SAFESTEREO: phase II randomized trial to compare stereotactic radiosurgery with fractionated stereotactic radiosurgery for brain metastases.

BACKGROUND: Stereotactic radiosurgery (SRS) is a frequently chosen treatment for patients with brain metastases and the number of long-term survivors is increasing. Brain necrosis (e.g. radionecrosis) is the most important long-term side effect of the treatment. Retrospective studies show a lower risk of radionecrosis and local tumor recurrence after fractionated stereotactic radiosurgery (fSRS, e.g. five fractions) compared with stereotactic radiosurgery in one or three fractions. This is especially true for patients with large brain metastases. As such, the 2022 ASTRO guideline of radiotherapy for brain metastases recommends more research to fSRS to reduce the risk of radionecrosis. This multicenter prospective randomized study aims to determine whether the incidence of adverse local events (either local failure or radionecrosis) can be reduced using fSRS versus SRS in one or three fractions in patients with brain metastases. METHODS: Patients are eligible with one or more brain metastases from a solid primary tumor, age of 18 years or older, and a Karnofsky Performance Status ≥ 70. Exclusion criteria include patients with small cell lung cancer, germinoma or lymphoma, leptomeningeal metastases, a contraindication for MRI, prior inclusion in this study, prior surgery for brain metastases, prior radiotherapy for the same brain metastases (in-field re-irradiation). Participants will be randomized between SRS with a dose of 15-24 Gy in 1 or 3 fractions (standard arm) or fSRS 35 Gy in five fractions (experimental arm). The primary endpoint is the incidence of a local adverse event (local tumor failure or radionecrosis identified on MRI scans) at two years after treatment. Secondary endpoints are salvage treatment and the use of corticosteroids, bevacizumab, or antiepileptic drugs, survival, distant brain recurrences, toxicity, and quality of life. DISCUSSION: Currently, limiting the risk of adverse events such as radionecrosis is a major challenge in the treatment of brain metastases. fSRS potentially reduces this risk of radionecrosis and local tumor failure. TRIAL REGISTRATION: ClincalTrials.gov, trial registration number: NCT05346367 , trial registration date: 26 April 2022.

Targeted therapy in older women with breast cancer - What's the target?

In this review, the results of the FOCUS (Female breast cancer in the elderly: Optimizing Clinical guidelines USing clinico-pathological and molecular data) program are summarized. This study was originally designed with the aim to define guidelines for the treatment of older women with breast cancer. With data from several studies within FOCUS, a prediction model can be constructed. Such a model helps to define individualized treatment for older patients with breast cancer, taking into account tumour characteristics and patient-related factors. At a clinical level, this model can provide the physician and the patient with accurate prediction to assist on the decision making of treatment strategies: this results into individualized treatment, not based on one individual marker, but on different pillars related to the patient, the tumour and the most suitable, appropriate treatment.

Assessing treatment effects in older breast cancer patients: systematic review of observational research methods.

Solid evidence of treatment effects in older women with breast cancer is lacking, as they are generally underrepresented in randomized clinical trials on which guideline recommendations are based. An alternative way to study treatment effects in older patients could be to use data from observational studies. However, using appropriate methods in analyzing observational data is a key condition in order to draw valid conclusions, as directly comparing treatments generally results in biased estimates due to confounding by indication. The aim of this systematic review was to investigate the methods that have been used in observational studies that assessed the effects of breast cancer treatment on survival, breast cancer survival and recurrence in older patients (aged 65 years and older). Studies were identified through systematic review of the literature published between January 1st 2009 and December 13th 2013 in the PubMed database and EMBASe. Finally, 31 studies fulfilled the inclusion criteria. Of these, 22 studies directly compared two treatments. Fifteen out of these 22 studies addressed the problem of confounding by indication, while seven studies did not. Nine studies used some form of instrumental variable analysis. In conclusion, the vast majority of observational studies that investigate treatment effects in older breast cancer patients compared treatments directly. These studies are therefore likely to be biased. Observational research will be essential to improve treatment and outcome of older breast cancer patients, but the use of accurate methods is essential to draw valid conclusions from this type of data.

Choosing relevant endpoints for older breast cancer patients in clinical trials: an overview of all current clinical trials on breast cancer treatment.

