Neoadjuvant irradiation of extremity soft tissue sarcoma with ions (Extrem-ion): study protocol for a randomized phase II pilot trial.

BACKGROUND: The standard of care treatment for soft tissue sarcoma of the extremities is a wide resection in combination with pre- or postoperative radiotherapy with high local control rates, sparing patients the necessity of amputation without compromising on overall survival rates. The currently preferred timing of radiotherapy is under debate. Albeit having higher rates of acute wound complications, late side effects like fibrosis, joint stiffness or edema are less frequent in preoperative compared to postoperative radiotherapy. This can be explained in smaller treatment volumes and a lower dose in the preoperative setting. Particles allow better sparing of surrounding tissues at risk, and carbon ions additionally offer biologic advantages and are preferred in less radiosensitive tumors. Hypofractionation allows for a significantly shorter treatment duration. METHODS: Extrem-ion is a prospective, randomized, monocentric phase II trial. Patients with resectable or marginally resectable, histologically confirmed soft tissue sarcoma of the extremities will be randomized between neoadjuvant proton or neoadjuvant carbon ion radiotherapy in active scanning beam application technique (39 Gy [relative biological effectiveness, RBE] in 13 fractions [5-6 fractions per week] in each arm). The primary objective is the proportion of therapies without wound healing disorder the first 120 days after surgery or discontinuation of treatment for any reason related to the treatment. The secondary endpoints of the study consist of local control, local progression-free survival, disease-free survival, overall survival, and quality of life. DISCUSSION: The aim of this study is to confirm that hypofractionated, preoperative radiotherapy is safe and feasible. The potential for reduced toxicity by the utilization of particle therapy is the rational of this trial. A subsequent randomized phase III trial will compare the hypofractionated proton and carbon ion irradiation in regards to local control. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04946357 ; Retrospectively registered June 30, 2021.

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.

[COVID-19-induced coagulopathy and thrombosis manifestations]. / COVID-19-induzierte Koagulopathien und thromboembolische Manifestationen.

CLINICAL ISSUE: Clinically, COVID-19 (coronavirus disease 2019) is increasingly seen as a systemic disease associated with multiorgan involvement through a hypercoagulatory condition in the sense of vasculopathy. STANDARD TREATMENT: Treatment with antiplatelet drugs or heparins appears to be indicated. The current evidence, at least for acetylsalicylic acid (ASA), is lacking. DIAGNOSTIC WORK-UP: Corresponding to the significant proportion of primarily microstructural vascular changes, the radiological diagnosis showed not only macrovascular pathologies, but also diffuse perfusion disorders. PERFORMANCE: Regional hypoperfusion in the lungs can be detected with and without pulmonary arterial embolism. Similar findings can be found in almost all organ systems. PRACTICAL RECOMMENDATIONS: A therapeutic intervention using low molecular weight heparins in hospitalized patients in situation-adapted dosage is indicated and is discussed in detail. In the detection of micro- and macrovascular thrombosis in the context of COVID-19, extended radiological diagnostics play a central role and are the basis of adapted therapy and secondary prevention.

[Radiological response assessment of modern immunotherapy using iRECIST]. / Radiologische Responsebeurteilung moderner Immuntherapien mithilfe von iRECIST.

CLINICAL/METHODICAL ISSUE: Modern immunotherapies in oncology show tumor response patterns differing from conventional chemotherapies including initial pseudo-progression. STANDARD RADIOLOGICAL METHODS: Response evaluation criteria in solid tumors (RECIST 1.1) represent the currently most used response criteria for conventional chemotherapy of solid tumors. However, atypical response patterns of immunotherapies are not correctly classified using RECIST 1.1 so that the effectiveness is also incorrectly interpreted. METHODICAL INNOVATIONS: In order to correctly interpret these atypical response patterns, special immune-related response criteria in solid tumors (iRECIST) have been published. In contrast to RECIST 1.1 according to iRECIST an initially unconfirmed progressive disease (iUPD) requires confirmation (iCPD) in clinically stable patients by subsequent control imaging after 4-8 weeks. New lesions are separately assessed within iRECIST. PERFORMANCE: The iRECIST procedure allows a standardized objective assessment of a possible pseudo-progression which can occur in up to 10% of cases depending on the immunomodulating drug and tumor entity. ACHIEVEMENTS: In principle, iRECIST was developed only for usage in trials testing modern immunotherapeutics. PRACTICAL RECOMMENDATIONS: The iRECIST procedure might also be helpful as an additional objective response criterium for clinical treatment decisions, taking the limitations into account.

