Intrafractional stability of MR-guided online adaptive SBRT for prostate cancer.

BACKGROUND: MR-guided online adaptive stereotactic body radiation therapy (SBRT) for prostate cancer aims to reduce toxicity by full compensation of interfractional uncertainties. However, the process of online adaptation currently takes approximately 45 min during which intrafractional movements remain unaccounted for. This study aims to analyze the dosimetric benefit of online adaptation and to evaluate its robustness over the duration of one treatment fraction. METHODS: Baseline MR-scans at a MR-linear accelerator were acquired for ten healthy male volunteers for generation of mock-prostate SBRT plans with a dose prescription of 5 × 7.25 Gy. On a separate day, online MR-guided adaptation (ViewRay® MRIdian) was performed, and thereafter MR images were acquired every 15 min for 1 h to assess the stability of the adapted plan. RESULTS: A dosimetric benefit of online MR-guided adaptive re-planning was observed in 90% of volunteers. The median D95CTV- and D95PTV-coverage was improved from 34.8 to 35.5 Gy and from 30.7 to 34.6 Gy, respectively. Improved target coverage was not associated with higher dose to the organs at risk, most importantly the rectum (median D1ccrectum baseline plan vs. adapted plan 33.3 Gy vs. 32.3 Gy). The benefit of online adaptation remained stable over 45 min for all volunteers. However, at 60 min, CTV-coverage was below a threshold of 32.5 Gy in 30% of volunteers (30.6 Gy, 32.0 Gy, 32.3 Gy). CONCLUSION: The dosimetric benefit of MR-guided online adaptation for prostate SBRT was robust over 45 min in all volunteers. However, intrafractional uncertainties became dosimetrically relevant at 60 min and we therefore recommend verification imaging before delivery of MR-guided online adapted SBRT.

Drug-drug interactions of new active substances: mibefradil example.

INTRODUCTION: Mibefradil was approved as a novel calcium antagonist in Switzerland in 1996. Following its launch as an antihypertensive and anti-anginal agent, there were reports about serious pharmacokinetic and pharmacodynamic interactions occurring with other drugs frequently administered to patients with cardiovascular diseases. Despite appropriate modifications of the prescribing information, such interactions continued to occur. The drug was finally withdrawn after a study in patients with congestive heart failure showed a trend to higher mortality with mibefradil. This increase in mortality could again be due to multiple interactions between mibefradil and other drugs. In retrospect, it can be concluded that several of the interactions, including the theoretical risk of severe toxicity in some patients, could have been and in fact were predicted on the basis of the data available before introduction to the market. Depending on the benefits, these problems would however not necessarily represent an unacceptable risk for a new active compound. RESULTS AND CONCLUSION: The most important points revealed by this analysis were: (1) when interpreting the results of interaction studies, it is important to consider not only the mean of the interaction effect but also the observed and the theoretically conceivable extreme effects in individual subjects and (2) a drug with a high interaction potential may represent a high risk even if an adequate warning is included in the product information. The need for specific pharmacokinetic and pharmacodynamic interaction studies with new drugs and the limitations of the pivotal clinical efficacy and safety studies during phase III in order to reveal such interactions are discussed.

[Retrospective study of drug-induced agranulocytosis in hospitalized patients in Geneva and comparison with cases reported to IOCM]. / Etude rétrospective des cas d'agranulocytose médicamenteuse hospitalisés à Genève et comparaison avec les cas notifiés à l'OICM.

In a retrospective study, 19 cases classified as idiosyncratic drug-induced agranulocytosis were found among 162 files of patients hospitalized in internal medicine clinics of the university hospital where this diagnosis had been coded. This would give an estimated incidence of 2.6 cases per million inhabitants per year for the Geneva area. In most cases several drugs were implicated in causation of the episodes. Suspected drugs were those commonly reported in the literature, but also some drugs which might already have been taken to treat infectious complications of agranulocytosis. A comparison of the Geneva cases with those notified to the Swiss Intercantonal Office for the Control of Medicines reveals a similar profile of involved drugs.

Renal biopsy findings and followup of renal function in rheumatoid arthritis patients treated with cyclosporin A. An update from the International Kidney Biopsy Registry.

OBJECTIVE: To review data from the International Kidney Biopsy Registry, which describes the occurrence of cyclosporin A (CSA)-induced nephropathy, and to discuss the potential risk factors for its development. METHODS: The report examines data on a total of 60 first and 14 second renal biopsies performed in rheumatoid arthritis (RA) patients treated with CSA for up to 87 months. RESULTS: Five of the 60 patients with RA included in the Biopsy Registry had findings consistent with CSA-induced nephropathy at first biopsy. One further patient had such findings at second biopsy. Of the 22 patients who started CSA at dosages < 4 mg/kg/day and subsequently received dosages no higher than 5 mg/kg/ day, none developed CSA-induced nephropathy. Continuous assessment of renal function did not show any evidence of deterioration over time in patients maintained on low-dose CSA. CONCLUSION: The data indicate that in RA patients being treated according to current dosing recommendations, the risk of developing CSA-induced nephropathy is low.

[Large-cell eosinophilic tumors of the thyroid gland]. / Grosszellig-eosinophile Tumoren der Schilddrüse.

Problems surrounding malignancy of large-cell oxyphilic thyroid tumors, frequently but not quite correctly designated as Hürthle-cell tumors, are still under discussion. Whether a reliable histopathological diagnosis of malignancy can already be made on the primary lesion was tested in a series of 55 large-cell oxyphilic tumors of the thyroid seen at the Department of Pathology of the University of Zurich between 1962 and 1973, hence with a follow-up period of at least 10 years. One case was excluded due to insufficient histological slides. 34 of the remaining 54 neoplasms were reclassified histopathologically as carcinomas, 15 as adenomas and 5 as borderline tumors with doubtful malignancy. In 16 of the 35 carcinoma patients the clinical course or later pathological findings were in accordance with the histopathological diagnosis of malignancy. 6 patients had local recurrences and in 7 cases the clinical data were insufficient. Only 5 of the 34 cancer cases definitely showed no further signs of malignancy. On the other hand, only one of the 7 adenoma patients developed lung metastases, 15 years after thyroidectomy, though in this case only one histological slide could be re-examined, which is obviously an insufficient number to exclude malignancy. 3 of the 5 patients with borderline lesions followed up over a period of at least 10 years developed no signs of malignancy. In the light of these results, some 2/3 of large-cell oxyphilic thyroid tumors must be classified as carcinomas (mainly follicular) provided that only isolated tumors and not large-cell oxyphilic nodules of adenomatous goiters are considered. Benign large-cell oxyphilic tumors of the thyroid do, however, exist. Histopathologically it is quite possible to diagnose a primary lesion accurately as malignant or benign, if it is screened very carefully for capsular perforation and vascular invasion, the most reliable signs of malignancy in such tumors apart from metastases.