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Although isolated central nervous system (CNS) relapses are rare, they may become a serious clinical problem in intensively treated patients with high-risk neuroblastoma (NBL). The aim of this study is the presentation and assessment of the incidence and clinical course of isolated CNS relapses. Retrospective analysis involved 848 NBL patients treated from 2001 to 2019 at 8 centres of the Polish Paediatric Solid Tumours Study Group (PPSTSG). Group characteristics at diagnosis, treatment and patterns of relapse were analysed. Observation was completed in December 2020. We analysed 286 high risk patients, including 16 infants. Isolated CNS relapse, defined as the presence of a tumour in brain parenchyma or leptomeningeal involvement, was found in 13 patients (4.5%; 8.4% of all relapses), all of whom were stage 4 at diagnosis. Isolated CNS relapses seem to be more common in young patients with stage 4 MYCN amplified NBL, and in this group they may occur early during first line therapy. The only or the first symptom may be bleeding into the CNS, especially in younger children, even without a clear relapse picture on imaging, or the relapse may be clinically asymptomatic and found during routine screening. Although the incidence of isolated CNS relapses is not statistically significantly higher in patients after immunotherapy, their occurrence should be carefully monitored, especially in intensively treated infants, with potential disruption of the brain-blood barrier.

Although isolated central nervous system (CNS) relapses are rare, they may become a serious clinical problem in intensively treated patients with high-risk neuroblastoma (NBL). The aim of the study is presentation, assessment of incidence and the clinical course of isolated CNS relapses. Retrospective analysis involved 848 NBL patients treated from 2001 to 2019 at 8 centers of the Polish Pediatric Solid Tumors Study Group (PPSTSG). Group characteristics at diagnosis, treatment and patterns of relapse were analyzed. Observation was completed in December 2020. We analyzed 286 high risk patients, including 16 infants. Isolated CNS relapse, defined as presence of a tumor in brain parenchyma or leptomeningeal involvement, was found in 13 patients (4.5%, 8.4% of all relapses), all of them were stage 4 at diagnosis. Isolated CNS relapses seem to be more common in young patients with stage 4 MYCN amplified NBL, and in this group they may occur early during the first line therapy. The only or the first one symptom may be bleeding into CNS, especially in younger children, even without clear relapse picture on imaging, or the relapse may be clinically asymptomatic and found on routine screening. Although incidence of isolated CNS relapses is not statistically significantly higher in patients after immunotherapy, their occurrence should be carefully monitored, especially in intensively treated infants, with potential disruption of brain-blood barrier.

Pipe bursts and leaks in district heating networks are a problem both for the economic operation and for the supply reliability of the connected consumers. In case of a leakage, pressure and flow rate conditions near the defect change. These changes spread to the entire network within a short period of time and, depending on the size of the leakage, partly lead to drastically changed network conditions. After a leakage is detected, it is necessary to localize the leakage as accurate as possible in order to shut down the affected network segment and maintain the network’s stability. This article discusses and compares three different approaches for leakage localization (pressure wave detection, model-based numeric-analytical and machine learning) that exploit different properties of simulation models and sensor information from the real network.

Die homoopathische Herangehensweise bei Patienten einer psychiatrischen Klinik wird anhand von 2 Kasuistiken erlautert. Die Patienten besserten sich unter Kalium bromatum und Ferrum carbonicum. The individualized homeopathic approach in a psychiatric clinic is demonstrated in 2 cases. Patients got better with kalium bromatum respectively ferrum carbonicum.

