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.

[TSH secreting adenoma of pituitary gland (TSHom) - rare cause of hyperthyroidism in pregnancy]. / TSH-sezernierendes Hypophysenadenom (TSHom) - seltene Ursache einer Hyperthyreose in der Schwangerschaft.

HISTORY AND ADMISSION FINDINGS: A 28 year-old woman in her first pregnancy was referred to the department of obstetrics and gynecology at 24 weeks of gestation because of pregnancy-induced hypertension. INVESTIGATIONS: Thyroid stimulating hormone (TSH), free T3 and free T4 were elevated. Antibody screening did not show antithyroid peroxidase (anti-TPO) antibodies and TSH receptor antibodies. Clinical findings were suspicious of TSH secreting pituitary tumour (TSH-om) or thyroid hormone resistance (RTH). In absence of clinical sings of elevated intracranial pressure magnetic resonance imaging (MR) was discussed but not carried out and planned after delivery. A visual-field defect was ruled out by orbital field evaluation. TREATMENT AND COURSE: Treatment with 3 × 50 mg propylthiouracil daily was initiated. However, normal fT3/fT4 titers could not be achieved. Serum levels were in the high normal ranges and TSH remained increased. The clinical situation of the patient improved resulting in a normal delivery at term. The healthy newborn was breast feed and MR imaging of the mother revealed a 5×8 mm tumor of the pituitary gland. CONCLUSION: In pregnant women with pregnancy-induced hypertension thyroid diseases have to be ruled out. Rare causes of hyperthyreoidism are TSH secreting pituitary tumors or thyroid hormone resistance (RTH). Treatment of choice for hyperthyreoidism in pregnancy is propylthiouracil. Normal vaginal delivery and breast feeding are possible. Following delivery it is mandatory to determine an individual treatment strategy.

Risk stratification in middle-aged patients with congestive heart failure: prospective comparison of the Heart Failure Survival Score (HFSS) and a simplified two-variable model.

AIMS: The performance of a US-American scoring system (Heart Failure Survival Score, HFSS) was prospectively evaluated in a sample of ambulatory patients with congestive heart failure (CHF). Additionally, it was investigated whether the HFSS might be simplified by assessment of the distance ambulated during a 6-min walk test (6'WT) instead of determination of peak oxygen uptake (peak VO(2)). METHODS AND RESULTS: In 208 middle-aged CHF patients (age 54+/-10 years, 82% male, NYHA class 2.3+/-0.7; follow-up 28+/-14 months) the seven variables of the HFSS: CHF aetiology; heart rate; mean arterial pressure; serum sodium concentration; intraventricular conduction time; left ventricular ejection fraction (LVEF); and peak VO(2), were determined. Additionally, a 6'WT was performed. The HFSS allowed discrimination between patients at low, medium and high risk, with mortality rates of 16, 39 and 50%, respectively. However, the prognostic power of the HFSS was not superior to a two-variable model consisting only of LVEF and peak VO(2). The areas under the receiver operating curves (AUC) for prediction of 1-year survival were even higher for the two-variable model (0.84 vs. 0.74, P<0.05). Replacing peak VO(2) with 6'WT resulted in a similar AUC (0.83). CONCLUSION: The HFSS continued to predict survival when applied to this patient sample. However, the HFSS was inferior to a two-variable model containing only LVEF and either peak VO(2) or 6'WT. As the 6'WT requires no sophisticated equipment, a simplified two-variable model containing only LVEF and 6'WT may be more widely applicable, and is therefore recommended.

Oxygen stress increases prolyl cis/trans isomerase activity and expression of cyclophilin 18 in rabbit blastocysts.