With the ongoing ageing of western societies, the proportion of older breast cancer patients will increase. For several years, clinicians and researchers in geriatric oncology have urged for new clinical trials that address patient-related endpoints such as functional decline after treatment of older patients. The aim of this study was to present an overview of trial characteristics and endpoints of all currently running clinical trials in breast cancer, particularly in older patients. The clinical trial register of the United States National Institutes of Health Differences was searched for all current clinical trials on breast cancer treatment. Trial characteristics and endpoints were retrieved from the register and differences in characteristics between studies in older patients specifically (defined as a lower age-limit of 60 years or older) and trials in all patients were assessed using χ(2) tests. We included 463 clinical trials. Nine trials (2 %) specifically investigated breast cancer treatment in older patients. Ninety-one breast cancer trials included any patient-related endpoint (20 %), while five trials specifically addressing older patients included any patient-related endpoint (56 %, P = 0.02). Five of the trials in older patients incorporated a geriatric assessment (56 %). Clinical trials still rarely incorporate patient-related endpoints, even in trials that specifically address older patients. Trials that are specifically designed for older patients do not often incorporate a geriatric assessment in their design. This implicates that current clinical studies are not expected to fill the gap in knowledge concerning treatment of older breast cancer patients in the next decade.

Estimating the surface area of nonconvex particles from central planar sections.

In this paper, we present a new surface area estimator in local stereology. This new estimator is called the 'Morse-type surface area estimator' and is obtained using a two-stage sampling procedure. First a plane section through a fixed reference point of a three-dimensional structure is taken. In this section plane, a modification of the area tangent count method is used. The Morse-type estimator generalizes Cruz-Orive's pivotal estimator for convex objects to nonconvex objects. The advantages of the Morse-type estimator over existing local surface area estimators are illustrated in a simulation study. The Morse-type estimator is well suited for computer-assisted confocal microscopy and we demonstrate its practicability in a biological application: the surface area estimation of the nuclei of giant-cell glioblastoma from microscopy images. We also present an interactive software that allows the user to efficiently obtain the estimator.

Diabetes in relation to breast cancer relapse and all-cause mortality in elderly breast cancer patients: a FOCUS study analysis.

BACKGROUND: In developed countries, 40% of breast cancer patients are >65 years of age at diagnosis, of whom 16% additionally suffer from diabetes. The aim of this study was to assess the impact of diabetes on relapse-free period (RFP) and overall mortality in elderly breast cancer patients. PATIENTS AND METHODS: Patients were selected from the retrospective FOCUS cohort, which contains detailed information of elderly breast cancer patients. RFP was calculated using Fine and Gray competing risk regression models for patients with diabetes versus patients without diabetes. Overall survival was calculated by Cox regression models, in which patients were divided into four groups: no comorbidity, diabetes only, diabetes and other comorbidity or other comorbidity without diabetes. RESULTS: Overall, 3124 patients with non-metastasized breast cancer were included. RFP was better for patients with diabetes compared with patients without diabetes (multivariable HR 0.77, 95% CI 0.59-1.01), irrespective of other comorbidity and most evident in patients aged ≥75 years (HR 0.67, 95% CI 0.45-0.98). The overall survival was similar for patients with diabetes only compared with patients without comorbidity (HR 0.86, 95% CI 0.45-0.98), while patients with diabetes and additional comorbidity had the worst overall survival (HR 1.70, 95% CI 1.44-2.01). CONCLUSION: When taking competing mortality into account, RFP was better in elderly breast cancer patients with diabetes compared with patients without diabetes. Moreover, patients with diabetes without other comorbidity had a similar overall survival as patients without any comorbidity. Possibly, unfavourable effects of (complications of) diabetes on overall survival are counterbalanced by beneficial effects of metformin on the occurrence of breast cancer recurrences.

Postoperative complications and survival of elderly breast cancer patients: a FOCUS study analysis.

Old age is associated with comorbidity and decreased functioning which influences treatment decisions in elderly breast cancer patients. The purpose of this study was to identify risk factors for complications after breast cancer surgery in elderly patients, and to assess mortality in patients with postoperative complications. The FOCUS cohort is a detailed retrospective cohort of all breast cancer patients aged 65 years and older who were diagnosed between 1997 and 2004 in the South-West of the Netherlands. Risk factors for postoperative complications were assessed using univariable and multivariable logistic regression models. One-year survival and overall survival were calculated using univariable and multivariable Cox Regression models, and relative survival was calculated according to the Ederer II method. 3179 patients received surgery, of whom 19 % (n = 618) developed 1 or more postoperative complication(s). The odds ratio of having postoperative complications increased with age [OR 1.85 (95 % confidence interval (CI) 1.37-2.50, p = 0.001) in patients >85 years] and number of concomitant diseases [OR 1.71 (95 % CI 1.30-2.24, p ≤ 0.001) for 4 or more concomitant diseases]. One-year overall survival, overall survival, and relative survival were worse in patients with postoperative complications [multivariable HR 1.49 (95 % CI 1.05-2.11), p = 0.025. HR 1.21, (95 % CI 1.07-1.36), p = 0.002 and RER 1.19 (95 % CI 1.05-1.34), p = 0.006 respectively]. Stratified for comorbidity, relative survival was lower in patients without comorbidity only. Increasing number of concomitant disease increased the risk of postoperative complications. Although elderly patients with comorbidity did have a higher risk of postoperative complications, relative mortality was not higher in this group. This suggests that postoperative complications in itself did not lead to higher relative mortality, but that the high relative mortality was most likely due to geriatric parameters such as comorbidity or poor physical function.