Die Therapieoptionen beim fortgeschrittenen, Radioiod-refraktaren DTC waren bisher auserst limitiert und beschrankten sich weitgehend auf zytotoxische Chemotherapie mit schlechten Ansprechraten, die nach den amerikanischen und europaischen Leitlinien nicht mehr als Erstlinientherapie empfohlen wird. Unser zunehmendes Verstandnis der komplexen molekularen Pathogenese der Schilddrusenkarzinome mit der Identifizierung molekularer Targets ermoglichte die Entwicklung und klinische Translation biologisch gezielter Therapien. Der Einsatz der Multityrosinkinase-Inhibitoren und anderer biologisch gezielter Substanzen hat das Management von Patienten mit fortgeschrittenem Radioiod-refraktarem DTC in der letzten Dekade signifikant verandert. Sorafenib wurde dabei aktuell im Mai 2014 als erste dieser Substanzen fur die Therapie fortgeschrittener DTC zugelassen. Eine Reihe andere Substanzen, wie Pazopanib, Vandetanib, Cabozantinib, Axitinib, Sunitinib, Vemurafenib steht aufgrund ihrer Zulassung bei anderen Tumorentitaten zum Einsatz im individuellen Heilversuch zur Verfugung. Aufgrund der sehr beeindruckenden Daten aus der Phase-III-Studie, wird fur Lenvatinib die Zulassung beim metastasierten Radioiod-refraktaren DTC fur 2015 erwartet.

Background and purpose The aim of the present study was to evaluate factors predicting the recurrence pattern determined by [ 18 F]FET-PET imaging in patients with newly diagnosed glioblastoma after combined radio-chemotherapy treated according to the EORTC/NCIC trial. Material and methods Seventy-nine patients with newly diagnosed GBM treated with radiotherapy plus temozolomide (75mg/m 2 /d) followed by adjuvant cyclic (5/28days) temozolomide (150–200mg/m 2 ) were retrospectively analysed. Recurrence patterns were assessed by means of positron-emission-tomography with [ 18 F]FET and additional MRI; in 54 patients MGMT methylation status was evaluated. Results Whilst 49.4% of the patients had an in-field recurrence, 12.6% an ex-field recurrence and 3.8% a recurrence at the field margin, 34.2% of the patients did not relapse during follow-up (median 595days). Considering all patients included in this study, 41.5% (12/29) of the MGMT methylated population had no relapse, 37.9% (11/29) had an in-field-recurrence and 20.7% (6/29) an ex-field/marginal recurrence, whilst 28.0% (7/25) of the MGMT unmethylated population had no relapse, 64.0% (16/25) had an in-field-recurrence and 8.0% (2/25) an ex-field/marginal recurrence ( p =0.15). Conclusions After the administration of temozolomide concomitant with and adjuvant to radiotherapy in patients with glioblastoma, the pattern determined by [ 18 F]FET-PET seems to be associated with MGMT methylation status.

Purpose Reirradiation is a treatment option for recurrent high-grade glioma with proven but limited effectiveness. Therapies directed against vascular endothelial growth factor have been shown to exert certain efficacy in combination with chemotherapy and have been safely tested in combination with radiotherapy in a small cohort of patients. To study the feasibility of reirradiation combined with bevacizumab treatment, the toxicity and treatment outcomes of this approach were analyzed retrospectively. Patients and Methods After previous treatment with standard radiotherapy (with or without temozolomide) patients with recurrent malignant glioma received bevacizumab (10 mg/kg intravenous) on Day 1 and Day 15 during radiotherapy. Maintenance therapy was selected based on individual considerations, and mainly bevacizumab-containing regimens were chosen. Patients received 36 Gy in 18 fractions. Results The data of the medical charts of the 30 patients were analyzed retrospectively. All were irradiated in a single institution and received either bevacizumab ( n = 20), no additional substance ( n = 7), or temozolomide ( n = 3). Reirradiation was tolerated well, regardless of the added drug. In 1 patient treated with bevacizumab, a wound dehiscence occurred. Overall survival was significantly better in patients receiving bevacizumab ( p = 0.03, log-rank test). In a multivariate proportional hazards Cox model, bevacizumab, Karnovsky performance status, and World Health Organization grade at relapse turned out to be the most important predictors for overall survival. Conclusion Reirradiation with bevacizumab is a feasible and effective treatment for patients with recurrent high-grade gliomas. A randomized trial is warranted to finally answer the question whether bevacizumab adds substantial benefit to a radiotherapeutic retreatment setting.

