Multi-center planning study of radiosurgery for intracranial metastases through Automation (MC-PRIMA) by crowdsourcing prior web-based plan challenge study.

BACKGROUND: Planning radiosurgery to multiple intracranial metastases is complex and shows large variability in dosimetric quality among planners and treatment planning systems (TPS). This project aimed to determine whether autoplanning using the Muliple Brain Mets (AutoMBM) software can improve plan quality and reduce inter-planner variability by crowdsourcing results from prior international planning study. METHODS: Twenty-four institutions autoplanned with AutoMBM on a five metastases case from a prior international planning competition from which population statistics (means and variances) of 23 dosimetric metrics and resulting composite plan score (maximum score = 150) of other TPS (Eclipse, Monaco, RayStation, iPlan, GammaPlan, MultiPlan) were crowdsourced. Plan results of AutoMBM and each of the other TPS were compared using two sample t-tests for means and Levene's tests for variances. Plan quality of AutoMBM was correlated with the planner' experience and compared between academic and non-academic centers. RESULTS: AutoMBM produced plans with comparable composite plan score to GammaPlan, MultiPlan, Eclipse and iPlan (127.6 vs. 131.7 vs. 127.3 vs. 127.3 and 126.7; all p > 0.05) and superior to Monaco and RayStation (118.3 and 108.6; both p < 0.05). Inter-planner variability of overall plan quality was lowest for AutoMBM among all TPS (all p < 0.05). AutoMBM's plan quality did not differ between academic and non-academic centers and uncorrelated with planning experience (all p > 0.05). CONCLUSIONS: By plan crowdsourcing prior international plan challenge, AutoMBM produces high and consistent plan quality independent of the planning experience and the institution that is crucial to addressing the technical bottleneck of SRS to intracranial metastases.

The feasibility of prostate-specific membrane antigen positron emission tomography(PSMA PET/CT)-guided radiotherapy in oligometastatic prostate cancer patients

Background. To investigate the efficacy and toxicity of 68Ga-PSMA-HBED-CC (68Ga-PSMA) PET-CT-guided RT in the treatment of oligometastatic prostate cancer retrospectively. Methods. A total of 23 prostate cancer patients with biochemical relapse, of which 13 were castration sensitive (CS) and 10 castration resistant (CR), were treated with intensity-modulated and image-guided RT (IMRT-IGRT) on ≤3 metastases detected by 68Ga PSMA PET-CT. Androgen deprivation therapy was continued in CR patients. Results. A total of 38 metastases were treated. The involved sites were pelvic bone (n = 16), pelvic lymph nodes (n = 11), paraaortic lymph nodes (n = 6), ribs (n = 3) and vertebral body (n = 2). The median PSA prior to RT was 1.1 ng/mL (range 0.1-29.0 ng/mL). A median dose of 43.5 Gy (range 30-64 Gy) was delivered by IMRT-IGRT in 12-27 fractions. At a median follow-up of 7 months (range 2-17 months), 19 patients (83%) were in remission. Four patients (17%) developed distant recurrences. The actuarial 1-year LC, PFS and OS rates were 100, 51 (95% CI 8-83%) and 100%. Univariate analysis demonstrated a statistically significantly better PFS in CS patients as compared to CR patients (1-year PFS 67 vs. 0%, p < 0.01). One patient experienced grade 2 acute gastrointestinal toxicity. Grade 3 or more toxicity events were not observed. Conclusions. By providing optimal LC, low toxicity and a promising PFS in CS patients, the current retrospective study illustrated that 68Ga PSMA PET-CT-guided RT may be an attractive treatment strategy in patients with oligometastatic prostate cancer. Validation by randomized trials is eagerly awaited (AU)

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The feasibility of prostate-specific membrane antigen positron emission tomography(PSMA PET/CT)-guided radiotherapy in oligometastatic prostate cancer patients.

BACKGROUND: To investigate the efficacy and toxicity of 68Ga-PSMA-HBED-CC (68Ga-PSMA) PET-CT-guided RT in the treatment of oligometastatic prostate cancer retrospectively. METHODS: A total of 23 prostate cancer patients with biochemical relapse, of which 13 were castration sensitive (CS) and 10 castration resistant (CR), were treated with intensity-modulated and image-guided RT (IMRT-IGRT) on ≤3 metastases detected by 68Ga PSMA PET-CT. Androgen deprivation therapy was continued in CR patients. RESULTS: A total of 38 metastases were treated. The involved sites were pelvic bone (n = 16), pelvic lymph nodes (n = 11), paraaortic lymph nodes (n = 6), ribs (n = 3) and vertebral body (n = 2). The median PSA prior to RT was 1.1 ng/mL (range 0.1-29.0 ng/mL). A median dose of 43.5 Gy (range 30-64 Gy) was delivered by IMRT-IGRT in 12-27 fractions. At a median follow-up of 7 months (range 2-17 months), 19 patients (83%) were in remission. Four patients (17%) developed distant recurrences. The actuarial 1-year LC, PFS and OS rates were 100, 51 (95% CI 8-83%) and 100%. Univariate analysis demonstrated a statistically significantly better PFS in CS patients as compared to CR patients (1-year PFS 67 vs. 0%, p < 0.01). One patient experienced grade 2 acute gastrointestinal toxicity. Grade 3 or more toxicity events were not observed. CONCLUSIONS: By providing optimal LC, low toxicity and a promising PFS in CS patients, the current retrospective study illustrated that 68Ga PSMA PET-CT-guided RT may be an attractive treatment strategy in patients with oligometastatic prostate cancer. Validation by randomized trials is eagerly awaited.

