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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.

Acromegaly is a rare disease. Improvements in lifespan in these patients have recently been reported due to transsphenoidal surgery (TSS), advances in medical therapy, and strict criteria for defining disease remission. This document reports the opinions of a group of Italian experts who have gathered together their prolonged clinical experience in the diagnostic and therapeutic challenges of acromegaly patients. Both GH and IGF-I (only IGF-I in those treated with Pegvisomant) are needed in the diagnosis and follow-up. Comorbidities (cardio-cerebrovascular disease, sleep apnea, metabolic derangement, neoplasms, and bone/joint disease) should be specifically addressed. Any newly diagnosed patient should be referred to a multidisciplinary team experienced in the treatment of pituitary adenomas.

Chordoma is a rare slow-growing neoplastic bone lesion. However, they show an invasive local growth and high recurrence rate, leading to an overall survival rate of 65% at 5 years and 35% at 10 years. We conducted a pooled and meta-analysis comparing recurrence rate, post-operative-complications, and survival in patients undergoing either microsurgical (MA) or endoscopic approaches (EA). Search of literature was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to identify surgical series of clivus chordomas published between January 1990 and March 2018 on Pubmed, Scopus, and Cochrane. Two different statistical analyses have been performed: a pooled analysis and a single-arm meta-analysis of overall recurrence rate and subgroup meta-analysis of complications in the subgroups open surgery and endoscopic surgery. After full-text screening, a total of 58 articles were included in the pooled analysis and 27 studies were included for the study-level meta-analysis. Pooled analysis—the extent of resection was the only association that remained significant (subtotal: HR = 2.18, p = 0.004; partial: HR = 4.40, p < 0.001). Recurrence was more prevalent among the surgical patients (45.5%) compared to endoscopic ones (23.7%). Meta-analysis—results of the cumulative meta-analysis showed an overall rate of recurrence of 25.6%. MA recurrence rate was 31.8% (99% CI 14-52.8), EA recurrence rate was 19.4% (5.4-39.2). CSF leak rate for the endoscopic group was 10.3% (99%CI 5-17.3) and 9.5% (99%CI 1.2-24.6) for the open surgery group. The partial removal versus total removal has an influence on recurrence rate (p < 0.001). MA recurrence rate was 31.8%; EA recurrence rate was 19.4%. The extent of resection is confirmed as a statistically significant factor affecting the risk for recurrence both with the pooled analysis and with the meta-analysis. Meta-analysis demonstrated that older patients tend to recur more than young patients, especially in surgical group.

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.

Background: Somatic mutations in the ubiquitin-specific protease 8 (USP8) gene have recently been shown to occur in ACTH-secreting pituitary adenomas, thus calling attention to the ubiquitin system in corticotrope adenomas. Objectives: Assess the consequences of USP8 mutations and establish the role of ubiquitin on ACTH turnover in human ACTH-secreting pituitary adenomas. Methods: USP8 mutation status was established in 126 ACTH-secreting adenomas. Differences in ACTH secretion and POMC expression from adenoma primary cultures and in microarray gene expression profiles from archival specimens were sought according to USP8 sequence. Ubiquitin/ACTH coimmunoprecipitation and incubation with MG132, a proteasome inhibitor, were performed in order to establish whether ubiquitin plays a role in POMC/ACTH degradation in corticotrope adenomas. Results: USP8 mutations were identified in 29 adenomas (23%). Adenomas presenting USP8 mutations secreted greater amounts of ACTH and expressed POMC at higher levels compared to USP wild-type specimens. USP8 mutant adenomas were also more sensitive to modulation by CRH and dexamethasone in vitro. At microarray analysis, genes associated with endosomal protein degradation and membrane components were downregulated in USP8 mutant adenomas as were AVPR1B, IL11RA, and PITX2. Inhibition of the ubiquitin-proteasome pathway increased ACTH secretion and POMC itself proved a target of ubiquitylation, independently of USP8 sequence status. Conclusions: Our study has shown that USP8 mutant ACTH-secreting adenomas present a more “typical” corticotrope phenotype and reduced expression of several genes associated with protein degradation. Further, ubiquitylation is directly involved in intracellular ACTH turnover, suggesting that the ubiquitin-proteasome system may represent a target for treatment of human ACTH-secreting adenomas.