Surgical treatment of early stage breast cancer in elderly: an international comparison.

Over 40% of breast cancer patients are diagnosed above the age of 65. Treatment of these elderly patients will probably vary over countries. The aim of this study was to make an international comparison (several European countries and the US) of surgical and radiation treatment for elderly women with early stage breast cancer. Survival comparisons were also made. Data were obtained from national or regional population-based registries in the Netherlands, Switzerland, Ireland, Belgium, Germany, and Portugal. For the US patients were selected from the Surveillance, Epidemiology, and End Results (SEER) database. Early stage breast cancer patients aged ≥ 65 diagnosed between 1995 and 2005 were included. An international comparison was made for breast and axillary surgery, radiotherapy after breast conserving surgery (BCS), and relative or cause-specific survival. Overall, 204.885 patients were included. The proportion of patients not receiving any surgery increased with age in many countries; however, differences between countries were large. In most countries more than half of all elderly patients received breast conserving surgery (BCS), with the highest percentage in Switzerland. The proportion of elderly patients that received radiotherapy after BCS decreased with age in all countries. Moreover, in all countries the proportion of patients who do not receive axillary surgery increased with age. No large differences in survival between countries were recorded. International comparisons of surgical treatment for elderly women with early stage breast cancer are scarce. This study showed large international differences in treatment of elderly early stage breast cancer patients, with the most striking result the large proportion of elderly who did not undergo surgery at all. Despite large treatment differences, survival does not seem to be affected in a major way.

Short-term tissue response of lapine carotid artery microanastomoses to BioGlue.

BACKGROUND: Minimally invasive coronary artery surgery needs fast, reliable and easy methods of carrying out anastomoses. The aim of our study was to evaluate the use of BioGlue in sutureless vascular anastomoses in the lapine model. METHODS: In 24 New Zealand white rabbits, 43 transsected carotid arteries were re-anastomosed using either a combination of balloon catheterisation and BioGlue or a conventional suture. In five carotid arteries, only BioGlue was applied. The animals were euthanised and tissue samples were taken for histological and immunohistological examination. RESULTS: A higher inflammatory cell infiltrate was present in the glue control and glue anastomosis groups, with the invasion of inflammatory cells located especially at the junction between the wall with and the wall without glue. Early calcification was detected in two arteries. CONCLUSION: The results of this short-term study show that the rabbit is an adequate as well as a sensitive model for the study of microanastomoses by glueing. Marked inflammatory reactions developed which may lead to vascular sclerosis or stenosis, and long-term studies are necessary to elucidate this problem further.

Algorithms to estimate the rose of directions of a spatial fibre system.

Summary The directional measure (which is up to normalization the rose of directions) is used to quantify anisotropy of stationary fibre processes in three-dimensional space. There exist a large number of approaches to estimate this measure from the rose of intersections (which is the mean number of intersections of fibres with lower dimensional test sets). Three recently suggested nonparametric algorithms to solve this problem are reviewed and compared. They were obtained from solutions of a least squares problem, a more general convex optimization problem and a linear program, respectively. Application to two different carbon fibre architectures and to simulated data allow an empirical comparison of these approaches. In addition, estimators for the associated zonoid (or Steiner compact) are suggested. This set turns out to be an intuitive tool for visualization.

Directional analysis of digitized three-dimensional images by configuration counts.

A method for estimating the orientated rose of normal directions of a three-dimensional (3D) set Z from a digitization of Z, i.e. a voxel image, is presented. It is based on counts of informative configurations in n x n x n voxel cubes. An algorithm for finding all informative configurations is proposed and an estimation procedure is described in detail for the case n= 2. The presented method is a 3D version of a method of estimating the orientated rose of binary planar images using n x n configurations. A new feature is the design-based approach, being more appropriate for biomedical image analysis than the formerly applied model-based approach.

Directional analysis of digitized planar sets by configuration counts.

The oriented rose of normal directions of a random set Z can be used to quantify its anisotropy. A method for estimating this quantity from a digitization of Z in a sampling window, i.e. its pixel image, is presented. The image is analysed locally by considering pixel squares of size n x n. This allows us to count the number of different types of n x n configurations in the pixel image. We show that it suffices to restrict attention to the so-called informative configurations. The number of informative configurations increases only polynomially in n. An algorithm to find these informative configurations is presented. Furthermore, estimators of the oriented rose based on counts of observed informative configurations are derived. The procedure is illustrated by a simulated example and an analysis of a microscopic image of steel.