Evaluating the photodynamic efficacy of nebulized curcumin-loaded liposomes prepared by thin-film hydration and dual centrifugation: In vitro and in ovo studies.

Lung cancer, one of the most common causes of high mortality worldwide, still lacks appropriate and convenient treatment options. Photodynamic therapy (PDT) has shown promising results against cancer, especially in recent years. However, pulmonary drug delivery of the predominantly hydrophobic photosensitizers still represents a significant obstacle. Nebulizing DPPC/Cholesterol liposomes loaded with the photosensitizer curcumin via a vibrating mesh nebulizer might overcome current restrictions. In this study, the liposomes were prepared by conventional thin-film hydration and two other methods based on dual centrifugation. The liposomes' physicochemical properties were determined before and after nebulization, showing that liposomes do not undergo any changes. However, morphological characterization of the differently prepared liposomes revealed structural differences between the methods in terms of lamellarity. Internalization of curcumin in lung adenocarcinoma (A549) cells was visualized and quantified. The generation of reactive oxygen species because of the photoreaction was also proven. The photodynamic efficacy of the liposomal formulations was tested against A549 cells. They revealed different phototoxic responses at different radiant exposures. Furthermore, the photodynamic efficacy was investigated after nebulizing curcumin-loaded liposomes onto xenografted tumors on the CAM, followed by irradiation, and evaluated using positron emission tomography/computed tomography and histological analysis. A decrease in tumor metabolism could be observed. Based on the efficacy of curcumin-loaded liposomes in 2D and 3D models, liposomes, especially with prior film formation, can be considered a promising approach for PDT against lung cancer.

In vitro and in ovo photodynamic efficacy of nebulized curcumin-loaded tetraether lipid liposomes prepared by DC as stable drug delivery system.

Lung cancer is one of the most common causes of high mortality worldwide. Current treatment strategies, e.g., surgery, radiotherapy, chemotherapy, and immunotherapy, insufficiently affect the overall outcome. In this study, we used curcumin as a natural photosensitizer in photodynamic therapy and encapsulated it in liposomes consisting of stabilizing tetraether lipids aiming for a pulmonary drug delivery system against lung cancer. The liposomes with either hydrolyzed glycerol-dialkyl-glycerol tetraether (hGDGT) in different ratios or hydrolyzed glycerol-dialkyl-nonitol tetraether (hGDNT) were prepared by dual centrifugation (DC), an innovative method for liposome preparation. The liposomes' physicochemical characteristics before and after nebulization and other nebulization characteristics confirmed their suitability. Morphological characterization using atomic force and transmission electron microscopy showed proper vesicular structures indicative of liposomes. Qualitative and quantitative uptake of the curcumin-loaded liposomes in lung adenocarcinoma (A549) cells was visualized and proven. Phototoxic effects of the liposomes were detected on A549 cells, showing decreased cell viability. The generation of reactive oxygen species required for PDT and disruption of mitochondrial membrane potential were confirmed. Moreover, the chorioallantoic membrane (CAM) model was used to further evaluate biocompatibility and photodynamic efficacy in a 3D cell culture context. Photodynamic efficacy was assessed by PET/CT after nebulization of the liposomes onto the xenografted tumors on the CAM with subsequent irradiation. The physicochemical properties and the efficacy of tetraether lipid liposomes encapsulating curcumin, especially liposomes containing hGDNT, in 2D and 3D cell cultures seem promising for future PDT usage against lung cancer.

Radiotracers for Imaging of Inflammatory Biomarkers TSPO and COX-2 in the Brain and in the Periphery.

Inflammation involves the activation of innate immune cells and is believed to play an important role in the development and progression of both infectious and non-infectious diseases such as neurodegeneration, autoimmune diseases, pulmonary and cancer. Inflammation in the brain is marked by the upregulation of translocator protein (TSPO) in microglia. High TSPO levels are also found, for example, in macrophages in cases of rheumatoid arthritis and in malignant tumor cells compared to their relatively low physiological expression. The same applies for cyclooxgenase-2 (COX-2), which is constitutively expressed in the kidney, brain, thymus and gastrointestinal tract, but induced in microglia, macrophages and synoviocytes during inflammation. This puts TSPO and COX-2 in the spotlight as important targets for the diagnosis of inflammation. Imaging modalities, such as positron emission tomography and single-photon emission tomography, can be used to localize inflammatory processes and to track their progression over time. They could also enable the monitoring of the efficacy of therapy and predict its outcome. This review focuses on the current development of PET and SPECT tracers, not only for the detection of neuroinflammation, but also for emerging diagnostic measures in infectious and other non-infectious diseases such as rheumatic arthritis, cancer, cardiac inflammation and in lung diseases.

