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Anatomic variation has a significant dosimetric impact in intensity-modulated proton therapy. Weekly or biweekly computed tomography (CT) scans, called quality assurance CTs (QACTs), are used to monitor anatomic and resultant dose changes to determine whether adaptive plans are needed. Frequent CT scans result in unwanted QACT dose and increased clinical workloads. This study proposed utilizing patient setup cone-beam CTs (CBCTs) and treatment plan robustness to reduce the frequency of QACTs.We retrospectively analyzed data from 27 patients with head-and-neck cancer, including 594 CBCTs, 136 QACTs, and 19 adaptive plans. For each CBCT, water-equivalent thickness (WET) along the pencil-beam path was calculated. For each treatment plan, the WET of the first-day CBCT was used as the reference, and the mean WET changes (ΔWET) in each following CBCT was used as the surrogate of proton range change. Using CBCTs acquired prior to a QACT, we predicted the ΔWET on the QACT day by a linear regression model. The impact of range change on target dose was calculated as the predicted ΔWET weighted by the monitor units of each field. In addition, plan robustness was estimated from the robust dose-volume histograms (DVHs) and combined with ΔWET to reduce QACT frequency. Robustness was estimated from the distance between the DVH curves of the nominal and worst scenarios.When the estimated mean ΔWET was 6.5 mm (or 7.5 mm if the robustness was 95%), the QACT could be skipped without missing any adaptive planning; otherwise a QACT was required. Overall, 41% of QACTs could be eliminated when ΔWET was 6.5 mm and 56% when ΔWET was 7.5 mm, and robustness was 95%. At least one QACT could have been omitted in 25 of the 27 cases under skipping thresholds at ΔWETs 7.5 mm and R 95%.This study suggests that the number of QACTs can be greatly reduced by calculating range change in patient setup CBCTs and can be further reduced by combining this information with analyses of plan robustness.

Introduction. The glucocorticoid receptor is pivotal to control corticotrophin (ACTH) secretion and its function is closely linked to the heat shock protein 90 (HSP90) chaperone complex. Impaired sensitivity to glucocorticoid feedback is a hallmark of human corticotroph adenomas, i.e., Cushing’s disease, a disorder with few medical treatment options. Silibinin, a HSP90 inhibitor, has been studied in tumoral corticotroph cells and its use proposed in Cushing’s disease. Aim of the present study was to further investigate the effect of silibinin on human corticotroph adenomas in vitro. Methods. Seven human ACTH-secreting pituitary adenomas were established in culture and treated with 10 – 50 µM silibinin with/without dexamethasone for up to 72 hours. ACTH medium levels were measured and POMC and glucocorticoid receptor, i.e., NR3C1, gene expression assessed. Results. Silibinin reduced spontaneous ACTH secretion and restored sensitivity to steroid negative feedback to a different extent in individual adenomas. POMC expression was decreased both in control and dexamethasone-treated wells in specimens sensitive to silibinin. Interestingly, silibinin reduced constitutive NR3C1 expression and reversed the dexamethasone-induced inhibition. Conclusions. Our findings indicate that silibinin can inhibit ACTH synthesis and secretion in individual human corticotroph adenomas and directly affects NR3C1 gene expression. These results reveal promising effects of this HSP90 inhibitor on human corticotroph adenomas and support an innovative target treatment for patients with Cushing’s disease.

Background: The aim of this study was to achieve a consensus on the minimum set of outcome measures and predictors to be used in the neurosurgical practice and on the timing of outcome assessment. Methods: A consensus building approach was employed. All neurosurgical departments in Lombardy (Italy) were invited to participate by the Carlo Besta Neurologic Institute IRCCS Foundation. Three workshops were organized during which a multidisciplinary group called Neurosurgical Outcome Network (NEON) was created and the methodology to select outcome measures, predictors, and timing of outcome assessment was established. Eight working groups were created for the different neurosurgical diseases (neuro-oncological, skull base, vascular, traumatic, spinal, peripheral nervous system, malformation, functional) and 8 workshops were organized to identify the outcome measures and predictors specific for each of the neurosurgical diseases based on the experts' clinical practice and the existing literature. Results: A total of 20 neurosurgical departments participated in this study. Specific outcome measures, predictors and the timing of outcome assessment were identified for each of the 8 neurosurgical diseases. Moreover, a list of variables common to all pathologies were identified by the NEON group as further data to be collected. Conclusions: A consensus on the minimum set of outcome measures and predictors and the timing of outcome assessments for 8 neurosurgical diseases was achieved by a group of neurosurgeons of the Lombardy region, called NEON. These sets could be used in future studies for a more homogeneous data collection and as a starting point to reach further agreement also at national and international level.

Prolactinomas are the most frequent pituitary adenomas. Prolactinoma may occur in different clinical settings and always require an individually tailored approach. This is the reason why a panel of Italian neuroendocrine experts was charged with the task to provide indications for the diagnostic and therapeutic approaches that can be easily applied in different contexts. The document provides 15 recommendations for diagnosis and 54 recommendations for treatment, issued according to the GRADE system. The level of agreement among panel members was formally evaluated by RAND-UCLA methodology. In the last century, prolactinomas represented the paradigm of pituitary tumors for which the development of highly effective drugs obtained the best results, allowing to avoid neurosurgery in most cases. The impressive improvement of neurosurgical endoscopic techniques allows a far better definition of the tumoral tissue during surgery and the remission of endocrine symptoms in many patients with pituitary tumors. Consequently, this refinement of neurosurgery is changing the therapeutic strategy in prolactinomas, allowing the definitive cure of some patients with permanent discontinuation of medical therapy.