Patch-Based Nonlinear Image Registration for Gigapixel Whole Slide Images.

OBJECTIVE: Image registration of whole slide histology images allows the fusion of fine-grained information-like different immunohistochemical stains-from neighboring tissue slides. Traditionally, pathologists fuse this information by looking subsequently at one slide at a time. If the slides are digitized and accurately aligned at cell level, automatic analysis can be used to ease the pathologist's work. However, the size of those images exceeds the memory capacity of regular computers. METHODS: We address the challenge to combine a global motion model that takes the physical cutting process of the tissue into account with image data that is not simultaneously globally available. Typical approaches either reduce the amount of data to be processed or partition the data into smaller chunks to be processed separately. Our novel method first registers the complete images on a low resolution with a nonlinear deformation model and later refines this result on patches by using a second nonlinear registration on each patch. Finally, the deformations computed on all patches are combined by interpolation to form one globally smooth nonlinear deformation. The NGF distance measure is used to handle multistain images. RESULTS: The method is applied to ten whole slide image pairs of human lung cancer data. The alignment of 85 corresponding structures is measured by comparing manual segmentations from neighboring slides. Their offset improves significantly, by at least 15%, compared to the low-resolution nonlinear registration. CONCLUSION/SIGNIFICANCE: The proposed method significantly improves the accuracy of multistain registration which allows us to compare different antibodies at cell level.

[Organ toxicity of medicinal tumor therapy: morphological correlates]. / Organtoxizität medikamentöser Tumortherapien: morphologische Korrelate.

CLINICAL/METHODOLOGICAL ISSUE: In antineoplastic chemotherapy classical cytostatic drugs are increasingly being supplemented by antibodies and so-called targeted therapies. In addition to the antineoplastic effect and general intolerance quite characteristic morphological changes can often be found and identified by the radiologist. The distinction between findings indicating side effects versus tumor progression or an infectious etiology is essential. FACTS AND CIRCUMSTANCES: Classical antineoplastic chemotherapy interacts with DNA and RNA synthesis, DNA repair or the mitosis process. In contrast modern targeted anticancer therapies act at the level of signal transduction pathways.Localized, organ-related changes are related to the metabolic characteristics of organs or anatomical features such as the properties of the local blood-tissue barrier. Toxicity associated findings often resemble fulminant tumor progression. EVALUATION: In new targeted anti-cancer therapies toxicity often occurs in a non-cumulative way; therefore, morphological changes are often precursors of the manifestation of clinical toxicity. PRACTICAL RECOMMENDATIONS: Oncological radiology requires increasingly active interdisciplinary dialogue in order to delineate morphological correlates of organ toxicity against tumor progression and initiate appropriate therapeutic measures.

MRI in lung cancer: a pictorial essay.

Imaging studies play a critical role in the diagnosis and staging of lung cancer. CT and 18-fluorodeoxyglucose positron emission tomography CT (PET/CT) are widely and routinely used for staging and assessment of treatment response. Many radiologists still use MRI only for the assessment of superior sulcus tumours, and in cases where invasion of the spinal cord canal is suspected. MRI can detect and stage lung cancer, and this method could be an excellent alternative to CT or PET/CT in the investigation of lung malignancies and other diseases. This pictorial essay discusses the use of MRI in the investigation of lung cancer.

Patterns of reoccurrence of segmental dystonia after discontinuation of deep brain stimulation.

