Somatostatin receptor type 2 (SST2) is the main pharmacological target of medical therapy for GH-secreting pituitary tumors, but molecular mechanisms regulating its expression and signaling are ...largely unknown. The aim of this study was to investigate the role of cytoskeleton protein filamin A (FLNA) in SST2 expression and signaling in somatotroph tumor cells. We found a highly variable expression of FLNA in human GH-secreting tumors, without a correlation with SST2 levels. FLNA silencing in human tumoral cells did not affect SST2 expression and localization but abolished the SST2-induced reduction of cyclin D1 (−37% ± 15% in control cells, P < .05 vs basal) and caspase-3/7 activation (+63% ± 31% in control cells, P < .05 vs basal). Overexpression of a FLNA dominant-negative mutant that specifically prevents SST2-FLNA binding reduced SST2 expression after prolonged agonist exposure (−55% ± 5%, P < .01 vs untreated cells) in GH3 cells. Moreover, SST2-induced apoptotic effect (77% ± 54% increase of caspase activity, P < .05 vs basal) and SST2-mediated ERK1/2 inhibition (48% ± 17% reduction of ERK1/2 phosphorylation, P < .01 vs basal) were abrogated in cells overexpressing another FLNA mutant that prevents FLNA interaction with partner proteins but not with SST2, suggesting a scaffold function of FLNA in somatotrophs. In conclusion, these data demonstrate that FLNA is involved in SST2 stabilization and signaling in tumoral somatotrophs, playing both a structural and functional role.
Many surrogate-based motion models (SMMs), proposed to guide motion management in radiotherapy, are constructed by correlating motion of an external surrogate and internal anatomy during ...CT-simulation. Changes in this correlation define model break down. We validate a methodology that incorporates fluoroscopic (FL) images acquired during treatment for SMM construction and update. Under a prospective IRB, 4DCT scans, VisionRT (VRT) surfaces, and orthogonal FLs were collected from five lung cancer patients. VRT surfaces and two FL time-series were acquired pre- and post-treatment. A simulated annealing optimization scheme was used to estimate optimal lung deformations by maximizing the mutual information (MI) between digitally reconstructed radiographs (DRRs) of the SMM-estimated 3D images and FLs. Our SMM used partial-least-regression and was trained using the optimal deformations and VRT surfaces from the first breathing-cycle. SMM performance was evaluated using the MI score between reference FLs and the corresponding SMM or phase-assigned 4DCT DRRs. The Hausdorff distance for contoured landmarks was used to evaluate target position estimation error. For four out of five patients, two principal components approximated lung surface deformations with submillimeter accuracy. Analysis of the MI score between more than 4000 pairs of FL and DRR demonstrated that our model led to more similarity between the FL and DRR images compared to 4DCT and DRR images from a model based on an a priori correlation model. Our SMM consistently displayed lower mean and 95th percentile Hausdorff distances. For one patient, 95th percentile Hausdorff distance was reduced by 11 mm. Patient-averaged reductions in mean and 95th percentile Hausdorff distances were 3.6 mm and 7 mm for right-lung, and 3.1 mm and 4 mm for left-lung targets. FL data were used to evaluate model performance and investigate the feasibility of model update. Despite variability in breathing, use of post-treatment FL preserved model fidelity and consistently outperformed 4DCT for position estimation.
Purpose
The management of pituitary adenomas in the elderly has become a relevant clinical issue, in relationship with improved life expectancy and spreading use of imaging techniques. In this ...single-center and retrospective study, we investigated the impact of age on peri- and postsurgical outcomes in patients undergoing transnasal sphenoidal (TNS) surgery for pituitary adenomas.
Methods
One-hundred-sixty-nine patients (62% males) undergoing endoscopic transphenoidal (TNS) surgery for nonfunctioning pituitary adenomas (NFPAs) were enrolled. Patients were subdivided into three groups according to age tertiles: ≤56 (group 1), 57–69 (group 2), and ≥70 (group 3) years. Postsurgical and endocrinological outcomes were evaluated and compared among the three age groups.
Results
37/169 patients (21.9%) developed at least one perisurgical complication, without significant association with the patients’ age (
P
= 0.838), Charlson co-morbidity score (
P
= 0.326), and American Society of Anesthesiologist score (
P
= 0.616). In the multivariate regression analysis, the adenoma size resulted the only determinant of perisurgical complication (odds ratio OR 1.07, 95% confidence interval C.I. 1.00–1.13;
P
= 0.044). The development and the recovery of at least one pituitary hormone deficiency were observed in 12.2% and 14.2% of patients, respectively. The risk of developing new pituitary hormone deficiencies was correlated with cavernous sinus invasion as evaluated by magnetic resonance imaging (hazard ratio HR 4.19, 95% C.I. 1.39–12.66;
P
= 0.010), whereas the probability to normalize at least one pituitary hormone deficiency was significantly correlated with younger age of patients (HR 0.27, 95% CI 0.12–0.61;
P
= 0.002).
