Fractionated stereotactic radiotherapy of intracranial postoperative cavities after resection of brain metastases - Clinical outcome and prognostic factors.

Background and Purpose: After surgical resection of brain metastases (BM), radiotherapy (RT) is indicated. Postoperative stereotactic radiosurgery (SRS) reduces the risk of local progression and neurocognitive decline compared to whole brain radiotherapy (WBRT). Aside from the optimal dose and fractionation, little is known about the combination of systemic therapy and postoperative fractionated stereotactic radiotherapy (fSRT), especially regarding tumour control and toxicity. Methods: In this study, 105 patients receiving postoperative fSRT with 35 Gy in 7 fractions performed with Cyberknife were retrospectively reviewed. Overall survival (OS), local control (LC) and total intracranial brain control (TIBC) were analysed via Kaplan-Meier method. Cox proportional hazards models were used to identify prognostic factors. Results: Median follow-up was 20.8 months. One-year TIBC was 61.6% and one-year LC was 98.6%. Median OS was 28.7 (95%-CI: 16.9-40.5) months. In total, local progression (median time not reached) occurred in 2.0% and in 20.4% radiation-induced contrast enhancements (RICE) of the cavity (after median of 14.3 months) were diagnosed. Absence of extracranial metastases was identified as an independent prognostic factor for superior OS (p = <0.001) in multivariate analyses, while a higher Karnofsky performance score (KPS) was predictive for longer OS in univariate analysis (p = 0.041). Leptomeningeal disease (LMD) developed in 13% of patients. Conclusion: FSRT after surgical resection of BM is an effective and safe treatment approach with excellent local control and acceptable toxicity. Further prospective randomized trials are needed to establish standardized therapeutic guidelines.

Impact of (forensic) expert opinions according to the Istanbul Protocol in Germany-results and insights of the in:Fo-project.

As part of a third-party funded project, expert opinions according to the Istanbul Protocol (IP) standards were compiled in Germany on a larger scale for the first time. The assessment process was initiated for 130 project participants. Statistical analysis on numerous variables was performed to test the impact of the expert opinions, foremost of the forensic medical expert opinions, on the individuals' asylum proceedings. The variables were drawn from forensic medical expert opinions and reports of findings, questionnaires for the study participants' counsellors in the project and a query on the asylum status of the study participants. Regression analysis and bivariate analysis on two dependent variables-subjective impact on the asylum procedure from the counsellors' point of view and objective change in the asylum status-were performed to test for an influence on asylum procedures. No statistically significant results were obtained for the objective change of the study participants' asylum status. For the subjective dependent variable, a positive prediction was possible when simultaneously controlling for the independent variables introduction of a forensic medical expert opinion and highest IP grade; a negative prediction was possible when simultaneously controlling for the independent variables introduction of a forensic medical expert opinion and use of IP grading. Apart from the statistical analysis, a positive effect of the assessment on the psychosocial well-being of the study participants could be demonstrated. The results differed from other European studies which demonstrated a correlation between the objective outcome of an asylum procedure (asylum status) and, for example, specific types of violence or the number of documented injuries. Differences also occurred in the use of the plausibility grades proposed by the IP, which questions their use in cases in which the reported torture happened a relevant time ago. Therefore, compiling individually worded evaluations instead of using the IP grading system-if possible, by an experienced forensic physician-is recommended in this scenario. Still, the assessment of alleged torture experiences should follow the IP guidelines, since psychological assessments are of especially high importance in cases with healed physical injuries and since the results also demonstrated a positive effect on the psychosocial well-being of the study participants.

Isocitrate-dehydrogenase-mutant lower grade glioma in elderly patients: treatment and outcome in a molecularly characterized contemporary cohort.