Simple Summary Giant pituitary adenomas are highly invasive tumors whose treatment is challenging. Surgery is their management mainstay. However, there is no consensus about the type of approach. Open transcranial, microscopic, and endoscopic trans-sphenoidal approaches have all been employed, alone or in combination. Extended endoscopic endonasal techniques may represent a versatile and safe one-stage approach. Our research aimed at evaluating prospectively their applicability, effectiveness, and safety in a multicenter series, to acquire further evidence toward its use in the treatment of those challenging lesions. Ninety-six patients were recruited and followed-up for 52.4 months on average. Most of them (81.2%) presented with visual deficits and >50% had various degrees of adenohypophysis insufficiency. Resection of at least 75% of initial volume was achieved in all cases, with 98.7% visual improvement, >50% endocrine deficit recovery and a permanent complication rate of 4.2%, indicating extended endoscopic endonasal approaches as a valuable treatment option. Abstract Purpose: To evaluate factors influencing clinical and radiological outcome of extended endoscopic endonasal transtuberculum/transplanum approach (EEA-TTP) for giant pituitary adenomas (GPAs). Methods: We recruited prospectively all consecutive GPAs patients undergoing EEA-TTP between 2015 and 2019 in 5 neurosurgical centers. Preoperative clinical and radiologic features, visual and hormonal outcomes, extent of resection (EoR), complications and recurrence rates were recorded and analyzed. Results: Of 1169 patients treated for pituitary adenoma, 96 (8.2%) had GPAs. Seventy-eight (81.2%) patients had visual impairment, 12 (12.5%) had headaches, 3 (3.1%) had drowsiness due to hydrocephalus, and 53 (55.2%) had anterior pituitary insufficiency. EoR was gross or near-total in 46 (47.9%) and subtotal in 50 (52.1%) patients. Incomplete resection was associated with lateral suprasellar, intraventricular and/or cavernous sinus extension and with firm/fibrous consistence. At the last follow-up, all but one patient (77, 98.7%) with visual deficits improved. Headache improved in 8 (88.9%) and anterior pituitary function recovered in 27 (50.9%) patients. Recurrence rate was 16.7%, with 32 months mean recurrence-free survival. Conclusions: EEA-TTP is a valid option for GPAs and seems to provide better outcomes, lower rate of complications and higher EoR compared to one- or multi-stage microscopic, non-extended endoscopic transsphenoidal, and transcranial resections.

The presence of coronary artery calcium (CAC0) is associated with increased cardiac-related mortality and is a common indication to initiate statin therapy to prevent future long-term cardiac-related adverse events. CAC is also well visualized on noncontrast chest computed tomography simulation (CT sim) scans used for breast radiation planning. We hypothesize that by screening for incidental CAC on CT sims, radiation oncologists could help identify patients who may benefit from additional preventive medical interventions with their primary care physician or cardiologist.A retrospective analysis of 126 consecutive patients with breast cancer treated with external beam radiation therapy at a single institution was performed. Noncontrast CT sim scans were reviewed for the presence of CAC and the 10-year risk of atherosclerotic cardiovascular disease (ASCVD) was calculated to identify patients who may benefit from initiating statin therapy. Patients with CAC0 and/or ASCVD risk20% were identified as those who may benefit from statin therapy.Out of 72 patients with CAC0, only 12(16%) had reported pre-existing coronary artery disease and 32(44%) were not already on recommended statin therapy. CAC0 visualized on CT sim was able to identify 29 additional patients who would benefit from statin beyond what the ASCVD risk calculator could identify.Observation of incidental CAC on breast radiation-planning CT scans identified patients who could benefit from cardiac-related preventive strategies. By increasing attention, awareness, and reporting of incidental CAC visible on CT sims, radiation oncologists may fulfill a unique role to bridge a potential gap in cardiovascular preventive medicine.

Pituitary carcinomas (PCa) are extremely rare, indistinguishable from pituitary adenomas on histopathological grounds and have a poor prognosis. Most PCa start as PRL or ACTH secreting tumors in males, with relapsing invasive behaviour, refractoriness to medical and radiotherapy and increasing hormonal levels. The presence of distant metastases is still required for the diagnosis of PCa. The association with genetic endocrine diseases must be taken into account, since it adds further risk of evolution towards malignancy. Intradural spinal metastases have also been reported, so a complete craniospinal MR evaluation is recommended, when clinically indicated. We report a case of PCa, associated with MEN1 syndrome, with evidence of meningeal spread to the tentorium cerebelli, clival dura and spinal drop metastases mimicking spinal nerves schwannomas.

Silibinin, a milk thistle extract with known hepatoprotective effects, has recently been shown to act upon tumoral corticotropes and revert the Cushingoid phenotype in an allograft mouse model (Riebold et al 2015). Silbinin is known to inhibit HSP90 -a chaperone to the glucocorticoid receptor- thereby restoring sensitivity to glucocorticoid negative feedback in tumoral corticotropes. Aim of the present study was to assess the effect of silibinin on ACTH synthesis and secretion by human corticotrope adenomas in vitro. Methods: Eight human ACTH-secreting pituitary adenomas were collected during surgery and established in culture as per our protocol (Pecori Giraldi et al 2011). Specimens were treated with 10 - 50 µM silibinin for up to 72 hours. ACTH medium levels were measured by Elisa; POMC expression was assessed by RT-PCR (Cassarino et al 2017). Results. Silibinin reduced spontaneous ACTH secretion to a variable extent in individual adenomas: from 32 to 79% of baseline at 4h, and 54 - 85 % of baseline at 48 and 72h. Silibinin was also effective in reinstating or enhancing sensitivity to steroid negative feedback: ACTH decreases during 10–50 µM silibinin incubation ranged from 10 to 63% of dexamethasone-treated wells at 4 hours, 70 -80% at 48 hours and 36 to 80% at 72 hours, indicating long-lasting effect on glucocorticoid sensitivity. Silibinin induced a variable decrease in POMC expression, both as regards expression in control and dexamethasone-treated wells; some specimens exhibited a marked sensitivity to the inhibitory effect, with POMC expression decreasing to less than 50% of control. Conclusions:, this data suggests that silibinin can inhibit ACTH secretion and POMC synthesis and restore sensitivity to negative glucocorticoid feedback. References: Cassarino et al (2017) Endocrine55: 853–860. Pecori Giraldi et al (2011) Journal of Neuroendocrinology23:1214–21. Riebold et al (2015) Nature Medicine21:276–280.

