Toward Transpulmonary Chemoembolization with Degradable Starch Microspheres: Systematic Analysis of Local and Systemic Effects in a Porcine Model.

PURPOSE: To investigate local and systemic effects of transpulmonary chemoembolization (TPCE) with degradable starch microspheres (DSM) and doxorubicin. The long-term goal is to establish DSM-TPCE as a treatment option for pulmonary malignancies. MATERIALS AND METHODS: Nine pigs underwent TPCE of either the right or left lower lobe pulmonary artery (LLPA) and bland embolization (TPE) of the contralateral LLPA. Before the procedures, macroaggregated albumin (MAA) particles were injected into both LLPAs, to exclude systemic shunting. Pulmonary arterial pressure, heart rate and oxygenation were recorded immediately before and at 1, 3, 5 and 10 min after treatment. To investigate possible nontarget embolization, animals underwent cerebral MRI (cMRI). We killed the animals after a contrast-enhanced chest computed tomography (CT) and performed a pathologic examination at 12 h (3), 24 h (3) and 72 h (3) after treatment. RESULTS: All experiments were technically successful. Mean injected DSM dose until stasis was similar in TPCE and TPE (4.3 ± 1.4 vs. 4.0 ± 1.4 mL). Pulmonary arterial pressure increased significantly 3 min after treatment (TPE: 17 ± 5 vs. 27 ± 7 mmHg; TPCE: 22 ± 6 vs. 36 ± 8 mmHg). No significant changes in heart rate or peripheral oxygenation levels occurred. We observed no evidence of structural lung damage or permanent perfusion disruption on CT. MAA test injection and cMRI revealed no shunting or nontarget embolization. The pathologic assessment revealed nonspecific local inflammation of the lung parenchyma. CONCLUSION: In this large-animal model, TPCE and TPE appear feasible and safe. We observed a mild increase in pulmonary arterial pressure. Nontarget embolization did not occur. TPCE, as well as TPE, did not cause structural damage to the normal lung parenchyma.

[Lutetium-177-PSMA radioligand therapy : Consensus within the framework of GKV-funded care between the university hospitals in Aachen, Bonn, Düsseldorf, Essen, and Cologne and the MDK Nordrhein]. / Lutetium-177-PSMA-Radioligandentherapie : Konsensus im Rahmen der GKV-finanzierten Versorgung zwischen den Hochschulkliniken in Aachen, Bonn, Düsseldorf, Essen und Köln und dem MDK Nordrhein.

In the last 3 years, Lutetium-177 prostate-specific membrane antigen radioligand therapy (Lu-177-PSMA-RLT) has received increasing attention in nuclear medicine as a new form of treatment for castration-resistant metastatic prostate cancer. This therapy combines the radionuclide Lutetium-177, which has been therapeutically used in nuclear medicine for many years, with a molecular target of the transmembrane prostate-specific membrane antigen expressed by prostate cancer cells. Since there are no prospective randomized studies on Lu-177-PSMA-RLT and the question of reimbursement has repeatedly been the subject of review by the MDK Nordrhein (Medischenische Dienst der Krankenversicherung), there was a desire because of the increasing number of patients being treated to clarify under which circumstances Lu-177-PSMA-RLT can be reimbursed by German statutory health insurance. The goals of this article are to help treating physicians understand how this new therapy option works, to integrate it in the overall therapy concept for castration-resistant metastatic prostate cancer, and, above all, to use Lu-177-PSMA-RLT-based on the current data-at the right place in the therapy sequence of castration-resistant metastatic prostate cancer.

Balancing the benefits and harms of thyroid cancer surveillance in survivors of Childhood, adolescent and young adult cancer: Recommendations from the international Late Effects of Childhood Cancer Guideline Harmonization Group in collaboration with the PanCareSurFup Consortium.

Radiation exposure to the thyroid gland during treatment of childhood, adolescent and young adult cancer (CAYAC) may cause differentiated thyroid cancer (DTC). Surveillance recommendations for DTC vary considerably, causing uncertainty about optimum screening practices. The International Late Effects of Childhood Cancer Guideline Harmonization Group, in collaboration with the PanCareSurFup Consortium, developed consensus recommendations for thyroid cancer surveillance in CAYAC survivors. These recommendations were developed by an international multidisciplinary panel that included 33 experts in relevant medical specialties who used a consistent and transparent process. Recommendations were graded according to the strength of underlying evidence and potential benefit gained by early detection and appropriate management. Of the two available surveillance strategies, thyroid ultrasound and neck palpation, neither was shown to be superior. Consequently, a decision aid was formulated to guide the health care provider in counseling the survivor. The recommendations highlight the need for shared decision making regarding whether to undergo surveillance for DTC and in the choice of surveillance modality.