PURPOSE: Lower-grade glioma (LGG) is rare among patients above the age of 60 ("elderly"). Previous studies reported poor outcome, likely due to the inclusion of isocitrate dehydrogenase (IDH) wildtype astrocytomas and advocated defensive surgical and adjuvant treatment. This study set out to question this paradigm analyzing a contemporary cohort of patients with IDH mutant astrocytoma and oligodendroglioma WHO grade 2 and 3. METHODS: Elderly patients treated in our department for a supratentorial, hemispheric LGG between 2009 and 2019 were retrospectively analyzed for patient-, tumor- and treatment-related factors and progression-free survival (PFS) and compared to patients aged under 60. Inclusion required the availability of subtype-defining molecular data and pre- and post-operative tumor volumes. RESULTS: 207 patients were included, among those 21 elderlies (10%). PFS was comparable between elderly and younger patients (46 vs. 54 months; p = 0.634). Oligodendroglioma was more common in the elderly (76% vs. 46%; p = 0.011). Most patients underwent tumor resection (elderly: 81% vs. younger: 91%; p = 0.246) yielding comparable residual tumor volumes (elderly: 7.8 cm3; younger: 4.1 cm3; p = 0.137). Adjuvant treatment was administered in 76% of elderly and 61% of younger patients (p = 0.163). Uni- and multi-variate survival analyses identified a tumor crossing the midline, surgical strategy, and pre- and post-operative tumor volumes as prognostic factors. CONCLUSION: Elderly patients constitute a small fraction of molecularly characterized LGGs. In contrast to previous reports, favorable surgical and survival outcomes were achieved in our series comparable to those of younger patients. Thus, intensified treatment including maximal safe resection should be advocated in elderly patients whenever feasible.

MR-guided adaptive versus ITV-based stereotactic body radiotherapy for hepatic metastases (MAESTRO): a randomized controlled phase II trial.

BACKGROUND: Stereotactic body radiotherapy (SBRT) is an established local treatment method for patients with hepatic oligometastasis or oligoprogression. Liver metastases often occur in close proximity to radiosensitive organs at risk (OARs). This limits the possibility to apply sufficiently high doses needed for optimal local control. Online MR-guided radiotherapy (oMRgRT) is expected to hold potential to improve hepatic SBRT by offering superior soft-tissue contrast for enhanced target identification as well as the benefit of gating and daily real-time adaptive treatment. The MAESTRO trial therefore aims to assess the potential advantages of adaptive, gated MR-guided SBRT compared to conventional SBRT at a standard linac using an ITV (internal target volume) approach. METHODS: This trial is conducted as a prospective, randomized, three-armed phase II study in 82 patients with hepatic metastases (solid malignant tumor, 1-3 hepatic metastases confirmed by magnetic resonance imaging (MRI), maximum diameter of each metastasis ≤ 5 cm (in case of 3 metastases: sum of diameters ≤ 12 cm), age ≥ 18 years, Karnofsky Performance Score ≥ 60%). If a biologically effective dose (BED) ≥ 100 Gy (α/ß = 10 Gy) is feasible based on ITV-based planning, patients will be randomized to either MRgRT or ITV-based SBRT. If a lesion cannot be treated with a BED ≥ 100 Gy, the patient will be treated with MRgRT at the highest possible dose. Primary endpoint is the non-inferiority of MRgRT at the MRIdian Linac® system compared to ITV-based SBRT regarding hepatobiliary and gastrointestinal toxicity CTCAE III or higher. Secondary outcomes investigated are local, locoregional (intrahepatic) and distant tumor control, progression-free survival, overall survival, possible increase of BED using MRgRT if the BED is limited with ITV-based SBRT, treatment-related toxicity, quality of life, dosimetric parameters of radiotherapy plans as well as morphological and functional changes in MRI. Potential prognostic biomarkers will also be evaluated. DISCUSSION: MRgRT is known to be both highly cost- and labor-intensive. The MAESTRO trial aims to provide randomized, higher-level evidence for the dosimetric and possible consecutive clinical benefit of MR-guided, on-table adaptive and gated SBRT for dose escalation in critically located hepatic metastases adjacent to radiosensitive OARs. TRIAL REGISTRATION: The study has been prospectively registered on August 30th, 2021: Clinicaltrials.gov, "Magnetic Resonance-guided Adaptive Stereotactic Body Radiotherapy for Hepatic Metastases (MAESTRO)", NCT05027711.

The life cycle-dependent transcriptional profile of the obligate intracellular amoeba symbiont Amoebophilus asiaticus.