Any newly diagnosed patient should be referred to a multidisciplinary team experienced in the treatment of pituitary adenomas. The therapeutic management of acromegaly always requires a personalized strategy. Normal age-matched IGF-I values are the treatment goal. Transsphenoidal surgery by an expert neurosurgeon is the primary treatment modality for most patients, especially if there are neurological complications. In patients with poor clinical conditions or who refuse surgery, primary medical treatment should be offered, firstly with somatostatin analogs (SSAs). In patients who do not reach hormonal targets with first-generation depot SSAs, a second pharmacological option with pasireotide LAR or pegvisomant (alone or combined with SSA) should be offered. Irradiation could be proposed to patients with surgical remnants who would like to be free from long-term medical therapies or those with persistent disease activity or tumor growth despite surgery or medical therapy. Since the therapeutic tools available enable therapeutic targets to be achieved in most cases, the challenge is to focus more on the quality of life.

BACKGROUND: Somatic mutations in the ubiquitin-specific protease 8 (USP8) gene have recently been shown to occur in ACTH-secreting pituitary adenomas, thus calling attention to the ubiquitin system in corticotrope adenomas. OBJECTIVES: Assess the consequences of USP8 mutations and establish the role of ubiquitin on ACTH turnover in human ACTH-secreting pituitary adenomas. METHODS: USP8 mutation status was established in 126 ACTH-secreting adenomas. Differences in ACTH secretion and POMC expression from adenoma primary cultures and in microarray gene expression profiles from archival specimens were sought according to USP8 sequence. Ubiquitin/ACTH coimmunoprecipitation and incubation with MG132, a proteasome inhibitor, were performed in order to establish whether ubiquitin plays a role in POMC/ACTH degradation in corticotrope adenomas. RESULTS: USP8 mutations were identified in 29 adenomas (23%). Adenomas presenting USP8 mutations secreted greater amounts of ACTH and expressed POMC at higher levels compared to USP wild-type specimens. USP8 mutant adenomas were also more sensitive to modulation by CRH and dexamethasone in vitro. At microarray analysis, genes associated with endosomal protein degradation and membrane components were downregulated in USP8 mutant adenomas as were AVPR1B, IL11RA, and PITX2. Inhibition of the ubiquitin-proteasome pathway increased ACTH secretion and POMC itself proved a target of ubiquitylation, independently of USP8 sequence status. CONCLUSIONS: Our study has shown that USP8 mutant ACTH-secreting adenomas present a more “typical” corticotrope phenotype and reduced expression of several genes associated with protein degradation. Further, ubiquitylation is directly involved in intracellular ACTH turnover, suggesting that the ubiquitin-proteasome system may represent a target for treatment of human ACTH-secreting adenomas.

(1) Background. Cushing&rsquo, s disease presents gender disparities in prevalence and clinical course. Little is known, however, about sexual dimorphism at the level of the corticotrope adenoma itself. The aim of the present study was to evaluate molecular features of ACTH-secreting pituitary adenomas collected from female and male patients with Cushing&rsquo, s disease. (2) Methods. We analyzed 153 ACTH-secreting adenomas collected from 31 men and 122 women. Adenomas were established in culture and ACTH synthesis and secretion assessed in basal conditions as well as during incubation with CRH or dexamethasone. Concurrently, microarray analysis was performed on formalin-fixed specimens and differences in the expression profiles between specimens from male and female patients identified. (3) Results. ACTH medium concentrations in adenomas obtained from male patients were significantly lower than those observed in adenomas from female patients. This could be observed for baseline as well as modulated secretion. Analysis of corticotrope transcriptomes revealed considerable similarities with few, selected differences in functional annotations. Differentially expressed genes comprised genes with known sexual dimorphism, genes involved in tumour development and genes relevant to pituitary pathophysiology. (4) Conclusions. Our study shows for the first time that human corticotrope adenomas present sexual dimorphism and underlines the need for a gender-dependent analysis of these tumours. Differentially expressed genes may represent the basis for gender-tailored target therapy.