Conclusions
The results of this study reinforce the concept that endoscopic TNS surgery is a safe therapeutic option in the elderly patients with NFPA, even in presence of comorbidities and high anesthetic risk.
Background
Recurrence of acromegaly after successful surgery is a rare event, but no clear data are reported in the literature about its recurrence rates. This study aimed to evaluate the recurrence ...rate in a series of acromegalic patients treated by transsphenoidal surgery (TSS) with a long follow-up.
Methods
We retrospectively analyzed data from 283 acromegalic patients who underwent TSS at two pituitary units in Milan (Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico and IRCCS Humanitas Research Hospital). The diagnosis and recurrence of acromegaly were defined by both elevated IGF-1 levels and a lack of GH suppression based on appropriate criteria for the assay used at the time of diagnosis.
Results
After surgery, 143 patients (50%) were defined as not cured, 132 (47%) as cured and 8 (3%) as partially cured because of normalization of only one parameter, either IGF1 or GH. In the cured group, at the last follow-up (median time 86.8 months after surgery), only 1 patient (0.7%) showed full recurrence (IGF-1 + 5.61 SDS, GH nadir 1.27 µg/l), while 4 patients (3%) showed only increased IGF1. In the partially cured group at the last follow-up, 2/8 (25%) patients showed active acromegaly (IGF-1 SDS + 2.75 and + 3.62; GH nadir 0.6 and 0.5 µg/l, respectively).
Conclusions
In the literature, recurrence rates range widely, from 0 to 18%. In our series, recurrence occurred in 3.7% of patients, and in fewer than 1%, recurrence occurred with elevation of both IGF-1 and the GH nadir. More frequently (25%), recurrence came in the form of incomplete normalization of either IGF-1 or GH after surgery.
Purpose
We develop and validate a motion model that uses real‐time surface photogrammetry acquired concurrently with four‐dimensional computed tomography (4DCT) to estimate respiration‐induced ...changes within the entire irradiated volume, over arbitrarily many respiratory cycles.
Methods
A research, couch‐mounted, VisionRT (VRT) system was used to acquire optical surface data (15 Hz, ROI = 15 × 20 cm2) from the thoraco‐abdominal surface of a consented lung SBRT patient, concurrently with their standard‐of‐care 4DCT. The end‐exhalation phase from the 4DCT was regarded as reference and for each remaining phase, deformation vector fields (DVFs) with respect to the reference phase were computed. To reduce dimensionality, the first two principal components (PCs) of the matrix of nine DVFs were calculated. In parallel, ten phase‐averaged VRT surfaces were created. Surface DVFs and corresponding PCs were computed. A principal least squares regression was used to relate the PCs of surface DVF to those of volume DVFs, establishing a relationship between time‐varying surface and the underlying time‐varying volume. Proof‐of‐concept validation was performed during each treatment fraction by concurrently acquiring 30 s time series of real‐time surface data and “ground truth” kV fluoroscopic data (FL). A ray‐tracing algorithm was used to create a digitally reconstructed fluorograph (DRF), and motion trajectories of high‐contrast, soft‐tissue, anatomical features in the DRF were compared with those from kV FL.
Results
For five of the six fluoroscopic acquisition sessions, the model out‐performed 4DCT in predicting contour Dice coefficient with respect to fluoroscopy‐derived contours. Similarly, the model exhibited a marked improvement over 4DCT for patch positions on the diaphragm. Model patch position errors varied from 5 to −15 mm while 4DCT errors ranged between 5 and −22.4 mm. For one fluoroscopic acquisition, a marked change in the a priori internal–external correlation resulted in model errors comparable to those of 4DCT.
Conclusions
We described the development and a proof‐of‐concept validation for a volumetric motion model that uses surface photogrammetry to correlate the time‐varying thoraco‐abdominal surface to the time‐varying internal thoraco‐abdominal volume. These early results indicate that the proposed approach can result in a marked improvement over 4DCT. While limited by the duration of the fluoroscopic acquisitions as well as the resolution of the acquired images, the DRF‐based proof‐of‐concept technique developed here is model‐agnostic, and therefore, has the potential to be used as an in‐patient validation tool for other volumetric motion models.
•cAMP exerted opposite effects on different pituitary cell types proliferation.•The divergent cAMP effects were mimicked by Epac and PKA selective analogs.•Epac and PKA act through independent ...pathways activating Rap1 and CREB, respectively.
In the pituitary the activation of cyclic adenosine 3′-5′-monophosphate (cAMP) dependent pathways generates proliferative signals in somatotrophs, whereas in pituitary cells of other lineages its effect remains uncertain. Moreover, the specific role of the two main cAMP effectors, protein kinase A (PKA) and exchange proteins directly activated by cAMP (Epac), has not been defined.
