Correction to: Prognostic Factors in Overall Survival of Patients with Unresectable Intrahepatic Cholangiocarcinoma Treated by Means of Yttrium-90 Radioembolization: Results in Therapy-Naïve Patients.

The published article has an error in the first name initial of one of the authors. "M. Justinger" should be "C. Justinger" as shown in this erratum.

Prognostic Factors in Overall Survival of Patients with Unresectable Intrahepatic Cholangiocarcinoma Treated by Means of Yttrium-90 Radioembolization: Results in Therapy-Naïve Patients.

INTRODUCTION: To investigate prognostic factors in unresectable intrahepatic cholangiocarcinoma (ICC) therapy-naïve patients after yttrium-90 (Y-90) radioembolization (RE) therapy. MATERIALS AND METHODS: Between 2005 and 2016, 21 patients with ICC were treated with Y-90 RE only and their survival data were analyzed. Patients were stratified and response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. RESULT: The overall median survival was 15 months. Survival was significantly (p = 0.009) prolonged in patients with tumor burden of ≤ 25% (n = 8, OS 37.5 months) versus those with a tumor burden of 25-50% (n = 13, OS 15 months). The other variables: tumor morphology (infiltrative vs. peripheral), tumor distribution (solitary vs. multifocal), lobes involved (unilobar vs. bilobar), FDG PET status (FDG avid vs. non-avid), RE treatment sessions (1 session vs. 2 sessions), metastases (metastasis vs. no metastasis) and RECIST criteria, had no significant impact on survival. CONCLUSION: Tumor burden represents a key prognostic factor of survival in therapy-naïve patients with unresectable ICC treated with Y-90 RE therapy only.

Altered serotonin and dopamine transporter availabilities in brain of depressed patients upon treatment with escitalopram: A [123 I]ß-CIT SPECT study.

Altered SERT and DAT availabilities during treatment with escitalopram were investigated with [(123)I]2ß-carbomethoxy-3ß-(4-iodophenyl)tropane (ß-CIT) SPECT in a series of patients fulfilling the criteria for unipolar major depressive disorder (MDD). 27 patients (10m, 42±16y) with diagnosis of MDD were recruited for the study. All patients underwent neuropsychiatric testing for assessment of Hamilton Depression (HAM-D) and Beck Depression Inventory (BDI) scores. At baseline, [(123)I]ß-CIT SPECT recordings were acquired 4h (SERT-weighted) and 20-24h p.i (DAT-weighted). Follow-up scans and neuropsychiatric testing were performed after six weeks of stable escitalopram medication. Voxel-wise parametric maps of specific/ non-specific ratios-1 (~BPND) were calculated. At baseline, DAT-weighted BPND was 5.06±0.81 in striatum and SERT-weighted BPND was 0.94±0.18 in thalamus. There were significant negative correlations with age for DAT in striatum (R=-0.60; p<0.01) and SERT in thalamus (R=-0.45; p<0.05). Under SSRI treatment there was an apparent 42% occupancy of SERT in thalamus (p<0.0001), whereas DAT availability increased significantly by 20% in striatum (p<0.001); higher apparent SERT occupancy in thalamus was associated with lesser DAT increase in striatum (R=-0.62; p<0.005). The low apparent SERT occupancy may be confounded by alterations in SERT expression during treatment. Thus, [(123)I]ß-CIT SPECT revealed age-dependent declines in DAT and SERT availabilities in un-medicated MDD patients, comparable to that seen previously in healthy controls. At follow-up, the SSRI-evoked increase in DAT was less pronounced in the older patients, even though apparent SERT occupancy and clinical improvement were not age-dependent. Present findings may have implications for escitalopram dosage and side effect profile in younger MDD patients.

[Perfusion brain imaging with SPECT-technique. German Guideline S1]. / Hirnperfusions-SPECT mit 99mTc-Radiopharmaka. DGN-Handlungsempfehlung (S1-Leitlinie).