The transnasal approach to lesions involving the craniovertebral junction represents a technical challenge because of limited inferior exposure. The endoscopic transseptal approach (EtsA) with posterior nasal spine (PNS) removal is described. This technique can create a wide exposure of the craniovertebral junction, thereby increasing the caudal exposure.On patients undergoing anterior craniovertebral junction decompression, we calculated the degree of exposure on the sagittal plan through a paraseptal route, an EtsA without and with PNS removal. The horizontal exposure and working area with the latter approach were also evaluated.Five patients underwent the transnasal procedure. The age of patients ranged from 34-71 years. All patients harbored basilar impression. The mean postoperative Nurick grade (1, 8) was improved versus the average preoperative grade (3). The average follow-up duration was 16 months. All patients underwent occipitocervical fixation. The mean vertical distances, from the clinoid recess to the inferior most limit with the paraseptal approach, EtsA without and with PNS removal were 38.52, 44.12, and 51.16 mm, respectively. The difference between our approach and a standard paraseptal route was statistically significant (P = 0.041; P0.05). The mean horizontal distances were 31.68 mm (mononostril entry) and 35.37 mm (binostril entry). The mean working area was 1795.53 mmEndoscopic endonasal approaches to the craniovertebral junction are increasing, but the downward extension on the anterior cervical spine represents a limit. Therefore, many surgeons prefer transoral or transcervical approaches. The EtsA with PNS removal allows for a more caudal exposure than the standard paraseptal approach, with reduced nasal trauma.

Background Optimal vision and ergonomics are important factors contributing to achievement of good results during neurosurgical interventions. The operating microscope and the endoscope have partially filled the gap between the need for good surgical vision and maintenance of a comfortable posture during surgery. Recently, a new technology called video-assisted telescope operating monitor or exoscope has been used in cranial surgery. The main drawback with previous prototypes was lack of stereopsis. We present the first case report of cranial surgery performed using the VITOM 3D, an exoscope conjugating 4K resolution view and three-dimensional technology, and discuss advantages and disadvantages compared with the operating microscope. Case Description A 50-year-old patient with vertigo and headache linked to a petrous ridge meningioma underwent surgery using the VITOM 3D. Complete removal of the tumor and resolution of symptoms were achieved. The telescope was maintained over the surgical field for the duration of the procedure; a video monitor was placed at 2 m from the surgeons; and a control unit allowed focusing, magnification, and repositioning of the camera. Conclusions VITOM 3D is a video system that has overcome the lack of stereopsis, a major drawback of previous exoscope models. It has many advantages regarding ergonomics, versatility, and depth of field compared with the operating microscope, but the holder arm and the mechanism of repositioning, refocusing, and magnification need to be ameliorated. Surgeons should continue to use the technology they feel confident with, unless a distinct advantage with newer technologies can be demonstrated.

ACTH-secreting pituitary tumors are by definition partially autonomous, i.e., secrete ACTH independent of physiological control. However, only few, small-sized studies on proopiomelanocortin (POMC) and its regulation by corticotropin-releasing hormone (CRH) or glucocorticoids are available. Objective of the present study was to report on constitutive and CRH- and dexamethasone-regulated POMC, CRH (CRH-R1), and glucocorticoid receptor (NR3C1) gene expression in a large series of human corticotrope adenomas. Fifty-three ACTH-secreting adenomas were incubated with 10 nM CRH or 10 nM dexamethasone for 24 h. POMC, CRH-R1, NR3C1, and its alpha and beta isoforms were quantified and medium ACTH measured. Constitutive POMC expression proved extremely variable, with macroadenomas exhibiting higher levels than microadenomas. POMC increased during CRH in most specimens; conversely, changes induced by dexamethasone were varied, ranging from decrease to paradoxical increase. No correlation between POMC and ACTH was detected in any experimental condition. CRH-R1 expression was not linked to the response to CRH while NR3C1 was expressed at greater levels in specimens who failed to inhibit during dexamethasone; glucocorticoid receptor α was the more abundant isoform and subject to down-regulation by dexamethasone. Our results demonstrate a considerable variability in POMC expression among tumors and no correlation between POMC and ACTH, suggesting that POMC peptide processing/transport plays a major role in modulating ACTH secretion. Further, CRH-R1 and NR3C1 expression were not linked to the expected ligand-induced outcome, indicating that receptor signaling rather than abundance determines corticotrope responses. Our findings pave the way to new avenues of research into Cushing’s disease pathophysiology. Electronic supplementary material The online version of this article (doi:10.1007/s12020-016-0990-x) contains supplementary material, which is available to authorized users.