The aim of the present study is to determine new positron emission tomography (PET) imaging-related factors predictive of progression-free survival as well as survival in patients with recurrent malignant glioma (MG) prior to and after re-irradiation. Fifty-six patients with recurrent MG who underwent re-irradiation treatment and pretherapeutic dynamic [(18)F]-fluoroethyl-L-tyrosine (FET)-PET scan were retrospectively analyzed. The prognostic value of different parameters, such as biological tumor volume, maximal tumor uptake (SUV(max)/BG), mean tumor uptake (SUV(mean)/BG), as well as uptake kinetics, was evaluated. [(18)F]FET uptake kinetics was classified according to a five-point rating as category G(1-2) (strongly/mainly increasing kinetics), G(3) (mixed 1:1), or G(4-5) (mainly/strongly decreasing kinetics). Patients within the pretherapeutic kinetic group G(4-5) had significantly worse survival than the other two groups (p = 0.01). Multivariate analysis revealed that histologic grade, Karnofsky Performance Score (KPS), and kinetic group were independent significant predictors for survival after re-irradiation. The uptake kinetics of [(18)F]FET-PET is an independent determinant of overall and to a lesser extent also progression-free survival. Thus, [(18)F]FET-PET kinetics may provide valuable additional prognostic information for treatment decisions.

Molecular imaging studies have recently found inter- and intratumoral heterogeneity in World Health Organization (WHO) grade II gliomas. A correlative analysis with tumor histology, however, is still lacking. For elucidation we conducted the current prospective study. Fifty-five adult patients with an MRI-based suspicion of a WHO grade II glioma were included. [F-18]Fluoroethyltyrosine ((18)FET) uptake kinetic studies were combined with frame-based stereotactic localization techniques and used as a guide for stepwise (1-mm steps) histopathological evaluation throughout the tumor space. In tumors with heterogeneous PET findings, the O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation status and expression of mutated protein isocitrate dehydrogenase variant R132H (IDH1) were determined inside and outside of hot spot volumes. Metabolic imaging revealed 3 subgroups: the homogeneous WHO grade II glioma group (30 patients), the homogeneous malignant glioma group (10 patients), and the heterogeneous group exhibiting both low- and high-grade characteristics at different sites (15 patients). Stepwise evaluation of 373 biopsy samples indicated a strong correlation with analyses of uptake kinetics (p < 0.0001). A homogeneous pattern of uptake kinetics was linked to homogeneous histopathological findings, whereas a heterogeneous pattern was associated with histopathological heterogeneity; hot spots exhibiting malignant glioma characteristics covered 4-44% of the entire tumor volumes. Both MGMT and IDH1 status were identical at different tumor sites and not influenced by heterogeneity. Maps of (18)FET uptake kinetics strongly correlated with histopathology in suspected grade II gliomas. Anaplastic foci can be accurately identified, and this finding has implications for prognostic evaluation and treatment planning.

Background and purpose The aim of this study was to compare MRI-based morphological gross tumour volumes (GTVs) to biological tumour volumes (BTVs), defined by the pathological radiotracer uptake in positron emission tomography (PET) imaging with 18 F-fluoroethyltyrosine (FET), subsequently clinical target volumes (CTVs) and finally planning target volumes (PTVs) for radiotherapy planning of glioblastoma. Patients and methods Seventeen patients with glioblastoma were included into a retrospective protocol. Treatment-planning was performed using clinical target volume (CTV=BTV+20mm or CTV=GTV+20mm+inclusion of the edema) and planning target volume (PTV=CTV+5mm). Image fusion and target volume delineation were performed with OTP-Masterplan®. Initial gross tumour volume (GTV) definition was based on MRI data only or FET–PET data only (BTV), secondarily both data sets were used to define a common CTV. Results FET based BTVs (median 43.9cm 3 ) were larger than corresponding GTVs (median 34.1cm 3 , p =0.028), in 11 of 17 cases there were major differences between GTV/BTV. To evaluate the conformity of both planning methods, the index (CTV MRT ∩CTV FET )/(CTV MRT ∪CTV FET ) was quantified which was significantly different from 1 (0.73±0.03, p Conclusion With FET–PET-CT planning, the size and geometrical location of GTVs/BTVs differed in a majority of patients. It remains open whether FET–PET-based target definition has a relevant clinical impact for treatment planning.