Modern Photodynamic Glioblastoma Therapy Using Curcumin- or Parietin-Loaded Lipid Nanoparticles in a CAM Model Study.

Natural photosensitizers, such as curcumin or parietin, play a vital role in photodynamic therapy (PDT), causing a light-mediated reaction that kills cancer cells. PDT is a promising treatment option for glioblastoma, especially when combined with nanoscale drug delivery systems. The curcumin- or parietin-loaded lipid nanoparticles were prepared via dual asymmetric centrifugation and subsequently characterized through physicochemical analyses including dynamic light scattering, laser Doppler velocimetry, and atomic force microscopy. The combination of PDT and lipid nanoparticles has been evaluated in vitro regarding uptake, safety, and efficacy. The extensive and well-vascularized chorioallantois membrane (CAM) of fertilized hen's eggs offers an optimal platform for three-dimensional cell culture, which has been used in this study to evaluate the photodynamic efficacy of lipid nanoparticles against glioblastoma cells. In contrast to other animal models, the CAM model lacks a mature immune system in an early stage, facilitating the growth of xenografts without rejection. Treatment of xenografted U87 glioblastoma cells on CAM was performed to assess the effects on tumor viability, growth, and angiogenesis. The xenografts and the surrounding blood vessels were targeted through topical application, and the effects of photodynamic therapy have been confirmed microscopically and via positron emission tomography and X-ray computed tomography. Finally, the excised xenografts embedded in the CAM were analyzed histologically by hematoxylin and eosin and KI67 staining.

Photoactive Parietin-loaded nanocarriers as an efficient therapeutic platform against triple-negative breast cancer.

The application of photodynamic therapy has become more and more important in combating cancer. However, the high lipophilic nature of most photosensitizers limits their parenteral administration and leads to aggregation in the biological environment. To resolve this problem and deliver a photoactive form, the natural photosensitizer parietin (PTN) was encapsulated in poly(lactic-co-glycolic acid) nanoparticles (PTN NPs) by emulsification diffusion method. PTN NPs displayed a size of 193.70 nm and 157.31 nm, characterized by dynamic light scattering and atomic force microscopy, respectively. As the photoactivity of parietin is essential for therapy, the quantum yield of PTN NPs and the in vitro release were assessed. The antiproliferative activity, the intracellular generation of reactive oxygen species, mitochondrial potential depolarization, and lysosomal membrane permeabilization were evaluated in triple-negative breast cancer cells (MDA-MB-231 cells). At the same time, confocal laser scanning microscopy (CLSM) and flow cytometry were used to investigate the cellular uptake profile. In addition, the chorioallantoic membrane (CAM) was employed to evaluate the antiangiogenic effect microscopically. The spherical monomodal PTN NPs show a quantum yield of 0.4. The biological assessment on MDA-MB-231 cells revealed that free PTN and PTN NPs inhibited cell proliferation with IC50 of 0.95 µM and 1.9 µM at 6 J/cm2, respectively, and this can be attributed to the intracellular uptake profile as proved by flow cytometry. Eventually, the CAM study illustrated that PTN NPs could reduce the number of angiogenic blood vessels and disrupt the vitality of xenografted tumors. In conclusion, PTN NPs are a promising anticancer strategy in vitro and might be a tool for fighting cancer in vivo.

Diagnostic Impact of Dual-Time PET/CT with 68Gallium-PSMA in Prostate Cancer and 68Gallium-DOTATOC in Neuroendocrine Tumors.