In the past decade, surgical treatment of skull base pathologies has greatly advanced through the advent of the endoscope and later of the high definition endoscope. Recently a new type of three dimensional (3D) scope has been introduced to permit the surgeon a real stereoscopic vision of the operating field and to overcome the limitations of the 2D endoscopic set up. As with all new technologies a formalized adaptation period is essential for the surgeon to secure steady outcomes and low complications. To determine the subjective difficulties that one may encounter during this sensitive period we therefore devised and analyzed a questionnaire that evaluated the first ten procedures with the 3D device of junior and senior ENT and neurosurgeons. 52 consecutive patients were treated with purely 3D transnasal endoscopy for skull base pathologies. Sensation of strain or dizziness, difficulties in anatomical orientation and difficulties in performing the surgical gesture were assessed for each surgeon. The learning curve and difficulties of junior and senior surgeons are discussed and strategies to overcome the initial problems are devised. Our results confirm that after only few procedures, the advantages of the 3D endoscopic system including better visualization and depth perception are able to outweigh the inconveniences that go hand in hand with the learning of a new skill set.

Patients with Cushing’s disease are known to present a variable secretory response to stimulatory and inhibitory challenges. Evaluation of the secretory behaviour of pituitary adrenocorticotrophic hormone (ACTH)-secreting adenomas in vitro aids in the comprehension of its behaviour in vivo; however, given the small size of these tumours and the consequent paucity of material available to in vitro studies, a comprehensive study on the secretory behaviour of human corticotroph tumours has not yet been performed. The present study aimed to assess the spectrum of responses to the two main corticotroph modulators, corticotrophin-releasing hormone (CRH) and dexamethasone, in a large series of human ACTH-secreting pituitary tumours. Seventy-two ACTH-secreting pituitary tumours were collected during surgery and established in culture. Specimens were incubated with 10 nm CRH and/or 10 nm dexamethasone for 4 h and 24 h. Secretion in unstimulated, control wells was set at 100% and changes in ACTH concentrations by at least 20% were considered as responses. Parallel experiments in 12 rat anterior pituitary primary cultures were evaluated. A marked ACTH increase was observed during incubation with CRH in 70% of tumoural specimens at 4 h (range 124–3500% of control wells) and in 57% at 24 h (range 122–3323%). Dexamethasone reduced ACTH secretion in almost 50% of tumours (range 78–2% of control at 4 h; 76–3% at 24 h), whereas it did not affect ACTH medium levels in 30% of specimens and induced a paradoxical ACTH increase in 20% of tumours (range 130–327% of control at 4 h; 156–348% at 24 h). By comparison, CRH uniformly increased ACTH levels in rat anterior pituitary primary cultures (mean 745 ± 84% at 4 h; 347 ± 25% at 24 h), whereas dexamethasone decreased ACTH levels by 40–50% in all experiments. In conclusion, the present study of a large series of human ACTH-secreting pituitary tumours in vitro revealed a considerable variability in the responses to CRH and dexamethasone. This finding indicates the existence of multiple corticotroph tumoural phenotypes and may account for the different responses to physiological and pharmacological modulators in vivo.

Object Resident duty-hours restrictions have now been instituted in many countries worldwide. Shortened training times and increased public scrutiny of surgical competency have led to a move away from the traditional apprenticeship model of training. The development of educational models for brain anatomy is a fascinating innovation allowing neurosurgeons to train without the need to practice on real patients and it may be a solution to achieve competency within a shortened training period. The authors describe the use of Stratathane resin ST-504 polymer (SRSP), which is inserted at different intracranial locations to closely mimic meningiomas and other pathological entities of the skull base, in a cadaveric model, for use in neurosurgical training. Methods Silicone-injected and pressurized cadaveric heads were used for studying the SRSP model. The SRSP presents unique intrinsic metamorphic characteristics: liquid at first, it expands and foams when injected into the desired area of the brain, forming a solid tumorlike structure. The authors injected SRSP via different passages that did not influence routes used for the surgical approach for resection of the simulated lesion. For example, SRSP injection routes included endonasal transsphenoidal or transoral approaches if lesions were to be removed through standard skull base approach, or, alternatively, SRSP was injected via a cranial approach if the removal was planned to be via the transsphenoidal or transoral route. The model was set in place in 3 countries (US, Italy, and The Netherlands), and a pool of 13 physicians from 4 different institutions (all surgeons and surgeons in training) participated in evaluating it and provided feedback. Results All 13 evaluating physicians had overall positive impressions of the model. The overall score on 9 components evaluated—including comparison between the tumor model and real tumor cases, perioperative requirements, general impression, and applicability—was 88% (100% being the best possible achievable score where the evaluator strongly agreed with the proposed factor). Individual components had scores at or above 80% (except for 1). The only score that was below 80% was related to radiographic visibility of the model for adequate surgical planning (score of 74%). The highest score was given to usefulness in neurosurgical training (98%). Conclusions The skull base tumor model is an effective tool to provide more practice in preoperative planning and technical skills.

