folate (PEI-PCL-PEG-Fol) was synthesized and evaluated for targeted siRNA delivery via folate-FR recognition. The amphiphilic character of similar polymers was shown previously to support endosomal release of endocytosed nanocarriers and to promote formation of long circulating micelles. The obtained PEI-PCL-PEG-Fol exhibited less cytotoxicity in comparison with the corresponding ternary copolymer without folate (PEI-PCL-PEG) and with unmodified PEI25kDa. Stable micelle-like polyplexes with hydrodynamic diameters about 100 nm were found to have a zeta potential of +8.6 mV, which was lower than that of micelleplexes without folate-conjugation (+13-16 mV). Nonetheless, increased cellular uptake and in vitro gene knockdown of PEI-PCL-PEG-Fol/siRNA micelleplexes were observed in SKOV-3 cells, an FR overexpressing cell line, in comparison with the nonfolate-conjugated ones. Moreover, PEI-PCL-PEG-Fol/siRNA micelleplexes exhibited excellent stability in vivo during the analysis of 120 min and a longer circulation half life than hyPEI25kDa/siRNA polyplexes. Most interestingly, the targeted delivery system yielded 17% deposition of the i.v. injected siRNA per gram in the tumor after 24 h due to the effective folate targeting and the prolonged circulation.

Ein 59-jahriger Patient wurde mit rezidivierender Flush-Symptomatik und pathologisch erhohter 5-Hydroxyindolessigsaure im Sammelurin eingewiesen. Eine seit Jahren bekannte und als bland eingestufte Leberzyste konnte als Metastase einer neuroendokrinen Neoplasie des Ileums identifiziert werden. In zwei aufeinanderfolgenden Operationen wurde sowohl der Primartumor mit den mesenterialen Lymphknotenmetastasen als auch die zystische Lebermetastase reseziert. Nach Abschluss der operativen Behandlung verblieben eine R1-Situation mesenterial sowie paraaortale Lymphknoten mit Verdacht auf Metastasenbefall. Bei bekannter Einnahme von Phenprocoumon aufgrund einer Faktor-V-Leiden-Mutation wurde eine Therapie mit Lanreotid Autogel alle 4 Wochen tief s.c. eingeleitet. Hierunter blieb die Erkrankung stabil und bis heute ohne erneute klinische Zeichen eines Karzinoidsyndroms.

A 79-year-old patient presented with weight loss, subfebrile body temperature and unclear jaw pain. After ruling out malignant and infectious causes, positron emission tomography-computed tomography (PET-CT) revealed markedly elevated glucose utilization of the large thoracic and upper limb arteries, suggesting systemic vasculitis. Color-coded duplex sonography confirmed thickening of the wall of the external carotid artery consistent with vasculitis. The patient was diagnosed with giant cell arteritis involving the large thoracic arteries and the upper limb arteries but without involvement of the superficial temporal artery. Based on the involvement of the external carotid artery, the jaw pain could be classified as jaw claudication. Clinical and laboratory remission was achieved with systemic glucocorticoids which could subsequently be tapered. The patient is well and asymptomatic 12 months after diagnosis and 2 months without steroids.

The aim of this study is to investigate the feasibility and efficacy of PEC nanoparticles as delivery system for cancer chemotherapy. Assembly of paclitaxel-loaded nanoparticles with high loading efficiency and narrow-size distribution is successful. For non-invasive in vivo tracing, nanoparticle blends of chelator bearing poly(lactide) with PEC and PLGA are successfully prepared. Pharmacokinetic studies in mice reveal a twofold higher circulation time of PEC as compared to PLGA. A tumor model shows an accumulation of PEC NPs in cancerous tissue and a higher anti-tumor efficiency compared to the standard Taxol™, which is reflected in a significantly slower tumor growth compared to the NaCl control group.