Urodynamic changes in mice with experimental autoimmune encephalomyelitis correlate with neurological impairment.

AIMS: Neurogenic bladder dysfunction is a major issue in Multiple Sclerosis (MS). High intravesical pressure should be treated early. Available therapies are insufficient and there is need for drug development and investigation of pathogenesis. Experimental Autoimmune Encephalomyelitis (EAE) in rodents is a well validated model to study MS. Previous research has shown that these animals develop urinary symptoms. However, from clinical studies, we know that symptoms do not necessarily reflect changes in bladder pressure. This paper aims to provide a complete overview of urodynamic changes in a model for detrusor overactivity in MS. METHODS: Female C57Bl/6J mice, injected with MOG35-55 and control mice, injected with vehicle (Complete Freund's adjuvant), were monitored daily for neurologic symptoms. Within 1 month after symptom development, mice were used for cystometry or histology of the bladder. RESULTS: Increasing disease score correlated with increased micturition frequency, basal pressure, and average pressure, and with a decrease in functional bladder capacity, voiding amplitude, and maximum pressure. CONCLUSIONS: This paper provides a detailed description of bladder function in C57Bl/6J mice with Myelin Oligodendrocyte Glycoprotein peptide (MOG35-55 ) induced EAE. This EAE model induces detrusor overactivity in close relationship to neurological impairment. EAE in mice is a suitable model to study detrusor overactivity in MS. Neurourol. Urodynam. 35:450-456, 2016. © 2015 Wiley Periodicals, Inc.

Stereotactic radiotherapy for oligometastatic cancer: a prognostic model for survival.

BACKGROUND: Stereotactic radiotherapy (SRT) is a safe and locally effective treatment for patients with inoperable oligometastases. The challenge remains identifying subsets of patients that benefit in terms of overall survival (OS). PATIENTS AND METHODS: Between 2005 and 2011, 309 patients with ≤5 metastases were treated by stereotactic body radiotherapy (n=209) and/or by intracranial single or fractionated stereotactic radiotherapy (n=107). We analyzed OS and carried out a risk factor analysis. RESULTS: The median survival of all patients was 24 months. The 3-, 4- and 5-year OS rates were 32%, 25% and 19%, respectively. The following four risk factors were independently associated with impaired OS: nonadenocarcinoma histology (P<0.01), intracranial metastases (P<0.01), synchronous oligometastatic disease (P<0.01) and male gender (P=0.02). Patients with 0, 1 and 2 risk factors displayed a median survival (95% CI) of 40 (24-63), 29 (23-35) and 23 (16-29) months, respectively, and are defined as patients with good prognosis. Patients with 3 and 4 risk factors had a median survival of 9 (6-11) and 4 (1-7) months only and are defined as bad prognostic patients. CONCLUSIONS: We identified subsets of oligometastatic cancer patients with good prognosis after SRT. These patients are candidates for inclusion in prospective randomized trials for defining the role of SRT in the management of oligometastases.

Phase II study of helical tomotherapy for oligometastatic colorectal cancer.

BACKGROUND: To evaluate the efficacy and toxicity of helical tomotherapy in the treatment of oligometastatic colorectal cancer (CRC) patients who were not amenable for metastasectomy and/or (further) systemic treatment. PATIENTS AND METHODS: CRC patients with five or less metastases were enrolled. No limitations concerning dimension or localization of the metastases were imposed. Patients were treated with intensity-modulated and image-guided radiotherapy using helical tomotherapy, delivering a total dose of 40 Gy in fractions of 4 Gy. Positron emission tomography-computed tomography (PET-CT) was carried out at baseline and 3 months after the initiation of radiotherapy to evaluate the metabolic response rate according to PET Response Criteria in Solid Tumors (PERCIST) version 1.0. Side-effects were scored using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTC AE) version 3.0. RESULTS: Twenty-three patients were enrolled. A total of 52 metastases were treated. One patient (4%) experienced grade 3 vomiting; two patients (9%) grade 2 diarrhea and dysphagia, respectively. Twenty-two patients were evaluated by post-treatment PET-CT. Five (23%) and seven patients (32%) achieved a complete and partial metabolic response, respectively, resulting in an overall metabolic response rate of 55%. The actuarial 1-year local control, progression-free survival, and overall survival were 54%, 25% and 86%, respectively. CONCLUSION: The use of helical tomotherapy in oligometastatic CRC patients resulted in a promising metabolic response rate of 55%.