This paper describes the guideline for perfusion brain imaging with SPECT-technique published by the Association of the Scientific Medical Societies in Germany (AWMF).The purpose of this guideline is to provide practical assistance for indication, examination procedures, findings and their interpretation also reflecting the present state of the art. Information and instruction are given regarding indication, preparation of the patients and examination procedures of brain perfusion SPECT, including preparation and quality control of the tracer as well as the radiation dosimetry, technical performance of image acquisition with the gamma-camera and image processing. Also advices for interpretation of findings are given. In addition, possible pitfalls are described.

Dopaminergic neurotransmission in patients with schizophrenia in relation to positive and negative symptoms.

Schizophrenia is a complex dynamic disorder comprising a wide range of neurobiological alterations including dopaminergic dysfunction. The aim of the study was to investigate dynamic changes of dopaminergic neurotransmission in patients with schizophrenia (n=8, mean age 25.4 ± 5.8 years) in early stages of the disorder, compared to healthy control subjects (n=7, mean age 23.6 ± 2.7 years). A dynamic IBZM SPECT protocol was used to assess the endogenous dopamine release following an amphetamine challenge. Subjects received a bolus activity of 175 MBq followed by a continuous infusion of 45 MBq/h [123I]IBZM. SPECT scans were performed 2 h after bolus injection, and 1 h following the amphetamine challenge (0.3 mg/kg). Striatal IBZM binding to dopamine D2 receptors was assessed with a volume-of-interest (VOI) technique. The change in IBZM binding between pre- and post-challenge scans was used as a measure of endogenous dopamine release triggered by amphetamine. At baseline, patients showed higher mean striatal IBZM binding compared to controls (0.77 ± 0.09 vs. 0.68 ± 0.07, p=0.07). There was a statistically significant difference in IBZM binding between patients, with a predominance of negative vs. positive symptoms (0.84 ± 0.08 vs. 0.71 ± 0.04, p<0.05). Upon amphetamine challenge, mean IBZM binding decreased by about 4.9 ± 7.6% in controls (n=7) compared to a mean of 12.4 ± 5.8% in subjects with schizophrenia (p<0.05). In patients, paranoid symptoms showed a significant negative correlation with IBZM baseline binding, whereas there was a trend towards positive correlation with the decrease of IBZM binding under challenge. Negative symptoms showed positive associations with baseline IBZM binding. The data are in line with previous reports and contribute to the notion of a dynamic instability of the dopaminergic system in patients with schizophrenia, taking into account the psychopathology with respect to positive or negative symptoms.

Quantitative approaches to dopaminergic brain imaging.

During the last three decades dopaminergic brain imaging has emerged from a dedicated research tool to a widespread and routinely used application. The rationale behind this development is on the one hand the well known pathologic involvement of the dopaminergic pathway in various neuro-psychiatric diseases, and on the other hand the increasing availability of specific radioligands for picking up pre- and postsynaptic dopaminergic key functions. In particular the commercial availability of SPECT tracers but also the growing number of positron emission tomography/computed tomography (PET/CT) imaging devices has contributed to the steadily increasing number of diagnostic applications. In an era aiming for accurate diagnosis in the early and even preclinical stage of disease, refined methodologies are required to detect even subtle changes. In this context quantification of dopaminergic functions more and more gains importance. Whereas earlier visual assessment was considered sufficient to characterize findings, today refined quantitative tools have the potential to deliver information beyond. This review briefly addresses the development of quantitative methods for dopaminergic brain imaging, from simple manual ratio based applications to various automated methodologies, some of them including tools for correction of physical parameters such as scatter and septal penetration and partial volume effects. Voxel based analysis methods will be covered and also kinetic analyses will be briefly touched. The main focus is directed at SPECT rather than PET methodologies due to the clinical impact of the first. Finally, some thoughts regarding the impact of standardization and harmonization of protocols for imaging and processing will be discussed, including the use of normal data bases for reference.

[German guidelines for brain tumour imaging by PET and SPECT using labelled amino acids]. / PET- und SPECT-Untersuchungen von Hirntumoren mit radioaktiv markierten Aminosäuren.