A family of triazine dendrimers, differing in their core flexibility, generation number, and surface functionality, was prepared and evaluated for its ability to accomplish RNAi. The dendriplexes were analyzed with respect to their physicochemical and biological properties, including condensation of siRNA, complex size, surface charge, cellular uptake and subcellular distribution, their potential for reporter gene knockdown in HeLa/Luc cells, and ultimately their stability, biodistribution, pharmacokinetics and intracellular uptake in mice after intravenous (iv.) administration. The structure of the backbone was found to significantly influence siRNA transfection efficiency, with rigid, second generation dendrimers displaying higher gene knockdown than the flexible analogues while maintaining less off-target effects than Lipofectamine. Additionally, among the rigid, second generation dendrimers, those with either arginine-like exteriors or peripheries containing hydrophobic functionalities mediated the most effective gene knockdown, thus showing that dendrimer surface groups also affect transfection efficiency. Moreover, these two most effective dendriplexes were stable in circulation upon intravenous administration and showed passive targeting to the lung. Both dendriplex formulations were taken up into the alveolar epithelium, making them promising candidates for RNAi in the lung. The ability to correlate the effects of triazine dendrimer core scaffolds, generation number, and surface functionality with siRNA transfection efficiency yields valuable information for further modifying this non-viral delivery system and stresses the importance of only loosely correlating effective gene delivery vectors with siRNA transfection agents.

In search of optimizing siRNA delivery systems for systemic application, one critical parameter remains their stability in blood circulation. In this study, we have traced pharmacokinetics and biodistribution of each component of siRNA polyplexes formed with polyethylenimine 25 kDa (PEI) or PEGylated PEIs by in vivo real-time gamma camera recording, SPECT imaging, and scintillation counting of blood samples and dissected organs. In vivo behavior of siRNA and polymers were compared and interpreted in the context of in vivo stability of the polyplexes which had been measured by fluorescence fluctuation spectroscopy (FFS). Both pharmacokinetics and biodistribution of polymer-complexed siRNA were dominated by the polymer. PEGylated polymers and their siRNA polyplexes showed significantly less uptake into liver (13.6-19.7% ID of PEGylated polymer and 9.5-10.2% ID of siRNA) and spleen compared to PEI 25 kDa (liver deposition: 36.2% ID of polymer and 14.6% ID of siRNA). With non-invasive imaging methods we were able to predict both kinetics and deposition in living animals allowing the investigation of organ distribution in real time and at different time points. FFS measurements proved stability of the applied polyplexes under in vivo conditions which explained the different behavior of complexed from free siRNA. Despite their stability in circulation, we observed that polyplexes dissociated upon liver passage. Therefore, siRNA/(PEG-)PEI delivery systems are not suitable for systemic administration, but instead may be useful when the first-pass effect is circumvented, which is the case in local application.

This study describes the physicobiological characterization of PEI- and PEG-PEI polyplexes containing partially 2'-OMe modified 25/27mer dicer substrate siRNAs (DsiRNAs) and their in vivo behavior regarding biodistribution and systemic bioavailability after pulmonary application as well as their ability to knock down gene expression in the lung. Biophysical characterization included circular dichroism of siRNA in polyplexes, condensation efficiency of polymers and in vitro stability. After in vivo application, biodistribution and kinetics of radiolabeled polyplexes were quantified and recorded over time in three-dimensional SPECT images and by end point scintillation counting. The influence on lung tissue and on the humoral and cellular immunosystem was investigated, and finally knockdown of endogenous gene expression in the lung was determined qualitatively. While all of the polymers used in our study were proven to effectively condense siRNA, stability of the complexes depended on the PEG grafting degree. Interestingly, PEI 25 kDa, which showed the least interaction with mucin or surfactant in vitro, performed poorly in vivo. Our nuclear imaging approach enabled us to follow biodistribution of the instilled nanocarriers over time and indicated that PEGylated nanocarriers are more suitable for lung application. While moderate proinflammatory effects were attributed to PEI25k-PEG(2k)(10) nanocarriers, none of the treatments caused histological abnormalities. Our preliminary in vivo knockdown experiment suggests that PEG-PEI/siRNA complexes are promising nanomedicines for pulmonary siRNA delivery. These results encouraged us to further investigate possible adverse effects and to quantify in vivo gene silencing in the lung after intratracheal instillation of PEG-PEI/siRNA complexes.