Aim of this study was to investigate the effect of cAMP on pituitary adenomatous cells proliferation and to identify PKA and Epac differential involvement.
We found that cAMP increased DNA synthesis and cyclin D1 expression in somatotropinomas, whereas it reduced both parameters in prolactinomas and nonfunctioning adenomas, these effects being replicated in corresponding cell lines. Moreover, the divergent cAMP effects were mimicked by Epac and PKA analogs, which activated Rap1 and CREB, respectively.
In conclusion, we demonstrated that cAMP exerted opposite effects on different pituitary cell types proliferation, these effects being mediated by both Epac and PKA.
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.
Characterizing the biological effects of flattening filter-free (FFF) X-ray beams from linear accelerators is of importance, due to their increasing clinical availability. The purpose of this work is ...to determine whether in vitro cell survival is affected by the higher dose-per-pulse present in FFF beams in comparison with flattened X-ray beams. A Varian TrueBeam
®
linear accelerator was used to irradiate the T98G, V79-4 and U87-MG cell lines with a single fraction of 5 Gy or 10 Gy doses of X-rays. Beams with energies of 6 MegaVolt (MV), 6 MV FFF and 10 MV FFF were used, with doses-per-pulse as measured at the monitor chamber of 0.28, 0.78 and 1.31 mGy/pulse for 6 MV, 6 MV FFF and 10 MV FFF, respectively. The dose delivered to each Petri dish was verified by means of ionization chamber measurements. No statistically significant effects on survival fraction were observed for any of the cell lines considered, either as a function of dose-per-pulse, average dose rate or total dose delivered. Biological effects of higher instantaneous rates should not be excluded on the basis of in vitro experimental results such as the ones presented in this work. The next step toward an assessment of the biological impact of FFF beams will require in vivo studies.
Purpose: Dose rate regulated Tracking (DRRT) is known to be an efficient method which adaptively deliver tracking treatments when patient breathing is irregular. The interface for the dose rate ...controlling, however, is not commercially available. The Motion Management Interface (MMI, Varian Medical System, CA), which provides beam on/off switching during treatment is available for clinic. This study is to test if delivering the adaptive tumor tracking is feasible for irregular breathing using beam switching with MMI. Methods: Fifty‐five free breathing RPM traces acquired from lung cancer patients are used. The first day RPM traces of the patients are utilized to design preprogrammed tracking MLC patterns, of which periods are intentionally reduced by 20% in order to catch up the variation of patient breathing irregularity in the treatment day. Eligibility criteria for this technique is variation of amplitude and period less than 20%. An algorithm which determines beam on/off every 100 ms by considering the preprogrammed (MLC) positions and current breathing positions is developed. Tracking error and delivery efficiency is calculated by simulating the beam‐switching adaptive tracking from the RPM traces. Results: Breathing patterns of 38 patients (70%) met the eligibility criteria. Tracking errors of all of the cases who meet the criteria are less than 2mm (average 1.4mm) and the average delivery efficiency was 71%. Those of rest of the cases are 1.9 mm and 48%. Conclusions: Beam switching is effectively equivalent to the dose rate regulation for DRRT. Adaptive tracking with beam switching is feasible if patient selection is based on the eligibility criteria. NIH R01CA133539
Purpose: to present a method to generate retrospectively a pre‐selected motion phase cone‐beam CT image from the full motion cone‐beam CT acquired at standard rotation speed. Materials and Methods: ...the method consists of subtracting from the full CBCT all of the undesired motion phases and obtain a motion de‐blurred single‐phase CBCT image CTnm. This is accomplished by means of a subtraction CBCT (CTs) added to the full CBCT (CTm). CTs is obtained as follows: i) we sort the CBCT projections into each phase bin k according to the known motion trace; ii) compute the digitally reconstructed radiographs (DRR) from the full reconstruction at the gantry angles correlated to bin k; iii) generate a set of subtraction projections for phase k by subtracting the DRR from the original projection at the same gantry angle; v) reconstruct CTs from this single‐phase subtraction projection set; vi) add CTs to CTm to obtain CTnm. A qualitative assessment of the image quality improvement was performed using a simple shapes phantom. To quantitatively study the method, we used the image quality modules of a Catphan phantom, evaluated in a static scan and under anterior‐posterior motion. Results: The single phase CBCT reconstruction generated by our method successfully isolates the desired motion phase from the full motion CBCT, effectively reducing motion blur. It also shows improved image quality, with reduced streak artifacts with respect to the reconstructions from unprocessed phase‐sorted projections only. Conclusions: A novel CBCT motion de‐blurring algorithm has been developed and tested with phantom data. The algorithm allows to improve visualization of a single phase motion extracted from a standard CBCT dataset. NIH R01CA133539
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