For the primary diagnosis of brain tumours, morphological imaging by means of magnetic resonance imaging (MRI) is the current method of choice. The complementary use of functional imaging by positron emitting tomography (PET) and single photon emitting computerized tomography (SPECT) with labelled amino acids can provide significant information on some clinically relevant questions, which are beyond the capacity of MRI. These diagnostic issues affect in particular the improvement of biopsy targeting and tumour delineation for surgery and radiotherapy planning. In addition, amino acid labelled PET and SPECT tracers are helpful for the differentiation between tumour recurrence and non-specific post-therapeutic tissue changes, in predicting prognosis of low grade gliomas, and for metabolic monitoring of treatment response. The application of dynamic PET examination protocols for the assessment of amino acid kinetics has been shown to enable an improved non-invasive tumour grading. The purpose of this guideline is to provide practical assistance for indication, examination procedure and image analysis of brain PET/SPECT with labelled amino acids in order to allow for a high quality standard of the method. After a short introduction on pathobiochemistry and radiopharmacy of amino acid labelled tracers, concrete and detailed information is given on the several indications, patient preparation and examination protocols as well as on data reconstruction, visual and quantitative image analysis and interpretation. In addition, possible pitfalls are described, and the relevant original publications are listed for further information.

Radiofrequency ablation after selective internal radiation therapy with Yttrium90 microspheres in metastatic liver disease-Is it feasible?

This retrospective study analyzes, whether patients suffering from extensive hepatic metastatic disease treated with SIRT can become suitable candidates for RFA.Within 38 months 46 patients (26 female, 20 male; age 32-75 years) bearing an extensive hepatic metastatic disease were treated with SIRT. Patients suffered from metastases of breast cancer (16/46), colorectal cancer (CRC) (21/46), neuroendocrine (3/46), and other primary carcinomas (6/46). The indication for SIRT was otherwise untreatable metastases confined to the liver. Forty-three patients received single-session whole-liver radioembolization treatment using Yttrium90 resin microspheres with a mean activity of 2.13GBq. In 1 patient SIRT was confined to the left and in 2 patients to the right liver lobe. In 3 patients major complications (2/3 gastric ulceration and 1/3 oedematous pancreatitis) and in 24 patients minor complications occurred (acute abdominal/epigastric pain and/or nausea). Follow-up CT and/or MRI were obtained in 44 of 46 patients. In 5 of 44 patients tumor load decreased substantially (3/5 breast cancer, 1/5 CRC and 1/5 pancreatic cancer) making RFA feasible. The patients were referred for RFA after the first 3-month follow-up. RFA of the liver was successful in all cases in terms of complete ablation. In selected patients radioembolization is able to downstage liver metastases to an extent making a subsequent RFA suitable and therefore allows increasing the number of patients with a "complete response" after a minimally invasive therapy.

[Therapy response of liver tumors after selective internal radiation therapy]. / Therapieresponse von Lebertumoren nach selektiver interner Radiotherapie.

Selective internal radiation therapy (SIRT) is used for the treatment of patients with liver tumors, especially for those with hepatocellular carcinoma (HCC) or liver metastases from various primary tumors. Currently this innovative treatment concept is recommended when established state-of-the-art treatment regimes have failed and tumor progression is noted or if the treatment has to be abandoned because of intolerable toxic effects. For SIRT small biocompatible microspheres (SIR-Spheres(R)) are labelled with the radioactive isotope 90Yttrium, a pure beta emitter, and are superselectively infused into the hepatic arteries. The microspheres are collected in the precapillary vessels in and surrounding the tumor. The beta radiation of 90Yttrium has an average penetration in tissue of approximately 2.5 mm and results in very high doses of radiation being selectively targeted to metastases providing protection to the surrounding healthy liver tissue. In this paper we review the results of SIRT in patients with hepatic metastases from colorectal cancer, breast cancer, neuroendocrine tumors and primary liver cancer (HCC).