INTRODUCTION Inhaled drugs can only be effective if they reach the middle and small airways. This study introduces a system that combines a trans-nasal application of aerosols with noninvasive pressure support ventilation. METHODS In a pilot study, 7 COPD patients with GOLD stages II and III inhaled a radiolabeled marker dissolved in water via a trans-nasal route. The mean aerosol particle size was 5.5 µm. Each patient took part in two inhalation sessions that included two application methods and were at least 70 hours apart. During the first session ("passive method"), the patient inhaled the aerosol through an open tube system. The second session ("active method") included pressure support ventilation during the inhalation process. A gamma camera and planar scintigraphy was used to determine the distribution of aerosol particles in the patient's body and lung. RESULTS The pressure supported inhalation ("active method") results in an increased aerosol lung deposition compared to the passive method. Above all, we could demonstrate deposition in the lung periphery with relatively large aerosol particles (5.5 µm). DISCUSSION The results prove that the combination of trans-nasal inhalation with noninvasive pressure support ventilation leads to significantly increased particle deposition in the lung., Einleitung: lnhalativ applizierte Medikamente können ihre Wirkung nur dann besonders effektiv entfalten, wenn sie bis in die mittleren und kleinen Atemwege gelangen. Das vorgestellte Verfahren kombiniert eine transnasale Aerosolapplikation mit einer pneumatischen Schienung der kleinen Atemwege. Methode: Bei 7 Patienten mit COPD im Stadium II und III nach GOLD erfolgte eine transnasale Inhalation eines in Wasser gelösten radiopharmakologischen Marker-Präparats bei einer mittleren Partikelgröße von 5,5 µm. Bei allen Patienten wurden in einem Abstand von mindestens 70 Stunden zwei unterschiedliche Applikationsmethoden angewandt. Bei der ersten („passiv“) inhalierte der Patient transnasal durch ein offenes Schlauchsystem, bei der zweiten („aktiv“) erfolgte eine Inhalation mit Atmungsunterstützung durch positiven Atemwegsdruck (pneumatische Schienung). Die planaren Szintigramme der Lunge sowie des Ganzkörpers wurden angefertigt, um die Verteilung der Aerosolteilchen zu detektieren. Ergebnisse: Bei der unter nichtinvasiver druckunterstützter Atmung („aktiv“) durchgeführten transnasalen Inhalation kommt es, im Vergleich zur „passiven“ Inhalation, zu einer erhöhten Deposition des Aerosols in der Lunge. Darüber hinaus konnte bei der „aktiven“ und „passiven“ Inhalation ein Nachweis von Aerosolpartikeln in der Lungenperipherie bei verhältnismäßig großen Aerosolteilchen (5,5 µm) beobachtet werden. Diskussion: Die Ergebnisse belegen, dass die Kombination aus transnasaler Inhalation und nichtinvasiver druckunterstützender Beatmung (pneumatische Schienung) zu einer deutlich verbesserten Partikeldeposition in der Lunge führt.

With the aim to develop beneficial tracers for cerebral tumors, we tested two novel 5-iodo-2'-deoxyuridine (IUdR) derivatives, diesterified at the deoxyribose residue. The substances were designed to enhance the uptake into brain tumor tissue and to prolong the availability in the organism. We synthesized carrier added 5-[125I]iodo-3',5'-di-O-acetyl-2'-deoxyuridine (Ac2[125I]IUdR), 5-[125I]iodo-3',5'-di-O-pivaloyl-2'-deoxyuridine (Piv2[125I]IUdR) and their respective precursor molecules for the first time. HPLC was used for purification and to determine the specific activities. The iodonucleoside tracer were tested for their stability against human thymidine phosphorylase. DNA integration of each tracer was determined in 2 glioma cell lines (Gl261, CRL2397) and in PC12 cells in vitro. In mice, we measured the relative biodistribution and the tracer uptake in grafted brain tumors. Ac2[125I]IUdR, Piv2[125I]IUdR and [125I]IUdR (control) were prepared with labeling yields of 31-47% and radiochemical purities of >99% (HPLC). Both diesterified iodonucleoside tracers showed a nearly 100% resistance against degradation by thymidine phosphorylase. Ac2[125I]IUdR and Piv2[125I]IUdR were specifically integrated into the DNA of all tested tumor cell lines but to a less extend than the control [125I]IUdR. In mice, 24 h after i.p. injection, brain radioactivity uptakes were in the following order Piv2[125I]IUdR>Ac2[125I]IUdR>[125I]IUdR. For Ac2[125I]IUdR we detected lower amounts of radioactivities in the thyroid and stomach, suggesting a higher stability toward deiodination. In mice bearing unilateral graft-induced brain tumors, the uptake ratios of tumor-bearing to healthy hemisphere were 51, 68 and 6 for [125I]IUdR, Ac2[125I]IUdR and Piv2[125I]IUdR, respectively. Esterifications of both deoxyribosyl hydroxyl groups of the tumor tracer IUdR lead to advantageous properties regarding uptake into brain tumor tissue and metabolic stability.