Altered excitatory synaptic activity is likely a key factor in the neuronal hyperexcitability of developmental cerebral malformations. Using a combined morphologic and molecular approach, we investigated the NMDA receptor and related protein composition in human epileptic patients affected by periventricular nodular heterotopia, subcortical band heterotopia, or focal cortical dysplasia. Our results indicate that expression levels of specific NMDA receptor subunits are altered in both cerebral heterotopia and cortical dysplasia. A selective increase in the NR2B subunit was present in all cortical dysplasia, whereas the expression level of NR2A and NR2B subunits was significantly downregulated in all patients with heterotopia. NR2B upregulation in cortical dysplasia was greater in the total homogenate than the postsynaptic membrane fraction, suggesting that mechanisms other than increased ionic influx through the postsynaptic membrane may sustain hyperexcitability in dysplastic neurons. In cerebral heterotopia, the NR2A and NR2B downregulation was accompanied by less evident reduction of the SAP97 and PSD-95 proteins of the MAGUK family, thus suggesting that NMDA impairment was associated with altered molecular structure of the postsynaptic membrane. Our results demonstrate that diverse human developmental malformations are associated with different alterations of the NMDA receptor, which may contribute to the genesis of epileptic phenomena.

Summary background Somatostatin analogues (SA) are currently the mainstay in the medical treatment of acromegaly. However, even high doses of depot SA for prolonged periods do not achieve GH–IGF-I normalization in some patients. Even though some data were reported about the addition of cabergoline, a long-acting dopamine agonist (DA), to SA in resistant patients, definite data are still lacking. design Prospective open trial. patients In 19 acromegalic patients with active disease (34–82 years old, seven males, 12 females) resistant to chronic (9–12 months) depot SA (octreotide-LAR, 30 mg/28 days in 13 patients, lanreotide, 60 mg/28 days intramuscularly in six patients) cabergoline was added (combined treatment). In these patients, SA treatment had partially relieved GH and IGF-I hypersecretion but no patient had achieved ‘safe’ GH and normal IGF-I-values. Eight patients had PRL levels greater than 15 µg/l (range 16–60 µg/l; 1 µg = 21·2 mIU). Immunohistochemistry (IHC) was positive for PRL in four out of eight operated patients. results The addition of cabergoline, using the minimal effective and the maximal tolerated dose (range 1–3·5 mg/week), decreased GH from 6·6 ± 0·9 to 4·6 ± 0·6 µg/l (P = 0·018), and IGF-I from 552 ± 44 to 428 ± 54 µg/l (P = 0·019) after 6 months (median, range 3–18 Months). Combined treatment decreased GH to < 2·5 µg/l in four patients (21%) and normalized IGF-I for age in eight patients (42%). It obtained a decline of both GH and IGF-I (−49 ± 7%, and −47 ± 5%, respectively) in nine patients (47%), and a partial improvement in six (32%) patients (GH decreased by 43 ± 8% in four, and IGF-I by 35–38% in two patients). No change was observed in two patients, and worsening in two other patients. Results were not dependent on PRL status (serum levels or IHC). Combined treatment was well tolerated. conclusions The addition of cabergoline to depot SA-resistant acromegalic patients is effective, not dependent on PRL values and normalizes IGF-I levels in 42% of patients. The association of long-acting DA and SA deserves a more relevant role in the therapeutical algorithm of acromegaly.

Negli ultimi anni l’introduzione dell’endoscopio ha ampliato le possibilita di asportazione radicale dei tumori della regione sellare per via transnasosfenoidale. Presentiamo brevemente la tecnica, i vantaggi, gli svantaggi e i risultati.

To reduce the sequelae from CNS irradiation (RT), 16 children younger than 3 years with medulloblastoma-PNET (13 cases) and ependymoma (3 cases) were treated between 1987-1993 according to different postsurgical chemotherapy (CT) programs. None of these patients presented with metastases. Eleven patients were rendered disease-free by surgery, while 5 had residual tumor. Adjuvant therapy depended on patients' age, postsurgical status and parents' consent to radiotherapy (RT). Nine of the 16 infants remained alive in continuous complete remission from the first neoplasm (median follow-up 7 years). Three of them had been treated with CT alone and 6 with combined CT + RT (posterior fossa 4, whole CNS 2). Seven patients relapsed a median of 13 months after diagnosis, and all 7 of them died of their disease. Despite the omission of RT in 6 of the 16 patients and administration of only focal RT in 8 of the 16, the outcome of this series was satisfactory. Local failure (in 5/7 patients) was the major problem, despite the high dose of RT used in 2 of these 5. In 4 of 6 evaluable children school performance was satisfactory. One child in whom the entire CNS was irradiated developed glioblastoma multiforme 120 months after the first diagnosis of medulloblastoma.