Free-living amoebae often harbor obligate intracellular bacterial symbionts. Amoebophilus (A.) asiaticus is a representative of a lineage of amoeba symbionts in the phylum Bacteroidota. Here, we analyse the transcriptome of A. asiaticus strain 5a2 at four time points during its infection cycle and replication within the Acanthamoeba host using RNA sequencing. Our results reveal a dynamic transcriptional landscape throughout different A. asiaticus life cycle stages. Many intracellular bacteria and pathogens utilize eukaryotic-like proteins (ELPs) for host cell interaction and the A. asiaticus 5a2 genome shows a particularly high abundance of ELPs. We show the expression of all genes encoding ELPs and found many ELPs to be differentially expressed. At the replicative stage of A. asiaticus, ankyrin repeat proteins and tetratricopeptide/Sel1-like repeat proteins were upregulated. At the later time points, high expression levels of a type 6 secretion system that likely prepares for a new infection cycle after lysing its host, were found. This study reveals comprehensive insights into the intracellular lifestyle of A. asiaticus and highlights candidate genes for host cell interaction. The results from this study have implications for other intracellular bacteria such as other amoeba-associated bacteria and the arthropod symbionts Cardinium forming the sister lineage of A. asiaticus.

Effect of timing, technique and molecular features on brain control with local therapies in oncogene-driven lung cancer.

BACKGROUND: The improved efficacy of tyrosine kinase inhibitors (TKI) mandates reappraisal of local therapy (LT) for brain metastases (BM) of oncogene-driven non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: This study included all epidermal growth factor receptor-mutated (EGFR+, n = 108) and anaplastic lymphoma kinase-rearranged (ALK+, n = 33) TKI-naive NSCLC patients diagnosed with BM in the Thoraxklinik Heidelberg between 2009 and 2019. Eighty-seven patients (62%) received early LT, while 54 (38%) received delayed (n = 34; 24%) or no LT (n = 20; 14%). LT comprised stereotactic (SRT; n = 40; 34%) or whole-brain radiotherapy (WBRT; n = 77; 66%), while neurosurgical resection was carried out in 19 cases. RESULTS: Median overall survival (OS) was 49.1 months for ALK+ and 19.5 months for EGFR+ patients (P = 0.001), with similar median intracranial progression-free survival (icPFS) (15.7 versus 14.0 months, respectively; P = 0.80). Despite the larger and more symptomatic BM (P < 0.001) of patients undergoing early LT, these experienced longer icPFS [hazard ratio (HR) 0.52; P = 0.024], but not OS (HR 1.63; P = 0.12), regardless of the radiotherapy technique (SRT versus WBRT) and number of lesions. High-risk oncogene variants, i.e. non-del19 EGFR mutations and 'short' EML4-ALK fusions (mainly variant 3, E6:A20), were associated with earlier intracranial progression (HR 2.97; P = 0.001). The longer icPFS with early LT was also evident in separate analyses of the EGFR+ and ALK+ subsets. CONCLUSIONS: Despite preferential use for cases with poor prognostic factors, early LT prolongs the icPFS, but not OS, in TKI-treated EGFR+/ALK+ NSCLC. Considering the lack of survival benefit, and the neurocognitive effects of WBRT, patients presenting with polytopic BM may benefit from delaying radiotherapy, or from radiosurgery of multiple or selected lesions. For SRT candidates, the improved tumor control with earlier radiotherapy should be weighed against the potential toxicity and the enhanced intracranial activity of newer TKI. High-risk EGFR/ALK variants are associated with earlier intracranial failure and identify patients who could benefit from more aggressive management.

Soluble monomers, dimers and HLA-G-expressing extracellular vesicles: the three dimensions of structural complexity to use HLA-G as a clinical biomarker.

The HLA-G molecule belongs to the family of nonclassical human leukocyte antigen (HLA) class I. At variance to classical HLA class I, HLA-G displays (i) a low number of nucleotide variations within the coding region, (ii) a high structural diversity, (iii) a restricted peptide repertoire, (iv) a limited tissue distribution and (v) strong immune-suppressive properties. The physiological HLA-G surface expression is restricted to the maternal-fetal interface and to immune-privileged adult tissues. Soluble forms of HLA-G (sHLA-G) are detectable in various body fluids. Cellular activation and pathological processes are associated with an aberrant or a neo-expression of HLA-G/sHLA-G. Functionally, HLA-G and its secreted forms are considered to be key players in the induction of short- and long-term tolerance. Thus, its unique expression profile and tolerance-inducing functions render HLA-G/sHLA-G an attractive biomarker to monitor the systemic health/disease status and disease activity/progression for clinical approaches in disease management and treatments. Here, we place emphasis on (i) the current status of the tolerance-inducing functions by HLA-G/sHLA-G, (ii) the current complexity to implement this molecule as a meaningful clinical biomarker regarding the three dimensions of structural diversity (monomers, dimers and HLA-G-expressing extracellular vesicles) with its functional implications, and (iii) novel and future approaches to detect and quantify sHLA-G structures and functions.