Radiotherapy of head and neck malignancies results in severe damage to salivary glands. Irradiation-induced sialadenitis with xerostomia leads to a significant deterioration of the quality of life which lasts life-long. Here we show in a preliminary study that intraglandular application of botulinum toxin performed prior to radiation reduces significantly the radiation induced toxicity of the glandular tissue in rats.

The DNAzyme hgd40 was shown to effectively reduce expression of the transcription factor GATA-3 RNA which plays an important role in the regulation of Th2-mediated immune mechanisms such as in allergic bronchial asthma. However, uptake, biodistribution and pharmacokinetics of hgd40 have not been investigated yet. We examined local and systemic distribution of hgd40 in naive mice and mice suffering from experimental asthma. Furthermore, we evaluated the pharmacokinetics as a function of dose following single and repeated administration in rats and dogs. Using intranasal administration of fluorescently labeled hgd40 we demonstrated that the DNAzyme was evenly distributed in inflamed asthmatic mouse lungs within minutes after single dose application. Systemic distribution was investigated in mice using radioactive labeled hgd40. After intratracheal application, highest amounts of hgd40 were detected in the lungs. High amounts were also detected in the bladder indicating urinary excretion as a major elimination pathway. In serum, low systemic hgd40 levels were detected already at 5 min post application (p.a.), subsequently decreasing over time to non-detectable levels at 2h p.a. As revealed by Single Photon Emission Computed Tomography, trace amounts of hgd40 were detectable in lungs up to 7 days p.a. Also in the toxicologically relevant rats and dogs, hgd40 was detectable in blood only shortly after inhalative application. The plasma pharmacokinetic profile was dose and time dependent. Repeated administration did not lead to drug accumulation in plasma of dogs and rats. These pharmacokinetic of hgd40 provide guidance for clinical development, and support an infrequent and convenient dose administration regimen.

We investigated the effect of targeted gene therapy on heat shock protein 70 (Hsp70) expression in a melanoma tumor model (M21). M21 cells transfected with a plasmid containing the firefly luciferase reporter gene (ffluc), whose expression is driven by the hsp70 (hspa1b) or the cytomegalovirus (CMV) promoter, were grown to a size of 600 mm3. Five animals in each group were intravenously treated with an Arg-Gly-Asp peptide-nanoparticle/Raf-1 kinase inhibitor protein [RGD-NP/RAF(-)] complex. Bioluminescence imaging (BLI) (IVIS, Xenogen, Alameda, CA) was performed at set time intervals. Western blot analysis of the HSP70 protein was simultaneously performed. The size of the treated M21 tumors was nearly constant (637.8 ± 33.4 mm3 vs 674.8 ± 34.4 mm3). BLI showed that if transcription was controlled by the CMV promoter, firefly luciferase activity decreased to 51.1% ± 8.3%. When transcription was controlled by the hsp70 promoter, the highest firefly luciferase activity (4.4 ± 0.3-fold) was observed after 24 hours. In accordance with BLI, Western blot analysis showed an increase in the level of HSP70, with the maximum detection 24 hours after the injection of the RGD-NP/RAF(-) complex. Targeted antiangiogenic therapy can induce luciferase activity where transcription is controlled by an hsp70 promoter and HSP70 protein in melanoma tumors.