Genetisches Tracing septohippocampaler Projektionen

Der Hippocampus hat eine zentrale funktionelle Rolle beim Lernen, dem Abruf von Gedächtnisinhalten und der räumlichen Orientierung. Diese Kognitionsprozesse basieren auf einem komplexen Zusammenspiel einer Vielzahl erregender und hemmender hippocampaler Neurone und assoziierten Strukturen. Dabei ist seit geraumer Zeit bekannt, dass Projektionsneurone des medialen Septum-diagonalen Band von Broca Komplex (MSDB) im basalen Vorderhirn wesentlich zur Funktionalität dieses hippocampalen Neuronennetzwerks beitragen. Diese modulatorischen Projektionsneurone des MSDB können nach dem freigesetzten Neurotransmitter in eine cholinerge, GABAerge und glutamaterge Untergruppe unterteilt werden und projizieren über ein septohippocampales Fasersystem in den Hippocampus. Bisher angewandte anatomische Tracingmethoden zur Untersuchung ihrer Faserverteilung und der hippocampalen Zielstrukturen erlaubten jedoch keine eindeutige Unterscheidung der drei Projektionssysteme, bzw. der hippocampalen Innervationsziele. Eine von unserer Arbeitsgruppe angewandte genetische Tracingmethode ermöglicht hingegen eine spezifische Markierung definierter Neuronentypen des MSDB und ihrer septohippocampalen Projektionen mittels viraler Transduktion transgener Mauslinien. Die vorliegende Arbeit konnte mittels immunhistochemischer Färbungen und konfokaler Fluoreszenzmikroskopie zeigen, dass (1) der genetische Ansatz zur spezifischen Transduktion und Markierung cholinerger, bzw. GABAerger Neuronenpopulationen des MSDB führte, (2) deren axonale Projektionen ein areal- und laminaspezifisches Verteilungsmuster im Hippocampus aufweisen und (3) GABAerge Projektionsneurone putativ GABAerge Interneurone im Hippocampus kontaktieren und dabei präferentiell Interneurone des CA3 Areals im Vergleich zum Gyrus dentatus innervieren. Diese Ergebnisse bestätigen und erweitern unsere Kenntnisse über die septohippocampale Interaktion. Aufbauend auf diesen morphologisch-anatomischen Analysen ermöglichen weitergehende optogenetische Methoden mittels des identischen Versuchsansatzes eine spezifische Analyse der funktionellen, septohippocampalen Interaktion. Diese Kenntnisse werden wesentlich zu unserem Verständnis der funktionellen Grundlagen hippocampal-vermittelter Kognitionsprozesse und ihrer pathologischen Zustände, wie der Alzheimer’schen Demenz beitragen

NUT Midline Carcinoma in a Pregnant Woman

NUT midline carcinoma is a rare, highly aggressive tumor that involves midline structures, particularly in the head, neck and mediastinum. It is characterized by NUT gene translocations on chromosome 15. It typically impacts teenagers or young adults, and has a fulminant course leading to death in less than a year in most cases despite aggressive chemoradiotherapy. Due to its location, this tumor is frequently considered inoperable. We present a case of a sinonasal NUT midline carcinoma with orbital invasion discovered during the workup of sinusitis in a young, pregnant woman. The tumor was managed with definitive excision to negative margins followed by aggressive chemoradiation, with no evidence of recurrence for 12 months. We propose that diagnosis of NUT midline carcinoma should prompt recognition of the limitations of current medical therapy and rapid surgical intervention should be undertaken when possible

Progress of international hydrogen production network for the thermochemical Cu–Cl cycle

This paper presents recent advances by an international team which is developing the thermochemical copper–chlorine (Cu–Cl) cycle for hydrogen production. Development of the Cu–Cl cycle has been pursued by several countries within the framework of the Generation IV International Forum (GIF) for hydrogen production with the next generation of nuclear reactors. Due to its lower temperature requirements in comparison with other thermochemical cycles, the Cu–Cl cycle is particularly well matched with Canada's Generation IV reactor, SCWR (Super-Critical Water Reactor), as well as other heat sources such as solar energy or industrial waste heat. In this paper, recent developments of the Cu–Cl cycle are presented, specifically involving unit operation experiments, corrosion resistant materials and system integration

Extracranial Metastases of a Cerebral Glioblastoma: A Case Report and Review of the Literature