BACKGROUND: The timing of imaging for 68gallium (68Ga)-PSMA and 68Ga-DOTATOC are stated to be around 60 min post-injection (p.i.). In some lesions, late imaging (3-4 h p.i.) showed advantages. The aim of our evaluation was to demonstrate the relevance of an "early" late acquisition. METHODS: We retrospectively evaluated 112 patients who underwent 68Ga-DOTATOC-PET/CT and 82 patients who underwent 68Ga-PSMA-PET/CT. The first scan was acquired 60 min (±15 min) after application. In cases of diagnostic ambiguity, a second scan was performed 30-60 min later. Pathological lesions were analyzed. RESULTS: Almost half of all 68Ga-DOTATOC cases and about one-third of all 68Ga-PSMA examinations showed a change in findings due to the second acquisition. In total, 45.5% of neuroendocrine tumor (NET) patients and 66.7% of prostate cancer (PCa) patients showed relevant TNM classification changes. For 68Ga-PSMA, there were significant increases in sensitivity and specificity from 81.8% to 95.7% and from 66.7% to 100%, respectively. Statistically significant improvements in sensitivity (from 53.3% to 93.3%) and specificity (from 54.6% to 86.4%) were demonstrated for NET patients. CONCLUSION: Early second images can improve diagnostics with 68Ga-DOTATOC and 68Ga-PSMA PET/CT.

How to Xenograft Cancer Cells on the Chorioallantoic Membrane of a Fertilized Hen's Egg and Its Visualization by PET/CT and MRI.

The chorioallantoic membrane (CAM) of fertilized hen's eggs represents a unique and alternative model for cancer research. The CAM model provides an optimal platform for xenografting cancer cell lines and studying essential key factors. Tumor size and growth as well as angiogenesis can be investigated to evaluate the response of therapies and strategies against cancer. Preclinical imaging represented by magnetic resonance imaging and positron emission tomography/computed tomography can generate detailed anatomical and functional information and reveal excellent metabolic sensitivity. In the following, a guideline is introduced in order to find a simplified entrance to the CAM model in combination with modern preclinical imaging techniques. Finally, the presented procedures are additionally completed by histological studies in the form of hematoxylin and eosin as well as immunohistochemical staining.

Adoption of Lutetium-177 PSMA radioligand therapy for metastatic castration resistant prostate cancer: a total population analysis in Germany from 2016 to 2020.

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 < 0.005). In 2016, 25 departments of nuclear medicine offered this treatment, which increased to 44 nuclear medicine departments in 2020. In 2016, 16% of nuclear medicine departments (4/25) performed more than 100 177Lu-PSMA RLTs, which increased to 36% (16/44) in 2020 (p < 0.005). In 2016, 88% (22/25) of 177Lu-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. 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.

Basal cell adhesion molecule promotes metastasis-associated processes in ovarian cancer.

BACKGROUND: Basal cell adhesion molecule (BCAM) is a laminin α5 (LAMA5) binding membrane-bound protein with a putative role in cancer. Besides full-length BCAM1, an isoform lacking most of the cytoplasmic domain (BCAM2), and a soluble form (sBCAM) of unknown function are known. In ovarian carcinoma (OC), all BCAM forms are abundant and associated with poor survival, yet BCAM's contribution to peritoneal metastatic spread remains enigmatic. METHODS: Biochemical, omics-based and real-time cell assays were employed to identify the source of sBCAM and metastasis-related functions of different BCAM forms. OC cells, explanted omentum and a mouse model of peritoneal colonisation were used in loss- and gain-of-function experiments. RESULTS: We identified ADAM10 as a major BCAM sheddase produced by OC cells and identified proteolytic cleavage sites proximal to the transmembrane domain. Recombinant soluble BCAM inhibited single-cell adhesion and migration identically to membrane-bound isoforms, confirming its biological activity in OC. Intriguingly, this seemingly anti-tumorigenic potential of BCAM contrasts with a novel pro-metastatic function discovered in the present study. Thus, all queried BCAM forms decreased the compactness of tumour cell spheroids by inhibiting LAMA5 - integrin ß1 interactions, promoted spheroid dispersion in a three-dimensional collagen matrix, induced clearance of mesothelial cells at spheroid attachment sites in vitro and enhanced invasion of spheroids into omental tissue both ex vivo and in vivo. CONCLUSIONS: Membrane-bound BCAM as well as sBCAM shed by ADAM10 act as decoys rather than signalling receptors to modulate metastasis-related functions. While BCAM appears to have tumour-suppressive effects on single cells, it promotes the dispersion of OC cell spheroids by regulating LAMA5-integrin-ß1-dependent compaction and thereby facilitating invasion of metastatic target sites. As peritoneal dissemination is majorly mediated by spheroids, these findings offer an explanation for the association of BCAM with a poor clinical outcome of OC, suggesting novel therapeutic options.