The peptidyl-prolyl cis/trans isomerase (PPIase) activity and the expression of cyclophilins were studied in 6-day-old rabbit preimplantation embryos cultured under physiological and increased oxygen concentrations of 5% and 20% O(2), respectively. The PPIase activity was completely inhibited by cyclosporin A (CsA). The inhibitor of FK506-binding proteins, rapamycin, had no effect on the PPIase activity, indicating that the PPIase activity in rabbit blastocysts originates from cyclophilins. Using CsA affinity chromatography, only one cyclophilin with a molecular mass of about 17.8 kDa was separated. The cDNA of rabbit cyclophilin was cloned and sequenced. Analysis of the 682-base pair cDNA revealed an open reading frame coding for a polypeptide of 164 amino acid residues with a molecular weight of 17.83 kDa. Homologies of 90% and 96% for the cDNA and amino acid sequence, respectively, to the human CyP18 were found, suggesting that the novel rabbit cyclophilin is a member of the CyP18 family (rabCyP18). The transcription level of rabCyP18 mRNA was 8.3 +/- 0.6 pg in 100 ng total RNA in noncultured blastocysts. In vitro culture with moderate oxygen stress (20% O(2)) resulted in a 1.5-fold increase in rabCyP18 transcription and an increased PPIase activity compared to that of blastocysts cultured with 5% O(2). Increase in transcription rate and PPIase activity by oxygen stress suggests an involvement of CyP18 in oxygen defense in rabbit preimplantation embryos.

Detection of numerical chromosomal changes in 20 malignant fibrous histiocytomas by FISH.

We investigated 20 malignant fibrous histiocytomas (MFHs) with the help of specific centromeric probes for chromosomes 1, 3, 4, 6, 8, 9, 12, 16, 17 and 18. The results show a broad variation in the number of signals per nucleus. However, tumors can be assigned into four groups: i) with mostly disomic clones, ii) with a high percentage of polysomic clones, iii) with a considerable amount of monosomic and nullisomic clones and iv) with a tendency in both directions. A gain of spots per nucleus takes place in 75-100% of the investigated tumors - the highest incidence occurring with respect to chromosome 3. A loss of spots per nucleus occurred in 20-60% of the tumors - predominantly with respect to chromosome 1.

Cytogenetic characterization of ten malignant fibrous histiocytomas.

We examined 10 malignant fibrous histiocytomas (MFHs) using metaphase preparations. Six tumors showed clonal structural and/or numerical chromosomal aberrations, and four tumors had normal karyotypes. For the most part, chromosomes 1, 3, 6, 9, 12, 16, 18, and 20 were involved in structural aberrations. The breakpoint regions most frequently were in 1p32, 3p25, and the centromeric region of chromosomes 1 and 16. There was a conspicuous loss in chromosome 18. We detected ring chromosomes in two tumors. One tumor showed a high percentage of near-haploid cells. Our results show many parallels to data which have already been published. MFHs include a broad spectrum of tumors of widely different histology and clinical course. So it is not surprising to find a cytogenetic diversity of chromosomal aberrations in this study.

Gastroesophageal reflux in patients with sleep apnea syndrome.

UNLABELLED: Gastroesophageal reflux (GER) may be associated with pulmonary diseases. The aim of this study was to investigate the role of GER in patients with sleep apnea syndrome (SAS). We evaluated, therefore, in patients with SAS the occurrence of GER during simultaneous apnea monitoring, and whether GER is related to the severity of SAS. METHODS: 17 consecutive patients with proven SAS were divided into two groups according to the severity of SAS: (A) apnea index > or = 5 and < 15, n = 8; (B) apnea index > or = 15, n = 9. All patients underwent 24 hours pH-metry in the proximal and distal esophagus and simultaneous apnea monitoring during the night. RESULTS: There was a high occurrence of GER in patients with SAS, but no significant difference was found between the two groups with respect to reflux times at the distal or at the proximal esophageal site. Reflux episodes and apnea periods were not timely correlated. Most of the patients of both groups were obese. CONCLUSIONS: Patients with SAS often have GER. However, there is neither a relation of GER with the severity of SAS nor a timely association between GER- and SAS-episodes. Thus, it is unlikely that there is a direct link between GER and SAS. However, there may be factors predisposing for both diseases.

[Possibilities and limits of practice-oriented daily control measurements of linear accelerators]. / Möglichkeiten und Grenzen praxisorientierter täglicher Kontrollmessungen an Linearbeschleunigern.

Daily control measurements of the dose taken at a linear accelerator are described in order to present a practice-oriented measurement and evaluation method rendering possible a long-term quality control. This method allows to establish sudden parameter variations as well as to determine in a simple and precise manner long-term drifting effects with an amplitude within the range of measurement variations and a period of many months. During the time of six months, not only a drifting effect with a long period and an amplitude within the range of pro mille, but also a variation coefficient smaller than 0,3% could be determined.