The glioblastoma, a malignant human brain tumor, is known for its devastating intracranial progress and its dismal prognosis. Whereas treatment and research are most prominently focused on the primary tumor lesion, in recent years evidence has accumulated that points to the rare occurrence of extracranial glioblastoma metastases. We here present a case of a female patient with a known glioblastoma who was detected to harbor multiple metastases in the bones, lung, pleura, liver, mesentery, and the subcutaneous soft tissue. Pathogenetically, these metastatic lesions developed most probably after a local progression of the left temporal glioblastoma through the skull base, thus getting access to the systemic lymphatics. Similar cases of extensive glioblastoma metastization, their putative underlying mechanisms, and implications for clinical care are discussed. (C) 2018 The Author(s) Published by S. Karger AG, Base

Prognostic value of pre-irradiation FET PET in patients with not completely resectable IDH-wildtype glioma and minimal or absent contrast enhancement

In glioma patients, complete resection of the contrast-enhancing portion is associated with improved survival, which, however, cannot be achieved in a considerable number of patients. Here, we evaluated the prognostic value of O-(2-[18F]-fluoroethyl)-L-tyrosine (FET) PET in not completely resectable glioma patients with minimal or absent contrast enhancement before temozolomide chemoradiation. Dynamic FET PET scans were performed in 18 newly diagnosed patients with partially resected (n = 8) or biopsied (n = 10) IDH-wildtype astrocytic glioma before initiation of temozolomide chemoradiation. Static and dynamic FET PET parameters, as well as contrast-enhancing volumes on MRI, were calculated. Using receiver operating characteristic analyses, threshold values for which the product of paired values for sensitivity and specificity reached a maximum were obtained. Subsequently, the prognostic values of FET PET parameters and contrast-enhancing volumes on MRI were evaluated using univariate Kaplan–Meier and multivariate Cox regression (including the MTV, age, MGMT promoter methylation, and contrast-enhancing volume) survival analyses for progression-free and overall survival (PFS, OS). On MRI, eight patients had no contrast enhancement; the remaining patients had minimal contrast-enhancing volumes (range, 0.2–5.3 mL). Univariate analyses revealed that smaller pre-irradiation FET PET tumor volumes were significantly correlated with a more favorable PFS (7.9 vs. 4.2 months; threshold, 14.8 mL; P = 0.012) and OS (16.6 vs. 9.0 months; threshold, 23.8 mL; P = 0.002). In contrast, mean tumor-to-brain ratios and time-to-peak values were only associated with a longer PFS (P = 0.048 and P = 0.045, respectively). Furthermore, the pre-irradiation FET PET tumor volume remained significant in multivariate analyses (P = 0.043), indicating an independent predictor for OS. Our results suggest that pre-irradiation FET PET parameters have a prognostic impact in this subgroup of patients

NIMG-79. EARLY TREATMENT RESPONSE ASSESSMENT USING O-(2-18F-FLUOROETHYL)-L-TYROSINE (FET) PET COMPARED TO MRI IN MALIGNANT GLIOMAS TREATED WITH ADJUVANT TEMOZOLOMIDE CHEMOTHERAPY

AbstractBACKGROUNDThe goal of this prospective study was to compare the value of conventional MRI and O-(2-18F-fluoroethyl)-L-tyrosine (FET) PET for response assessment in patients with malignant glioma treated with first-line adjuvant temozolomide chemotherapy (TMZ).METHODSAfter biopsy/resection and completion of radiotherapy with concomitant temozolomide, 34 malignant glioma patients (glioblastoma, n=31; IDH-wildtype anaplastic astrocytoma, n=2; H3K27-mutated midline glioma, n=1) (age range, 20–66 years) were subsequently treated with adjuvant TMZ (5/28). FET-PET scans were performed at baseline and after 10–12 weeks. The first follow-up MRI after radiotherapy (9 ± 3 weeks) was compared with the early postoperative MRI. We obtained FET metabolic tumor volumes (MTV) and tumor/brain ratios (TBR). Threshold values of FET-PET parameters for treatment response were established by ROC analyses using the progression-free survival (PFS) ≤/>9 months as reference. MRI response assessment was based on RANO criteria. The predictive ability of FET-PET thresholds and MRI changes on early response assessment was evaluated subsequently concerning PFS using univariate survival estimates.RESULTSRelative TBR changes were not predictive for a PFS>9 months (P>0.05), whereas the absolute MTV at follow-up significantly predicted a PFS>9 months (P=0.016; threshold, 14.5 ml). The relative MTV change enabled the most significant PFS prediction. Responders defined by relative MTV changes (threshold, ≤0%) had a significantly 2-fold longer PFS than non-responders (16 vs. 8 months, P=0.003). RANO criteria at the first follow-up MRI after radiotherapy were not predictive for a PFS>9 months (P=0.260). CONCLUSIONS: FET-PET appears to be useful for identifying responders to adjuvant TMZ early after treatment initiation