Background: Somatostatin analogues are nowadays the milestone in the medical treatment of acromegaly. We evaluated the effects of a new 60 mg longer-acting formulation of lanreotide (LAN60) on GH/IGF-I levels and tumor size. Patients: Twenty-one acromegalics entered a prospective monocentric open study. Eight were consecutive “de novo” patients (group I). Thirteen patients sensitive to SA (GH levels < 2.5 μg/l and/or IGF-I normalization on chronic LAN 30 mg (LAN30) treatment) were switched to LAN60 (group II). Protocol: LAN60 was administered IM for 6 cycles at 28 day intervals. In group I when GH/IGF-I remained pathological, the intervals were shortened to 21 days for the last three cycles. Controls: GH/IGF-I at the end of the 1st, 3rd and 6th cycle; MRI at the end of the study in all patients in group I bearing an adenoma. Results: Group I. GH (p = 0.00638, below 2.5 μg/l in two patients) and IGF-I (p = 0.0289, normalized in 5) significantly decreased. In one of two patients shortening the LAN60 schedule was more effective in suppressing GH/IGF-I. Group II. No change in GH and IGF-I levels was observed with the administration of LAN60, instead of LAN30. On LAN60 GH remained below 2.5 μg/l in 8/10 patients and IGF-I normal in 11/11 patients that had attained those values on LAN30. Tumor markedly shrank (23% to 64% vs basal), from 1400 (664–1680) mm3 to 520 (500–960) mm3 (median, interquartile, p = 0.0218) in all the 5 evaluable patients. Conclusion: LAN60 is a very effective and longer-lasting formulation for the treatment of acromegaly. A closer administration schedule might achieve greater efficacy. Its effectiveness in shrinking tumor opens new perspectives in the therapy of acromegaly.

Several radiation dose- and time-dependent tissue sequelae develop following acute high-dose radiation exposure. One of the recognized delayed effects of such exposures is lung injury, characterized by respiratory failure as a result of pneumonitis that may subsequently develop into lung fibrosis. Since this pulmonary subsyndrome may be associated with high morbidity and mortality, comprehensive treatment following high-dose irradiation will ideally include treatments that mitigate both the acute hematologic and gastrointestinal subsyndromes as well as the delayed pulmonary syndrome. Currently, there are no drugs approved by the Food and Drug Administration to counteract the effects of acute radiation exposure. Moreover, there are no relevant large animal models of radiation-induced lung injury that permit efficacy testing of new generation medical countermeasures in combination with medical management protocols under the FDA animal rule criteria. Herein is described a nonhuman primate model of delayed lung injury resulting from whole thorax lung irradiation. Rhesus macaques were exposed to 6 MV photon radiation over a dose range of 9.0-12.0 Gy and medical management administered according to a standardized treatment protocol. The primary endpoint was all-cause mortality at 180 d. A comparative multiparameter analysis is provided, focusing on the lethal dose response relationship characterized by a lethal dose50/180 of 10.27 Gy [9.88, 10.66] and slope of 1.112 probits per linear dose. Latency, incidence, and severity of lung injury were evaluated through clinical and radiographic parameters including respiratory rate, saturation of peripheral oxygen, corticosteroid requirements, and serial computed tomography. Gross anatomical and histological analyses were performed to assess radiation-induced injury. The model defines the dose response relationship and time course of the delayed pulmonary sequelae and consequent morbidity and mortality. Therefore, it may provide an effective platform for the efficacy testing of candidate medical countermeasures against the delayed pulmonary syndrome.

Resident duty-hours restrictions have now been instituted in many countries worldwide. Shortened training times and increased public scrutiny of surgical competency have led to a move away from the traditional apprenticeship model of training. The development of educational models for brain anatomy is a fascinating innovation allowing neurosurgeons to train without the need to practice on real patients and it may be a solution to achieve competency within a shortened training period. The authors describe the use of Stratathane resin ST-504 polymer (SRSP), which is inserted at different intracranial locations to closely mimic meningiomas and other pathological entities of the skull base, in a cadaveric model, for use in neurosurgical training.Silicone-injected and pressurized cadaveric heads were used for studying the SRSP model. The SRSP presents unique intrinsic metamorphic characteristics: liquid at first, it expands and foams when injected into the desired area of the brain, forming a solid tumorlike structure. The authors injected SRSP via different passages that did not influence routes used for the surgical approach for resection of the simulated lesion. For example, SRSP injection routes included endonasal transsphenoidal or transoral approaches if lesions were to be removed through standard skull base approach, or, alternatively, SRSP was injected via a cranial approach if the removal was planned to be via the transsphenoidal or transoral route. The model was set in place in 3 countries (US, Italy, and The Netherlands), and a pool of 13 physicians from 4 different institutions (all surgeons and surgeons in training) participated in evaluating it and provided feedback.All 13 evaluating physicians had overall positive impressions of the model. The overall score on 9 components evaluated--including comparison between the tumor model and real tumor cases, perioperative requirements, general impression, and applicability--was 88% (100% being the best possible achievable score where the evaluator strongly agreed with the proposed factor). Individual components had scores at or above 80% (except for 1). The only score that was below 80% was related to radiographic visibility of the model for adequate surgical planning (score of 74%). The highest score was given to usefulness in neurosurgical training (98%).The skull base tumor model is an effective tool to provide more practice in preoperative planning and technical skills.