Diagnostic value of FDG-PET/CT in the diagnostic work-up of inflammation of unknown origin.

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.

Real-Life Performance of F-18-FDG PET/CT in Patients with Cervical Lymph Node Metastasis of Unknown Primary Tumor.

BACKGROUND: Neoplasms in the head and neck region possess higher glycolytic activity than normal tissue, showing increased glucose metabolism. F-18-Flourodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) can identify an unknown primary tumor (CUP). AIM: The aim of this study was to assess the real-life performance of F-18-FDG-PET/CT in detecting primary sites in patients with cervical lymph node metastasis of CUP. METHODS: A retrospective data analysis of 31 patients who received FDG-PET/CT between June 2009 and March 2015 in a CUP context with histologically confirmed cervical lymph node metastasis was included. RESULTS: In 48% of the patients (15/31), PET/CT showed suspicious tracer accumulation. In 52% of the patients (16/31), there was no suspicious radiotracer uptake, which was confirmed by the lack of identification of any primary tumor in 10 cases until the end of follow-up. FDG-PET/CT had a sensitivity of 67%, specificity of 91%, PPV of 92%, and NPV of 63% in detecting the primary tumor. Additionally, PET/CT showed suspicious tracer accumulation according to further metastasis in 32% of the patients (10/31). CONCLUSION: FDG-PET/CT imaging is a useful technique for primary tumor detection in patients in a cervical CUP context. Furthermore, it provides information on the ulterior metastasis of the disease.

Progressive Olfactory Impairment and Cardiac Sympathetic Denervation in REM Sleep Behavior Disorder.

BACKGROUND: Isolated rapid eye movement sleep behavior disorder (iRBD) is prodromal for Parkinson's disease (PD) and dementia with Lewy bodies (DLB). OBJECTIVE: We investigated the use of cardiac [123I]meta-iodo-benzyl-guanidine scintigraphy ([123I]MIBG) and olfactory testing- in comparison to [123I]N-ω-fluoropropyl-2ß-carbomethoxy-3ß-(4-iodophenyl)nortropane single photon emission computed tomography ([123I]FP-CIT-SPECT)- for identifying iRBD patients as prodromal phenotype of PD/DLB. METHODS: 37 RBD subjects underwent cardiac [123I]MIBG and brain [123I]FP-CIT-SPECT at baseline. Olfactory (Sniffin' Sticks), cognitive and motor functions were tested annually for ∼4 years. RESULTS: 29/37 (78.4%) subjects had a pathological [123I]MIBG, of whom 86.2% (25/29) presented at least a moderate hyposmia at baseline (threshold/discrimination/identification-(TDI-)score ≤25). 20/37 (54.1%) subjects had a pathological [123I]FP-CIT-SPECT, always combined with a pathological [123I]MIBG. In subjects with pathological [123I]MIBG, olfactory function worsened (mainly due to threshold and discrimination subscores) from baseline to follow-up (p = 0.005). Olfaction was more impaired in subjects with pathological [123I]MIBG compared to those with normal [123I]MIBG at baseline (p = 0.001) and follow-up (p < 0.001). UPDRS-III scores increased in subjects with both pathological [123I]MIBG and [123I]FP-CIT-SPECT. In this group, seven subjects phenoconverted to PD, all- except for one- presented with at least moderate hyposmia at baseline. CONCLUSION: A combination of the biomarkers "pathological [123I]MIBG" and "hyposmia" likely identifies iRBD patients in an early prodromal stage of PD/DLB, i.e., before nigrostriatal degeneration is visualized. One-third of the subjects with pathological [123I]MIBG had a normal [123I]FP-CIT-SPECT. Noteworthy, in iRBD subjects with pathological [123I]MIBG, olfactory impairment is progressive independent of the [123I]FP-CIT-SPECT status.

[High clinical value of bone scintigraphy as a staging method for breast cancer]. / Hohe klinische Wertigkeit der Skelettszintigrafie beim Staging des Mammakarzinoms.

BACKGROUND: 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. AIM: 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. PATIENTS AND METHODS: 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. RESULTS: 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%. CONCLUSION: 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.

Evaluation of machine learning strategies for imaging confirmed prostate cancer recurrence prediction on electronic health records.

BACKGROUND: 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. PURPOSE: 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). METHODS: 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). RESULTS: 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. CONCLUSION: 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.