The pattern of reoccurrence of symptoms after discontinuation of deep brain stimulation (DBS) has not been systematically studied in dystonia. Eight patients (mean age (SD) 53.8 (14.4) years) with segmental dystonia at a mean follow-up of 11.3 (4.2) months were studied after implantation of bilateral DBS electrodes in the internal globus pallidus using a standard video protocol and clinical rating scales, immediately and at 2 and 4 h after switching off DBS. Dystonic signs returned sequentially, with a rapid worsening of phasic and a slower worsening of tonic dystonic components. In all patients, phasic dystonic features appeared within a few minutes, whereas the tonic elements of dystonia reoccurred with a more variable delay. Differential clinical effects when withdrawing DBS might reflect its influence on different pathophysiological mechanisms in dystonia.

Impaired washout--embolism and ischemic stroke: further examples and proof of concept.

We previously posited that impaired washout of emboli was an important mechanism of brain infarction in patients with cerebral hypoperfusion. Hyperviscosity and hypoperfusion enhance thrombus formation promoting embolization of fresh thrombi. Hypoperfusion also reduces dissolution of emboli due to reduced flow velocity leading to classic hemodynamic patterns of stroke. To prove this concept further, we identified patients with severe hemodynamic compromise of either arterial or venous origin, or both, and natural or iatrogenic mechanisms of embolism. Three conditions were investigated in a stroke MRI protocol: 5 patients who had conventional cerebral angiography for the diagnosis of moyamoya disease, 1 patient with atrial fibrillation and thrombosis of the left transverse dural sinus and 1 patient with a patent foramen ovale with atrial septum aneurysm presenting with thrombosis of cortical cerebral veins. In all patients, subcortical arterial embolization within an atypical borderzone of hypoperfusion was observed.

Detection of delayed focal MR changes in the lateral hippocampus in transient global amnesia.

BACKGROUND: There is still limited knowledge on the location and etiology of transient global amnesia (TGA). MR studies including diffusion-weighted imaging (DWI) have been unable to demonstrate consistently the location and underlying pathology of TGA. OBJECTIVE: To investigate patients with TGA using serial DWI performed from the day of symptom onset through days 1 and 2. METHODS: After reporting negative DWI results in a previous study, the authors used a modified study design to investigate patients with TGA using serial DWI performed from the day of symptom onset through days 1 and 2. RESULTS: Of 31 consecutive patients studied, 26 developed a small, punctate DWI lesion in the lateral aspect of the hippocampal formation (pes and fimbria hippocampi) on either side (left, n = 15; right, n = 6) or bilaterally (n = 5). Lesions were rarely noted in the hyperacute phase (n = 2), but all became visible regularly at 48 hours. CONCLUSIONS: The study confirms the involvement of hippocampal parenchyma in the pathophysiology of TGA. The delayed detectability of the lesions may explain the incongruence of previous MR DWI studies in TGA patients.

[Glioblastoma multiforme as a manifestation of Turcot syndrome]. / Glioblastoma multiforme als Manifestation des Turcot-Syndroms.

Turcot's syndrome, clinically characterized by the coincident occurrence of primary tumors of the colon and the central nervous system, can genetically be divided into two syndromes: familial adenomatous polyposis (FAP) and hereditary nonpolyposis colon carcinoma (HNPCC). In the present case, a 60-year-old patient with glioblastoma multiforme and a history of hereditary malignomas is described as an example of a HNPCC-associated Turcot's syndrome. New molecular biological methods and results give deeper insight into clinical syndromes, and the better understanding improves diagnostics, therapy, and outcome estimations, even in rare diseases. In the present case, a new germinal mutation could be identified.

Amino acid metabolism in liver disease.

The impairment of transsulphuration during methionine degradation in hepatic failure can be counteracted by treatment with S-adenosylmethionine. Regarding the pathogenesis of hepatic encephalopathy, no convincing evidence exists for tryptophan, glutamine or glutamate being involved. Portal-systemic shunting-induced hyperammonaemia may reduce plasma branched-chain amino acids. The glucose effect on urea synthesis does not exist in cirrhosis.