Patients with high-risk differentiated thyroid cancer have a lower I-131 ablation success rate than low-risk ones in spite of a high ablation activity.

OBJECTIVE: To examine success rates in strictly defined high-risk differentiated thyroid cancer (DTC) patients who received a high-activity (≥5550 MBq) adjuvant postoperative I-131 therapy and compare these to the rates found in highest risk and low-risk patients. DESIGN: Retrospective database study. PATIENTS: We examined 377 patients with DTC who received I-131 ablation. Patients with distant metastases were classified as very high risk. Patients with primary tumours >4 cm, extensive extrathyroidal invasion (pT4a or pT4b in accordance with the 7th edition of the TNM system), and patients with ≥5 lymph node metastases or any lateral compartment lymph node metastases were considered high risk. All other patients were considered low risk. MEASUREMENTS: Ablation success rate at first TSH-stimulated follow-up. RESULTS: The ablation success rate was 72·6% in low-risk patients, 51·7% in high-risk patients and 13·8% in highest risk patients (all differences P < 0·001). In none of the groups, a significant difference in the initial I-131 activity was found between patients with successful and unsuccessful ablation (low risk: P = 0·16, high risk: P = 0·91 and highest risk: P = 0·48). Furthermore, there was no difference in ablation success between patients who received <5550 MBq and those who received ≥5550 Mbq (low risk: P = 0·31, high risk: P = 0·69 and highest risk: P = 0·22). CONCLUSIONS: Patients with high-risk DTC have a significantly reduced I-131 ablation success rate compared to low-risk ones in spite of high initial I-131 activities. As successful ablation is prognostically important, efforts should be made to improve outcome in these patients.

Clinical value of 68Ga-DOTATATE-PET/CT compared to stand-alone contrast enhanced CT for the detection of extra-hepatic metastases in patients with neuroendocrine tumours (NET).

PURPOSE: To compare and outline the beneficial skills of combined (68)Ga-DOTATATE positron emission tomography (PET) with concurrent contrast enhanced X-ray computed tomography (ceCT) against stand-alone ceCT in 54 patients with neuroendocrine tumours (NET). METHODS: Patients with histologically confirmed NET and available follow-up of at least 6 months (median 12.6 months; range 6.1-23.2) were included. PET/CT and ceCT images were initially analyzed separately by two blinded nuclear medicine physicians and two radiologists, respectively. In a second step all four physicians reviewed all detected lesions together reaching a consensus-grading for PET/ceCT. The results were then compared to the reference standard consisting of clinical follow-up data. RESULTS: With regard to true positive lesions, PET/ceCT vs. stand alone ceCT detected 139 vs. 48 bone-lesions, 106 vs. 71 lymph node metastases and 26 vs. 26 pulmonary lesions. On a per-patient basis, PET/ceCT achieved a higher sensitivity (100% vs. 47%) and specificity (89% vs. 49%) for bone lesions than ceCT. For lymph nodes the effect was similar (sensitivity 92% vs. 64% and specificity 83% vs. 59%). For the detection of pulmonary lesions the sensitivity was identical (100%) while specificity of PET/ceCT was superior to ceCT-alone (95% vs. 82%). CONCLUSION: In summary, the use of (68)Ga-DOTATATE PET/ceCT leads to an increase in sensitivity and specificity in the detection of extra-hepatic NET metastases compared to stand-alone ceCT. Therefore, (68)Ga-DOTATATE PET/ceCT should be the imaging modality of choice in patients with NET.

Timing of post 131I ablation diagnostic whole body scan in differentiated thyroid cancer patients. Less than four months post ablation may be too early.