EARLY TREATMENT RESPONSE ASSESSMENT USING O-(2-F-18-FLUOROETHYL)-L-TYROSINE (FET) PET COMPARED TO MRI IN MALIGNANT GLIOMAS TREATED WITH ADJUVANT TEMOZOLOMIDE CHEMOTHERAPY

AbstractBACKGROUNDThe goal of this prospective study was to compare the value of conventional MRI and O-(2-18F-fluoroethyl)-L-tyrosine (FET) PET for response assessment in patients with malignant glioma treated with first-line adjuvant temozolomide chemotherapy (TMZ).METHODSAfter biopsy/resection and completion of radiotherapy with concomitant temozolomide, 34 malignant glioma patients (glioblastoma, n=31; IDH-wildtype anaplastic astrocytoma, n=2; H3K27-mutated midline glioma, n=1) (age range, 20–66 years) were subsequently treated with adjuvant TMZ (5/28). FET-PET scans were performed at baseline and after 10–12 weeks. The first follow-up MRI after radiotherapy (9 ± 3 weeks) was compared with the early postoperative MRI. We obtained FET metabolic tumor volumes (MTV) and tumor/brain ratios (TBR). Threshold values of FET-PET parameters for treatment response were established by ROC analyses using the progression-free survival (PFS) ≤/>9 months as reference. MRI response assessment was based on RANO criteria. The predictive ability of FET-PET thresholds and MRI changes on early response assessment was evaluated subsequently concerning PFS using univariate survival estimates.RESULTSRelative TBR changes were not predictive for a PFS>9 months (P>0.05), whereas the absolute MTV at follow-up significantly predicted a PFS>9 months (P=0.016; threshold, 14.5 ml). The relative MTV change enabled the most significant PFS prediction. Responders defined by relative MTV changes (threshold, ≤0%) had a significantly 2-fold longer PFS than non-responders (16 vs. 8 months, P=0.003). RANO criteria at the first follow-up MRI after radiotherapy were not predictive for a PFS>9 months (P=0.260). CONCLUSIONS: FET-PET appears to be useful for identifying responders to adjuvant TMZ early after treatment initiation

Early treatment response assessment using 18^{18}F-FET PET compared to contrast-enhanced MRI in glioma patients after adjuvant temozolomide chemotherapy

The goal of this study was to compare the value of contrast-enhanced MRI and O-(2-[18F]fluoroethyl)-l-tyrosine (18F-FET) PET for response assessment in glioma patients after adjuvant temozolomide chemotherapy (TMZ). Methods: After biopsy or resection and completion of radiotherapy with concomitant TMZ, 41 newly diagnosed and histomolecularly characterized glioma patients (glioblastoma, 90%; age range, 20–79 y) were subsequently treated with adjuvant TMZ. MR and 18F-FET PET imaging were performed at baseline and after the second cycle of adjuvant TMZ. We obtained 18F-FET metabolic tumor volumes (MTVs) as well as mean and maximum tumor-to-brain ratios (TBRmean and TBRmax, respectively). Threshold values of 18F-FET PET parameters to predict outcome were established by receiver-operating-characteristic analyses using a median progression-free survival (PFS) of ≥ 9 mo and overall survival (OS) of ≥ 15 mo as reference. MRI response assessment was based on the Response Assessment in Neuro-Oncology (RANO) working group criteria. The predictive value of changes of 18F-FET PET and MRI parameters on survival was evaluated subsequently using univariate and multivariate survival estimates. Results: After 2 cycles of adjuvant TMZ chemotherapy, a treatment-induced reduction of MTV and TBRmax predicted a significantly longer PFS and OS (both P ≤ 0.03; univariate survival analyses) whereas RANO criteria were not significant (P > 0.05). Multivariate survival analysis revealed that TBRmax changes predicted a prolonged PFS (P = 0.012) and changes of MTV a prolonged OS (P = 0.005) independent of O6-methylguanine-DNA-methyltransferase promoter methylation and other strong prognostic factors. Conclusion: Changes of 18F-FET PET parameters appear to be helpful for identifying responders to adjuvant TMZ early after treatment initiation

Recent Canadian advances in nuclear-based hydrogen production and the thermochemical Cu-Cl cycle

This paper presents recent Canadian advances in nuclear-based production of hydrogen by electrolysis and the thermochemical copper-chlorine (Cu-Cl) cycle. This includes individual process and reactor developments within the Cu-Cl cycle, thermochemical properties, advanced materials, controls, safety, reliability, economic analysis of electrolysis at off-peak hours, and integrating hydrogen plants with Canada\u27s nuclear power plants. These enabling technologies are being developed by a Canadian consortium, as part of the Generation IV International Forum (GIF) for hydrogen production from the next generation of nuclear reactors