The 2014 liver ultrasound tracking benchmark.

The Challenge on Liver Ultrasound Tracking (CLUST) was held in conjunction with the MICCAI 2014 conference to enable direct comparison of tracking methods for this application. This paper reports the outcome of this challenge, including setup, methods, results and experiences. The database included 54 2D and 3D sequences of the liver of healthy volunteers and tumor patients under free breathing. Participants had to provide the tracking results of 90% of the data (test set) for pre-defined point-landmarks (healthy volunteers) or for tumor segmentations (patient data). In this paper we compare the best six methods which participated in the challenge. Quantitative evaluation was performed by the organizers with respect to manual annotations. Results of all methods showed a mean tracking error ranging between 1.4 mm and 2.1 mm for 2D points, and between 2.6 mm and 4.6 mm for 3D points. Fusing all automatic results by considering the median tracking results, improved the mean error to 1.2 mm (2D) and 2.5 mm (3D). For all methods, the performance is still not comparable to human inter-rater variability, with a mean tracking error of 0.5-0.6 mm (2D) and 1.2-1.8 mm (3D). The segmentation task was fulfilled only by one participant, resulting in a Dice coefficient ranging from 76.7% to 92.3%. The CLUST database continues to be available and the online leader-board will be updated as an ongoing challenge.

Prevalence of biofilms on surgical suture segments in wounds of dogs, cats, and horses.

The formation of biofilms on surgical implants is thought to play a major role in chronic infection and wound-healing disorders and has been rarely described in veterinary medicine. Due to poor and unreliable results from bacterial culturing, histology may be an economic tool for the detection of biofilms. In this study, the prevalence of biofilms on surgical suture materials and swabs with chronic wound-healing complications in dogs, cats, and horses was assessed by histologic examination using hematoxylin and eosin, Gram, and Giemsa stains, as well as periodic acid-Schiff reaction. Of the 91 tissue samples with intralesional suture material or swab residues associated with inflammation, only 2 contained bacterial colonies arranged in an extracellular polymeric matrix consistent with a biofilm. The results of this study suggest that biofilms on suture material may occur in veterinary medicine.

Next Generation Sequencing Analysis of Biofilms from Three Dogs with Postoperative Surgical Site Infection.

The composition of biofilms in chronic wound infections of dogs is unclear. In the present study, histologically identified biofilms attached to sutures in chronically infected wounds of three dogs were examined by next generation sequencing of total DNA extracted from formalin-fixed and paraffin-embedded tissue samples. The analysis identified an inhomogeneous bacterial composition in three tissues containing biofilms. Some of the identified bacterial families such as Staphylococci and Streptococci have been found before in biofilms associated with human and canine wounds but in this study were quantitatively in the minority. The majority of the reads classified as bacterial sequences had the highest identity with sequences belonging to the Porphyromonadaceae, Deinococcaceae, Methylococcaceae, Nocardiaceae, Alteromonadaceae, and Propionibacteriaceae and thus taxons of so far minor relevance in veterinary medicine.

[Locoregional deformation pattern of the patellar cartilage after different loading types - high-resolution 3D-MRI volumetry at 3 T in-vivo]. / Lokoregionäre Deformationsmuster im Patellarknorpel nach unterschiedlichen Belastungsparadigmen - hochauflösende 3-D-MR-Volumetrie bei 3 T in vivo.