[Diagnosis and treatment of colorectal liver metastases - workflow]. / Diagnostik und Therapie von Lebermetastasen kolorektaler Karzinome - Workflow.

In this review, standards of diagnosis and treatment of colorectal liver metastases are described on the basis of a workshop discussion. Algorithms of care for patients with synchronous / metachronous colorectal liver metastases or locoregional recurrent tumour are presented. Surgical resection is the procedure of choice in the curative treatment of liver metastases. The decision about the resection of liver metastases should consider the following parameters: 1. General operability of the patient (comorbidity); 2. Achievability of an R 0 situation: i. if necessary, in combination with ablative methods, ii. if necessary, neoadjuvant chemotherapy, iii. the ability to eradicate extrahepatic tumour manifestations; 3. Sufficient volume of the liver remaining after resection ("future liver remnant = FLR): i. if necessary, in combination with portal vein embolisation or two-stage hepatectomy; 4. The feasibility to preserve two contiguous hepatic segments with adequate vascular inflow and outflow as well as biliary drainage; 5. Tumour biological aspects ("prognostic variables"); 6. Experience of the surgeon and centre! Extrahepatic disease does not contraindicate hepatectomy for colorectal liver metastases provided a complete resection of both intra- and extrahepatic disease is feasible. Even in bilobar colorectal metastases and 5 or more tumours in the liver, a complete tumour resection has been described. The type of resection (hepatic wedge resection or anatomic resection) does not influence the recurrence rate. Preoperative volumetry is indicated when major hepatic resection is planned. The FLR should be 25 % in patients with normal liver, 40 % in patients who have received intensive chemotherapy or in cases of fatty liver, liver fibrosis or diabetes, and 50-60 % in patients with cirrhosis. In patients with initially unresectable colorectal liver metastases, preoperative chemotherapy enables complete resection in 15-30 % of the cases, whereas the value of neoadjuvant chemotherapy in patients with resectable liver metastases has not been sufficiently supported. In situ ablative procedures (radiofrequency ablation = RFA and laser-induced interstitial thermotherapy = LITT) are local therapy options in selected patients who are not candidates for resection (central recurrent liver metastases, bilobar multiple metastases and high-risk resection or restricted patient operability). Patients with tumours larger than 3 cm have a high local recurrence rate after percutaneous RFA and are not optimal candidates for this procedure. The physician's experience influences the results significantly, both after hepatectomy and after in situ ablation. Therefore, patients with colorectal liver metastases should be treated in centres with experience in liver surgery.

[18F]-FDG-PET in clinical stage I/II non-seminomatous germ cell tumours: results of the German multicentre trial.

PURPOSE: The aim of this study was to determine the predictive values of 2-[fluorine-18]fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET) in primary staging in patients with newly diagnosed non-seminomatous germ cell tumour (NSGCT) clinical stage I/II. PATIENTS AND METHODS: The hypothesis was that FDG-PET would improve the negative predictive value (NPV) from 70% to 90%, thus requiring a total of 169 patients. All scans underwent visual analysis by a reference team of nuclear medicine physicians. Results were validated by histology following retroperitoneal lymph node dissection. RESULTS: Only 72 of the planned 169 patients were included, due to poor accrual. The prevalence of nodal involvement was 26%. Correct nodal staging by FDG-PET was achieved in 83% compared with correct computed tomography (CT) staging in 71%. CT had a sensitivity and specificity of 41% and 95%, respectively. Positive predictive value (PPV) and NPV were 87% and 67%, respectively. FDG-PET had a sensitivity and specificity of 66% and 98%, respectively. PPV was 95%. The primary end point was not reached, with an NPV of 78%. CONCLUSION: FDG-PET as a primary staging tool for NSGCT yielded only slightly better results than CT. Both methods had a high specificity while false-negative findings were more frequent with CT. FDG-PET is mostly useful as a diagnostic tool in case of questionable CT scan.

The positive predictive value of O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET in the diagnosis of a glioma recurrence after multimodal treatment.