AIM: to determine whether the first three months after 131I ablation is too early to perform radioiodine diagnostic whole body scintigraphy (dxWBS) in differentiated thyroid carcinoma patients. PATIENTS, MATERIAL, METHODS: The files of 462 patients who were treated for DTC in our hospital were reviewed. All patients underwent surgical thyroidectomy. 146 patients had data available on a. a dxWBS which was performed less than four months (max 120 days) after 131I ablation with concurrent stimulated TSH stimulated thyroglobulin (Tg) measurement without further therapeutic measures between ablation and dxWBS and b. a second dxWBS or 131I therapy (rxWBS) within 1.5 years after ablation. RESULTS: A discordance between the initial and follow-up scan was found in 25/129 (19%) patients: of 54 patients with a positive initial dxWBS, scan results of a second dxWBS or rxWBS obtained with a suitable distance to the initial scan contradicted the initial one in 15 patients (27%). New lesions were discovered in 10/74 negative first dxWBS cases (14%). A discordance between the initial and follow-up stimulated Tg was found in 5/129 (4%) patients: 2/90 (2%) of patients with a negative stimulated Tg at initial dxWBS subsequently showed a positive results whereas 3/29 (10%) patients with an initially positive Tg showed a negative Tg level at the second procedure. CONCLUSION: Less than four months after 131I ablation is too early to perform radioiodine diagnostic whole body scintigraphy with concurrent TSH stimulated Tg measurement. The identification of the right, later, timepoint however requires further research.

No evidence for attenuated stress-induced extrastriatal dopamine signaling in psychotic disorder.

Stress is an important risk factor in the etiology of psychotic disorder. Preclinical work has shown that stress primarily increases dopamine (DA) transmission in the frontal cortex. Given that DA-mediated hypofrontality is hypothesized to be a cardinal feature of psychotic disorder, stress-related extrastriatal DA release may be altered in psychotic disorder. Here we quantified for the first time stress-induced extrastriatal DA release and the spatial extent of extrastriatal DA release in individuals with non-affective psychotic disorder (NAPD). Twelve healthy volunteers (HV) and 12 matched drug-free NAPD patients underwent a single infusion [(18)F]fallypride positron emission tomography scan during which they completed the control and stress condition of the Montreal Imaging Stress Task. HV and NAPD did not differ in stress-induced [(18)F]fallypride displacement and the spatial extent of stress-induced [(18)F]fallypride displacement in medial prefrontal cortex (mPFC) and temporal cortex (TC). In the whole sample, the spatial extent of stress-induced radioligand displacement in right ventro-mPFC, but not dorso-mPFC or TC, was positively associated with task-induced subjective stress. Psychotic symptoms during the scan or negative, positive and general subscales of the Positive and Negative Syndrome Scale were not associated with stress-induced [(18)F]fallypride displacement nor the spatial extent of stress-induced [(18)F]fallypride displacement in NAPD. Our results do not offer evidence for altered stress-induced extrastriatal DA signaling in NAPD, nor altered functional relevance. The implications of these findings for the role of the DA system in NAPD and stress processing are discussed.

Pretherapeutic dosimetry before 131I therapy of benign thyroid disease. A clinical practice assessment of dosimetric parameters.

AIM: To compare uptake measurements and different methods for the pretherapeutic determination of the effective thyroidal ¹³¹I half life (Teff) to the results of posttherapeutic dosimetric measurements. PATIENTS, METHODS: Retrospective study of 1538 patients who received their first RIT in our department for autonomous thyroid nodules (ATN), autonomous multinodular goiter (AMG) or Graves' disease (GD) between November 1999 and January 2011. Pretherapeutic measurements were performed at any combination of 24 h, 48 h and 6 days after 131I administration. Post-therapy dosimetric measurements were performed in 12 h intervals until discharge. Teff was determined through monoexponential curve fitting. RESULTS: Pretherapeutic Teff values based on measurements at 24 h and 48 h, 24 h and 6 d, 48 h and 6 d as well as on day 24 h, 48 h and 6 d yielded implausible (< 2 d or > 8 d) values for Teff, in 60.4%, 25.7%, 29.1 and 21.4% of available calculations, respectively. The plausible results showed significant, clinically relevant and sometimes considerable overestimations of Teff. Using empirically determined fixed disease specific Teff values resulted in a better congruence between the pre- and posttherapeutic dosimetry results. 24 h measurements were marginally more accurate than 48 h ones in AMG and GD whereas 48 h measurements were marginally more accurate in ATN; these differences are however not clinically relevant. 6 d measurements are clearly less accurate than those after 24 h or 48 h. CONCLUSION: In ATN, AMG and GD, pretherapeutic dosimetry can be performed by a single uptake measurement at 24 h or 48 h using a fixed, disease specific value for Teff. Additional later measurements do not yield a further clinically relevant contribution to accuracy of pretherapeutic dosimetry.

A comparison of rh-TSH and thyroid hormone withdrawal in patients with differentiated thyroid cancer: preliminary evidence for an influence of age on the subjective well-being in hypothyroidism.