PURPOSE: To analyze locoregional deformation patterns indicative of contact areas in patellar cartilage after different loading exercises. MATERIALS AND METHODS: 7 healthy patellae were examined in-vivo before and immediately after standardized loading (kneeling, squatting or knee bends) and after 90 minutes of rest using a sagittal 3D-T1-w FLASH WE sequence (22 msec/ 9.8 msec/ 15°/ 0.3 × 0.3 × 1.5 mm³) at 3 T. After cartilage segmentation and 3D reconstruction, voxel-based and global precision errors (PR) were calculated. The former were used to determine significant differences in local cartilage thickness. Voxel-based 2σ-thickness difference maps were calculated to visualize locoregional deformation patterns. Global changes in volume (Vol), mean thickness (mTh) and cartilage-bone-interface area (CBIA) were calculated. RESULTS: The voxel-based PR depended on cartilage thickness (D) ranging from 0.12 - 0.35 mm. For D ≥ 1 mm the RF was < 0.31 mm (< voxel size), and for D ≥ 2 mm, the RF was < 0.22 mm. The global PR was 83 mm³ (2.4 %) for Vol, 0.06 mm (2.0 %) for mTh and 16 mm² (1.4 %) for CBIA. The focal cartilage deformation equaled 14 % of the local thickness reduction. The deformation areas were oval and located in the peripheral medial (more vertically oriented, all exercises) and caudo-lateral (more horizontally oriented, kneeling and knee bends) aspects of the patella and were least pronounced in knee bends. Significant changes for Vol/mTh ranged from 2.1 to 3.7 %. CONCLUSION: This MRI-based study is the first to identify in-vivo voxel-based patellar cartilage deformation patterns indicating contact and loading zones after kneeling and squatting. These zones are anatomically and functionally plausible and may represent areas where stress induced degeneration and subsequent OA can originate. The data may facilitate understanding of individual knee loading properties and help to improve and validate biomechanical models for the knee.

[Results of the use of lithium to prevent recurrence of affective psychosis]. / Ergebnisse der Lithium-Rezidivprophylaxe affektiver Psychosen.

The efficacy of lithium treatment in preventing relapse in phasal psychoses was tested by the re-examination of 99 patients at a Dresden clinic whose treatment had on average exceeded ten years. Results and progress were compared with those of patients starting treatment since the introduction of the lithium treatment in the year 1979. Phase or subphase frequency and duration, conditions of treatment, suicide attempts, unfitness for work, and registration as a disabled person were among the aspects considered.

Effects of methohexitone, althesin, ketamine and droperidol on peripheral vagal transmission.

The effects of methohexitone, ketamine, Althesin and droperidol on the peripheral vagal transmission to the heart were studied in decerebrate cats by evaluating the influences of the drugs on the heart rate responses to vagal electrostimulation and the injection of acetylcholine i.v. The sites of the peripheral vagal transmission (vagal ganglia and sino-atrial pacemaker cells) were reached by the application of the drugs to the pericardial space. The bradycardia in response to vagal electrostimulation was attenuated by Althesin (2.1 x 10(-4)-3.3 x 10(-3) mol litre-1; expressed as the concentration of alphaxalone), ketamine (2.9 x 10(-4)-4.6 x 10(-3) mol litre-1) and droperidol (2.6 x 10(-5)-6.6 x 10(-4) mol litre-1) in a concentration-dependent manner, but not influenced by methohexitone (2.8 x 10(-4)-4.4 x 10(-3) mol litre-1). The bradycardia-attenuating effects were probably caused by an atropine-like action since the heart rate responses to the injection of acetylcholine i.v. were also attenuated by the same three drugs.

[Lithium strumas and their psychiatric relevance]. / Die Lithiumstruma und ihre psychiatrische Relevanz.

Basing on 172 clinically recorded goitres among 787 patients treated with lithium (21.9%) we studied the question as to whether goitre formation due to lithium has any relevance within the concept of relapse prevention in affective disorders. A statistical comparison of essential disease parameters between the group of patients suffering from struma (goitre) and the total group shows that there is no special type or course of affective disorder with a particular affinity to the development of struma. Likewise, we can conclude from a comparison of treatment course and effectively parameters between both groups that development of struma under influence on the course of treatment or on the efficiency of prophylaxis. The results point to an irrelevance of lithium goitre in respect of psychiatric effects (this does not imply that it is irrelevant in respect of general medical aspects or endocrinology).

[Clinical trial of contemnol tablets (lithium retard Spofa)]. / Klinische Erprobung von Contemnol-Tabletten (Lithium-Retard Spofa).

A report on the clinical testing of the lithium-retard medicament Contemnol (Spofa). It details the way lithium-retard treatment is objectively and subjectively superior to the earlier and still current general lithium treatment.

[Sea dumping of radioactive wastes]. / Meeresversenkung radioaktiver Abfälle.

This paper is an introduction to the problems of dumping at sea of radioactive wastes. A short survey is given on the dumping actions previously performed, the legal justification by international treaties, and the most important radioecological questions.