OBJECTIVE: To explore prospectively the positive predictive value of O-(2-[(18)F]fluoroethyl)-L-tyrosine (FET)-PET in selected patients with a magnetic resonance imaging (MRI)-based suspicion of a glioma recurrence or progression. Methods Patients with a supratentorial glioma (initial World Health Organization (WHO) grade II, III or IV) were considered eligible if they had both an MRI-(new/progressive contrast-enhancing lesion) and FET-PET-based diagnosis of a recurrence/progression after various forms and combinations of irradiation and chemotherapy. Criterion for tumour recurrence/progression in FET-PET was a standardized uptake value (SUVmax)/Background (BG) ratio of >2.0 in the late uptake phase. All patients underwent multimodal (MRI, FET-PET) imaging-guided stereotactic biopsy. The positive predictive value was defined as the proportion of MRI and FET-PET findings indicating glioma recurrence/progression that also tested positive for tumour recurrence/progression after stereotactic biopsy. RESULTS: Thirty-one patients with initially WHO grade II (17), WHO grade III (6), and grade IV glioma (8) were included. In 26 patients FET-PET results indicating tumour recurrence/progression were concordant with the biopsy results. In five patients histopathologic evaluation failed to reveal a "vital" tumour. FET-PET findings were also discordant with the radiographic and clinical follow-up in these five patients. The positive predictive value of FET-PET was 84%. CONCLUSION: The positive predictive value of FET-PET using the standard ratio method is high, but not high enough to replace stereotactic biopsy in this highly selected study cohort. Whether the calculation of FET uptake in the early phase and/or the evaluation of uptake kinetics will improve the positive predictive value of FET-PET deserves prospective evaluation.

[Developments and perspectives in radioablative techniques]. / Entwicklungen und Perspektiven radioablativer Verfahren.

The encouraging preliminary results of radioembolization therapy in hepatocellular carcinoma and liver metastases from colorectal cancer have suggested that this mode of therapy could also be successful in breast and neuroendocrine metastases from colorectal cancer. (90)Yttrium microspheres in combination with radiosensitizing agents and growth factor inhibitors present opportunities to evaluate its application in combinatorial treatment paradigms with modern chemotherapy regimens. Other randomized trials are needed in hepatocellular carcinoma, to compare radioembolization with (90)yttrium against transarterial chemoembolization, bland embolization, drug-eluting beads, and best supportive care. A further potential research area besides the application of radioembolization for extrahepatic tumors is the determination of quality of life in randomized studies comparing radioembolization with systemic chemotherapy regimens with or without percutaneous radiation therapies.

[Diagnosis of chronic osteitis of the bones in the extremities. Relative value of F-18 FDG-PET]. / Diagnostik der chronischen Osteitis des Extremitätenskeletts : Stellenwert der F-18-FDG-PET.

BACKGROUND: Noninvasive diagnosis continues to present a challenge in chronic bone infections. Positive intraoperative microbiological and/or histological results are regarded as the gold standard for confirmation of the diagnosis. The aim of the present study was to evaluate the value of F-18 FDG-PET in the diagnosis of chronic osteitis in the patients of a department devoted specifically to septic orthopaedic surgery. In particular, the study was intended to answer the question of whether the results of FDG-PET correlate with those found in intraoperatively removed biopsy specimens (microbiology, histology) and what value this method of investigation has relative to computed tomography (CT) and magnetic resonance imaging (MRI). METHODS: An F-18 FDG-PET examination was performed preoperatively in each of 50 patients with a suspected diagnosis of "chronic osteitis of bone/s in a limb". All these patients had a history of an open fracture and/or a previous operation on the affected limb. The FDG-PET results were analysed blind. All patients enrolled in the study were subsequently operated on. After surgery, the results of histological and microbiological examination of the biopsy specimens taken intraoperatively were compared with the results of the FDG-PET and of CT (n=22) and MRI (n=18). Finally, the sensitivity, specificity and accuracy of each method were determined. RESULTS: Postoperatively the biopsy specimens from 37 patients yielded positive results in the microbiological and/or histological tests. According to this gold standard, then, osteitis was not present in 13 patients. In the preoperative FDG-PET report 34 of the patients whose microbiological and/or histological results were positive were correctly diagnosed as infection positive. In addition, 4 false-positive results were observed. False-negative results were recorded in 3 patients and true-negative results, in 9. The sensitivity and specificity were 92% and 69%, respectively, for the entire group of patients. The accuracy was 86%. The sensitivity, specificity and accuracy were 47%, 60% and 50%, respectively, for CT and 82%, 43% and 67%, respectively, for MRI. CONCLUSION: F-18 FDG-PET is a promising diagnostic imaging method with high sensitivity and accuracy in the investigation of chronic osteitis. If the result of FDG-PET is negative chronic osteitis can be virtually excluded. The results presented suggest that it is superior to CT and MRI in sensitivity and accuracy. A definitive diagnosis of chronic osteitis will continue to require an invasive method in the future, in the form of removal of biopsy specimens for microbiological and histological tests.