We aimed to investigate the subjective well-being in patients with differentiated thyroid cancer after hormone withdrawal. Since this might be confounded by psycho-oncological processes unrelated to hypothyroidism we intended to minimize such factors by only including patients with a history of uneventful follow-up examinations for several years. We investigated 67 patients applying the General Health Questionnaire (GHQ-12) at 3 time points t1, t2, and t3. The time point t2 represented an intensified follow-up examination 5 years after thyroidectomy, which was performed either on hormone withdrawal (49 patients) or using rh-TSH (18 patients). The time points t1 and t3 took place during follow-up examinations 6 months before and after t2 in a euthyroid state. Additionally, we assessed the impact of age, gender, family status, and education on the GHQ-12 score at all 3 time points. Within the hormone withdrawal group the analyses demonstrated a significant difference between t1 and t2 as well as t3 and t2. Additionally, there was a significant negative correlation of age with GHQ-12 sum scores at t2, but not at t1 or t3. Subgroup analyses at t2 indicated that the subjective well-being in younger patients was more impaired compared to elderly patients. The between-group analysis showed no significant differences. However, concerning the age effect there was a significant difference between the subgroup of young hypothyroid patients and the total rh-TSH group at t2. We demonstrated preliminary evidence for an influence of age on the subjective well-being in hypothyroidism suggesting that younger subjects are subjectively more impaired by hypothyroidism than elderly ones.

Graves' disease occurring after surgery of a multinodular goiter: a case report.

The transition of toxic or nodular goiter to Graves' disease is known as a rare side effect of (131)I therapy. Here, we report the case of a 46-year-old German female with posttherapeutical Graves' disease after surgery of a multinodular goiter. Although the major part of the thyroid was excised the patient suffered from manifest Graves' disease including typical clinical and laboratory findings. Prior to surgery, no TSH receptor antibodies were found, although low TPO antibody titres could already be detected. It may thus be assumed that the therapeutic manipulation elicited the key change towards a TSH receptor antibody production in a predisposed organ or alternatively deteriorated a mild unapparent pre-existing Graves' disease. It might be concluded that the possibility of posttherapeutical Graves' disease should be considered in the presence of TPO antibodies prior to the surgical intervention.

[A comparative analysis of the binding sites of proteins regulating the transcription in the early development of Drosophila melanogaster, determined by the ChIP-chip method and the theoretically predicted clusters of the binding sites of these proteins].

DNA segments were analyzed for six proteins regulating the transcription in the early embryonic development of Drosophila melanogaster in which a significant binding of these proteins was observed by the method of immunoprecipitation of chromatin followed by the precipitation on the template (Chip-chip). The regions of high density of the theoretically predicted binding sites of these proteins in these fragments were considered. A comparison of the experimental and theoretical data for various pairwise combinations of the above-mentioned factors was made. It was shown that the intensity of data obtained by the ChiP-chip method significantly differs outside and inside identified clusters. A comparison of experimental data in various pairwise combinations of the factors showed that, despite the problems associated with a great noise in the ChiP-chip signal, a strong tendency of particular groups of factors to bind in the same DNA regions was revealed, which is consistent with the data about their functional coupling. Thus, a comparison of the data obtained by the ChiP-chip method makes it possible to distinguish functionally related regulatory subsystems even in the case of systems that are much less investigated than the system of the early embryonic development of Drosophila melanogaster.

The resting brain and our self: self-relatedness modulates resting state neural activity in cortical midline structures.

The resting brain shows high neural activity in various regions, the default-mode network, chief among them the cortical midline structures (CMS). The psychological correlate of high resting state neural activity in CMS remains however unclear though speculatively it has been associated with processing of internally-oriented self-relatedness. We used functional MRI to examine internally-oriented self-relatedness during the resting state period. This was indirectly done by letting subjects perceive emotional pictures followed by a fixation cross; the very same pictures were then rated subjectively according to their degree of self-relatedness in a postscanning session. This allowed us to correlate the picture ratings of self-relatedness with signal changes in the subsequent resting state period, i.e. fixation period. The emotional pictures' degree of self-relatedness parametrically modulated subsequent resting state signal changes in various CMS, including ventro- and dorsomedial prefrontal cortex and posterior cingulate cortex. This modulation could be distinguished from effects of emotion dimensions (e.g. valence, intensity) and evoked effects of self-relatedness during the stimulus period itself the latter being observed rather in subcortical regions, e.g. amygdala, ventral striatum, and tectum. In sum, our findings suggest that resting state neural activity in CMS is parametrically and specifically modulated by the preceding stimulus's degree of self-relatedness. This lends further support to the presumed involvement of these regions in processing internally-oriented self-relatedness as distinguished from externally-oriented self-relatedness.