Gating and tracking, 4D in thoracic tumours.

The limited ability to control for a tumour's location compromises the accuracy with which radiation can be delivered to tumour-bearing tissue. The resultant requirement for larger treatment volumes to accommodate target uncertainty restricts the radiation dose because more surrounding normal tissue is exposed. With image-guided radiation therapy (IGRT), these volumes can be optimized and tumouricidal doses may be delivered, achieving maximum tumour control with minimal complications. Moreover, with the ability of high precision dose delivery and real-time knowledge of the target volume location, IGRT has initiated the exploration of new indications in radiotherapy such as hypofractionated radiotherapy (or stereotactic body radiotherapy), deliberate inhomogeneous dose distributions coping with tumour heterogeneity (dose painting by numbers and biologically conformal radiation therapy), and adaptive radiotherapy. In short: "individualized radiotherapy". Tumour motion management, especially for thoracic tumours, is a particular problem in this context both for the delineation of tumours and organs at risk as well as during the actual treatment delivery. The latter will be covered in this paper with some examples based on the experience of the UZ Brussel. With the introduction of the NOVALIS system (BrainLAB, Feldkirchen, Germany) in 2000 and consecutive prototypes of the ExacTrac IGRT system, gradually a hypofractionation treatment protocol was introduced for the treatment of lung tumours and liver metastases evolving from motion-encompassing techniques towards respiratory-gated radiation therapy with audio-visual feedback and most recently dynamic tracking using the VERO system (BrainLAB, Feldkirchen, Germany). This evolution will be used to illustrate the recent developments in this particular field of research.

An overview of volumetric imaging technologies and their quality assurance for IGRT.

Image-guided radiation therapy (IGRT) aims at frequent imaging in the treatment room during a course of radiotherapy, with decisions made on the basis of this information. The concept is not new, but recent developments and clinical implementations of IGRT drastically improved the quality of radiotherapy and broadened its possibilities as well as its indications. In general IGRT solutions can be classified in planar imaging, volumetric imaging using ionising radiation (kV- and MV- based CT) or non-radiographic techniques. This review will focus on volumetric imaging techniques applying ionising radiation with some comments on Quality Assurance (QA) specific for clinical implementation. By far the most important advantage of volumetric IGRT solutions is the ability to visualize soft tissue prior to treatment and defining the spatial relationship between target and organs at risk. A major challenge is imaging during treatment delivery. As some of these IGRT systems consist of peripheral equipment and others present fully integrated solutions, the QA requirements will differ considerably. It should be noted for instance that some systems correct for mechanical instabilities in the image reconstruction process whereas others aim at optimal mechanical stability, and the coincidence of imaging and treatment isocentre needs special attention. Some of the solutions that will be covered in detail are: (a) A dedicated CT-scanner inside the treatment room. (b) Peripheral systems mounted to the gantry of the treatment machine to acquire cone beam volumetric CT data (CBCT). Both kV-based solutions and MV-based solutions using EPIDs will be covered. (c) Integrated systems designed for both IGRT and treatment delivery. This overview will explain some of the technical features and clinical implementations of these technologies as well as providing an insight in the limitations and QA procedures required for each specific solution.

Effect of prolonged c-kit receptor inhibition by imatinib mesylate on the uterine contractility of pregnant rabbits.

BACKGROUND: The c-kit receptor expressed by interstitial cells in the gastrointestinal tract is crucial to their pacemaking function. The function of similar c-kit-expressing myometrial cells is unknown. METHODS: Imatinib mesylate, a specific c-kit receptor antagonist, was administered to pregnant New Zealand white rabbits (term = 31 days, n = 35) from day 27 gestation by intramuscular injection twice daily at high (50 microg/kg) or medium (10 microg/kg) dose and compared with a control group injected with vehicle only. In a second phase, two further groups received imatinib at medium or low (1 mug/kg) dose for a longer duration starting from day 18 until delivery. Three does from the latter groups as well as controls underwent myometrial biopsy under general anesthesia after spontaneous vaginal birth. Contractility was recorded by isometric tensiometry. The outcome measures were delay of parturition and in vitro contractility characteristics. RESULTS: High-dose imatinib induced early delivery when compared with the control group (28.6 vs. 30.7 days, p < 0.001). The other groups delivered at term. No effect on in vitro contractility was apparent in any of the groups. CONCLUSIONS: c-kit receptor inhibition in pregnant rabbits does not delay significantly the length of gestation or change myometrial contractility in vitro.