Equipment-independent reference values for dopamine transporter imaging with 123I-FP-CIT.

AIM: Reliable reference values are helpful to interpret and compare the results of dopamine transporter imaging with SPECT. Since semi-quantitative reference values cannot be easily transferred between imaging equipments, this study aimed to establish equipment independent normal values for the true striatal binding of 123I-FP-CIT. PATIENTS, METHODS: Specific striatal FP-CIT binding of 6 healthy volunteers and 26 patients with essential tremor were used to generate a reference range by applying an equipment specific resolution dependent factor to compensate for recovery effects. This factor has been determined previously by a series of standardized phantom measurements of an anthropomorphic basal ganglia phantom. Herewith, the resulting DAT binding values represent the expected true specific binding in the striatum. RESULTS: On average, true specific striatal binding was 5.83 +/- 0.96 in healthy controls, 5.25 +/- 0.67 in patients with essential tremor and 5.36 +/- 0.75 in the entire study cohort. CONCLUSION: These preliminary results may serve as a basis for the generation of a generally accepted equipment independent reference range for dopamine transporter imaging with 123I-FP-CIT. By a simple phantom measurement that can be accomplished within one day factors related to specific imaging equipment and processing can be corrected for, resulting in specific binding values which may enable a more standardized interpretation of dopamine transporter scans.

Growth hormone response in low-dose apomorphine test correlates with nigrostriatal dopamine transporter binding in patients with Parkinson's disease.

Challenge with low-dose apomorphine causes a rise in growth hormone (GH) in patients with Parkinson's disease (PD). We studied 18 patients with early PD, who showed an increase of GH in the low-dose apomorphine test, by means of [(123)I] FP-CIT-SPECT. The mean specific dopamine transporter binding of the 18 patients was 1.50 +/- 0.56 in the striatum, 1.20 +/- 0.59 in the putamen, and 1.76 +/- 0.59 in the caudate nucleus. The increase of GH (1.05 +/- 1.01 ng/ml at baseline to 9.46 +/- 6.36 ng/ml 45 min after apomorphine injection; p < 0.001) was significant. There was a significant negative correlation of the increase of GH with the mean specific dopamine transporter binding in all three regions (r between -0.490 and -0.587; p between 0.04 and 0.01). Challenge with low-dose apomorphine may therefore be used as an indirect tool to measure the extent of nigrostriatal neurodegeneration in early PD.

Creatine supplementation in Parkinson disease: a placebo-controlled randomized pilot trial.

Mitochondrial dysfunction plays a major role in the pathogenesis of Parkinson disease (PD). Creatine (Cr) is an ergogenic compound that exerts neuroprotective effects in animal models of PD. We conducted a 2-year placebo-controlled randomized clinical trial on the effect of Cr in 60 patients with PD. Cr improved patient mood and led to a smaller dose increase of dopaminergic therapy but had no effect on overall Unified Parkinson's Disease Rating Scale scores or dopamine transporter SPECT.