Neural correlates of subliminal and supraliminal letter processing--an event-related fMRI study.

One problem of interpreting research on subconscious processing is the possibility that participants are weakly conscious of the stimuli. Here, we compared the fMRI BOLD response in healthy adults to clearly visible single letters (supraliminal presentation) with the response to letters presented in the absence of any behavioural evidence of visibility (subliminal presentation). No letter catch trials served as a control condition. Forced-choice responses did not differ from chance when letter-to-background contrast was low, whereas they were almost 100% correct when contrast was high. A comparison of fMRI BOLD signals for supraliminal and subliminal letters with the control trials revealed a signal increase in left BA 37 (fusiform gyrus). Comparison of supraliminal with subliminal letters showed a significant increase in the right inferior frontal gyrus (BA 44, partly extending to BA 9 and BA 45, as well as BA 46). Finally, a comparison of subliminal with supraliminal letters showed increases in the left middle temporal gyrus (BA 21) and the right extrastriate cortex (BA 19).

Materials for fuel-cell technologies.

Fuel cells convert chemical energy directly into electrical energy with high efficiency and low emission of pollutants. However, before fuel-cell technology can gain a significant share of the electrical power market, important issues have to be addressed. These issues include optimal choice of fuel, and the development of alternative materials in the fuel-cell stack. Present fuel-cell prototypes often use materials selected more than 25 years ago. Commercialization aspects, including cost and durability, have revealed inadequacies in some of these materials. Here we summarize recent progress in the search and development of innovative alternative materials.

Influence of patient position in myocardial SPECT on the diagnosis of CHD.

AIM: Of the study was to show that changing patient position from supine to prone results in improved specificity of myocardial SPECT (MS). METHODS: We examined the influence of patient position in MS on the diagnosis of coronary heart disease (CHD) in 151 patients. By using a Tc-99m-labeled compound (Tetrofosmin, Myoview, Nycomed, Amersham) examinations could be performed in supine and prone position within 35 minutes. Examinations were performed as a two-day stress-rest protocol with one gamma camera head and 180 degrees rotation without absorption correction. RESULTS: Semi-quantitative patient and heart phantom data show similar values for anterior and inferior wall in prone position in contrast to a lower count ratio of inferior to anterior wall in supine position. This demonstrates the importance of patient position with respect to artifacts specificity. Changing patient position from supine to prone mainly improves diagnostic specificity for CHD in the inferior wall in men (from 58% to 90%) and in the anterior wall in women (from 80% to 93%). Sensitivity is the same for both techniques. CONCLUSION: Changing patient position from supine to prone significantly improves diagnostic specificity while sensitivity remains unchanged.

[Liver metastases: diagnostic value of blood tests, scintiscanning, and laparoscopy (author's transl)]. / Lebermetastasen: dignostischer Wert von Bluttests, Szintigraphie und Laparoskopie

In 90 patients with known extra-hepatic malignancy the liver was examined for metastases. The diagnostic value of clinical information, blood examinations, 99mTc scintiscan, and laparoscopy for the diagnosis of the liver metastases was evaluated. Clinical data (age, sex, time since onset of symptoms and localisation of primary tumor) are of no diagnostic value. The most reliable blood tests are alkaline phosphatase (AP) and GOT. The probability of liver metastastases rises with increasingly abnormal values of AP and GOT. However, the probability is not much greater in cases with highly abnormal values than in cases with only moderate elevation of AP and GOT. Diagnostic accuracy of AP is optimal by using a cutoff point of 76 U/l (sensitivity 79%, specificity 64%). Bilirubin, prothrombin time, haemoglobin and blood sedimentation rate are of very little value. Combinations of AP with these blood tests does not improve diagnostic accuracy. Therefore, it is not useful to determine more blood tests than AP alone. Informed reading of liver scans has a specificity of 75% and a sensitivity of 91%. Blind reading of scans has a sensitivity of 94% and a specificity of 95%. This diagnostic accuracy cannot be improved by additional blood tests. Laparscopy has a sensitivity of 85% and a specificity of 95%. Scanning and laparoscopy are complementary methods. When optimal diagnostic accuracy is required both methods should be used.