Molecular imaging with ictal and interictal single-photon emission computed tomography (SPECT) as well as positron emission tomography (PET) rank among the established functional imaging tests for the presurgical evaluation of epileptic onset zone in patients with intractable partial epilepsy. In temporal lobe epilepsy the sensitivity of these methods was shown to be excellent, in particular if a multimodal platform is used, which combines the functional imaging with the additional morphological information of magnetic resonance imaging (MRI), but was lower in extra temporal lobe epilepsy. Functional imaging with SPECT and PET reflects seizure related changes of cerebral perfusion, glucose-metabolism and neuroreceptor status. In this review the usefulness of SPECT and PET imaging in clinical routine in epilepsy as well as the role of different neuroreceptor PET-tracer, which were used in epilepsy are discussed. The use of perfusion SPECT tracer allows the investigation of ictal activations, but the low temporal resolution of ictal perfusion SPECT often results in the detection of both the ictal onset zone as well as the propagation pathways, an area that has not always need to be resected in order to render a patient seizure free. The additional use of interictal PET with fluorine-18 fluorodeoxyglucose which measures regional cerebral metabolism or interictal perfusion SPECT enhance the informational value of ictal SPECT and were shown to be important tools to better define the ictal onset and surround inhibition zones. In recent years PET imaging of different cerebral neuroreceptor-systems inter alia GABA(A) receptors, serotonin receptors (5-HT(1A)), opioid receptors as well as dopamine receptors was used to investigate the neurochemical basis of epilepsy, the role of these neurotransmitters for the epileptogenesis as well as the spread of epileptic activity during seizures and partially entered in clinical routine. Currently some of these radioligands are also used to investigate new treatment approaches.

The safety and efficacy of cell-based therapies for neurodegenerative diseases depends on the mode of cell administration. We hypothesized that intranasally administered cells could bypass the blood-brain barrier by migrating from the nasal mucosa through the cribriform plate along the olfactory neural pathway into the brain and cerebrospinal fluid (CSF). This would minimize or eliminate the distribution of cellular grafts to peripheral organs and will help to dispense with neurosurgical cell implantation. Here we demonstrate transnasal delivery of cells to the brain following intranasal application of fluorescently labeled rat mesenchymal stem cells (MSC) or human glioma cells to naive mice and rats. After cells crossed the cribriform plate, two migration routes were identified: (1) migration into the olfactory bulb and to other parts of the brain; (2) entry into the CSF with movement along the surface of the cortex followed by entrance into the brain parenchyma. The delivery of cells was enhanced by hyaluronidase treatment applied intranasally 30 min prior to the application of cells. Intranasal delivery provides a new non-invasive method for cell delivery to the CNS.

We investigated the use of Ga-68-DOTA-Tyr 3 -octreotate (Ga-68-DOTA-TATE) positron emission tomography (PET) and standardized uptake values (SUVs) to predict the effectiveness of treatment with the somatostatin analogue octreotide acetate (Sandostatin LAR) in patients with neuroendocrine tumors (NETs). Thirty patients with well-differentiated NETs of the ileum (grades G1 and G2) were studied with Ga-68-DOTA-TATE. The average SUV of a 50% isocontour volume of interest covering the lesion with maximum uptake (SUV mean ) and the maximum SUV (SUV max ) were determined. Patients were followed up, and the time to progression was recorded. Twenty-one patients showed progressive disease at the end of the study; nine patients had stable disease. The median progression-free survival (PFS) was 51.0 weeks (95% confidence interval [CI] 26.4-75.6). A cutoff for the SUV max of 29.4 and for the SUV mean of 20.3 could separate between patients with a long PFS (69.0 weeks; 95% CI 9.8-128.2) and a short PFS (26.0 weeks; 95% CI 8.7-43.3) response to octreotide acetate therapy. Patients with high radiotracer uptake had significantly higher PFS with a 2.9-fold higher chance for stable disease after 45 weeks; however, the prognostic performance of SUV max on an individual basis was poor, with a sensitivity of 75% and a specificity of 64%. SUV max and SUV mean of NET tumor lesions in Ga-68-DOTA-TATE PET are important prognostic indices for predicting the response to therapy with octreotide acetate.