Prostate-Specific Membrane Antigen in Anaplastic and Poorly Differentiated Thyroid Cancer-A New Diagnostic and Therapeutic Target?

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.

Multicenter Analysis of Presacral Neuroendocrine Neoplasms-Clinicopathological Characterization and Treatment Outcomes of a Rare Disease.

Background and Aims: Neuroendocrine neoplasms (NENs) of the presacral space are an extremely rare disease entity with largely unknown outcome and no established standard of care treatment. Therefore, we wanted to analyze clinical presentation, histopathological findings, treatment outcomes, and prognosis in a multicentric patient cohort. Methods: We searched local databases of six German NEN centers for patients with presacral NEN. Retrospective descriptive analyses of age, sex, stage at diagnosis, symptoms, grade, immunohistochemical investigations, biomarkers, treatment, and treatment outcome were performed. Kaplan-Meier analysis was used to determine median overall survival. Results: We identified 17 patients (11 female, 6 male) with a median age of 50 years (range, 35-66) at diagnosis. Twelve cases presented initially with distant metastases including bone metastases in nine cases. On pathological review the majority of patients had well-differentiated G2 tumors. Immunohistochemical profile resembled rectal NENs. All but one patient had non-functioning tumors. Somatostatin receptor imaging was positive in 14 of 15 investigated cases. Eight patients were treated surgically including palliative resections; 14 patients received somatostatin analogs with limited efficacy. With 14 PRRTs completed, 79% showed clinical benefit, whereas only one patient with neuroendocrine carcinoma (NEC) responded to chemotherapy. Treatment with everolimus in three patients was not successful, whereas cabozantinib resulted in a disease stabilization in a heavily pretreated patient. During a median observation period of 44.5 months, 6 patients died. Median overall survival was not reached. Conclusion: Presacral NEN are histopathologically similar to rectal NENs. Presacral NEN should be considered as possible primary in NEN of unknown primary. The majority of tumors is non-functioning and somatostatin receptor positive. PRRT demonstrated promising activity; tyrosine kinase inhibitors warrant further investigations. Further molecular characterization and prospective evaluation of this rare tumor entity are needed.

Clinical Relevance of [18F]Florbetaben and [18F]FDG PET/CT Imaging on the Management of Patients with Dementia.

PET of ß-Amyloid plaques (Aß) using [18F]florbetaben ([18F]FBB) and [18F]fluorodeoxyglucose ([18F]FDG) increasingly aid clinicians in early diagnosis of dementia, including Alzheimer's disease (AD), frontotemporal disease, dementia with Lewy bodies, and vascular dementia. The aim of this retrospective analysis was to evaluate clinical relevance of [18F]FBB, [18F]FDG PET and complimentary CSF measurements in patients with suspected dementia. In this study, 40 patients with clinically suspected or history of dementia underwent (1) measurement of Aß peptides, total tau, and p-tau protein levels in the cerebrospinal fluid (CSF) compared with healthy controls (HC); (2) clinical and neuropsychological assessment, which included Consortium to Establish a Registry for Alzheimer's Disease neuropsychological assessment battery (CERAD-NAB); (3) [18F]FBB and [18F]FDG PET imaging within an average of 3 weeks. The subjects were within 15 days stratified using PET, CSF measurements as HC, mild cognitive impaired (MCI) and dementia including Alzheimer´s disease. The predictive dementia-related cognitive decline values were supporting the measurements. PET images were evaluated visually and quantitatively using standard uptake value ratios (SUVR). Twenty-one (52.5%) subjects were amyloid-positive (Aß+), with a median neocortical SUVR of 1.80 for AD versus 1.20 relative to the respective 19 (47.5 %) amyloid-negative (Aß-) subjects. Moreover, the [18F]FDG and [18F]FBB confirmed within a sub-group of 10 patients a good complimentary role by correlation between amyloid pathology and brain glucose metabolism in 8 out of 10 subjects. The results suggest the clinical relevance for [18F]FBB combined with [18F]FDG PET retention and CFS measurements serving the management of our patients with dementia. Therefore, [18F]FBB combined with [18F]FDG PET is a helpful tool for differential diagnosis, and supports the patients' management as well as treatment.

Perioperative diagnostics of patients referred for radioiodine therapy of differentiated thyroid carcinoma: referral center experience in an iodine-insufficient country.

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.