Prepro-thyrotrophin-releasing hormone (TRH) (178-199), a 22-amino acid cleavage product of the TRH prohormone, has been postulated to act as an adrenocorticotrophin hormone (ACTH)-release inhibitor. Indeed, although in vitro evidence indicates that this peptide may inhibit basal and stimulated ACTH secretion in rodent anterior pituitary primary cultures and cell lines, not all studies concur and no study has as yet evaluated the effect of this peptide in Cushing's disease. The present study aimed to test the effect of preproTRH(178-199) in human tumoural corticotrophs. Twenty-four human ACTH-secreting pituitary tumours (13 macroadenomas, 11 microadenomas) were collected during surgery and incubated with 10 or 100 n. m preproTRH(178-199). ACTH secretion was assessed after 4 and 24 h of incubation by immunometric assay and expressed relative to levels observed in control, unchallenged wells (= 100%). Parallel experiments were performed in rat anterior pituitary primary cultures. A clear inhibition of ACTH secretion at 4 and 24 h was observed in 12 specimens (for 10 n. m ppTRH: 70 ± 4% control at 4 h and 83 ± 5% control at 24 h; for 100 n. m ppTRH: 70 ± 4% control at 4 h and 85 ± 5% control at 24 h), whereas a mild and short-lasting stimulatory effect was observed in three tumours and no changes in ACTH secretion in the remaining nine tumoural specimens. The inhibitory effect of preproTRH(178-199) was more evident in macroadenomas and significantly correlated with sensitivity to dexamethasone inhibition. Significant inhibition of ACTH secretion by preproTRH(178-199) in rat pituitary cultures was observed after 24 h of incubation. The present study conducted in a large series of human corticotroph tumours shows that preproTRH(178-199) inhibits tumoural ACTH secretion in a sizable proportion of specimens, in close relation to the size of the tumour and its sensitivity to glucocorticoid negative feedback. This appears a promising avenue of research and further studies are warranted to explore the full scope of preproTRH(178-199) as a regulator of ACTH secretion. © 2010 The Authors. Journal Compilation © 2010 Blackwell Publishing Ltd.

Kilovoltage x-ray projection images (kV images for brevity) are increasingly available in image guided radiotherapy (IGRT) for patient positioning. These images are two-dimensional (2D) projections of a three-dimensional (3D) object along the x-ray beam direction. Projecting a 3D object onto a plane may lead to ambiguities in the identification of anatomical structures and to poor contrast in kV images. Therefore, the use of kV images in IGRT is mainly limited to bony landmark alignments. This work proposes a novel subtraction technique that isolates a slice of interest (SOI) from a kV image with the assistance of a priori information from a previous CT scan. The method separates structural information within a preselected SOI by suppressing contributions to the unprocessed projection from out-of-SOI-plane structures. Up to a five-fold increase in the contrast-to-noise ratios (CNRs) was observed in selected regions of the isolated SOI, when compared to the original unprocessed kV image. The tomographic image via background subtraction (TIBS) technique aims to provide a quick snapshot of the slice of interest with greatly enhanced image contrast over conventional kV x-ray projections for fast and accurate image guidance of radiation therapy. With further refinements, TIBS could, in principle, provide real-time tumor localization using gantry-mounted x-ray imaging systems without the need for implanted markers.

Background: Peri-operative steroids are administered routinely to patients with pituitary adenoma undergoing transsphenoidal adenomectomy (TSA). Aim: To evaluate hypothalamic-pituitary-adrenal (HPA) axis before and after programmed endoscopic TSA (E-TSA) in patients with clinically non-functioning pituitary macroadenoma (NFPA). Design: Open prospective. Setting: Tertiary referral hospitals. Patients: Seventy-two consecutive patients (20–87 yr, 37 males). Interventions: Adrenal steroid replacement therapy (ASRT) was given only in patients with hypocortisolism [08:00 h cortisol (F) 90%) selective resection of the adenoma in all, F and clinical picture were checked at day 2. The low-dose (1 µg) ACTH test (LDACTH) was performed at 6 weeks and repeated at 12 months. Results: Hypocortisolism was present pre-operatively in 14 patients (19.4%), persisted post-operatively in all but one, and was detected de novo at the post-operative day 2 control in 6 (10.3%). In all but one the post-operative day 2 basal F and peak F during LDACTH test were concordant. No patient whose F was > 8 µg/dl was treated with ASRT or developed symptoms of adrenal failure during the follow-up (1–11 yr, median 5). Conclusions: HPA function is usually preserved in NFPA and is infrequently impaired after complete tumor removal by E-TSA. The 08:00 h. plasma cortisol evaluation before and 2 days after surgery, using as cut-off the value of 8 µg/dl, allows full evaluation of HPA status. Peri-operative steroid treatment should be given only in patients with hypocortisolism.