Objective Glucose-dependent insulinotropic polypeptide receptor (GIPR) overexpression has been recently described in a proportion of gsp− somatotropinomas and suggested to be associated with the ...paradoxical increase of GH (GH-PI) during an oral glucose load. Design and methods This study was aimed at linking the GIP/GIPR pathway to GH secretion in 25 somatotropinomas-derived primary cultures and correlating molecular with clinical features in acromegalic patients. Given the impairment of the GIP/GIPR axis in acromegaly, an additional aim was to assess the effect of GH/IGF-1 stimulation on GIP expression in the enteroendocrine cell line STC-1. Results Nearly 80% of GIPR-expressing somatotropinomas, all of them negative for gsp mutations, show increased GH secretion upon GIP stimulation, higher sensitivity to Forskolin but not to somatostatin analogs. Besides increased frequency of GH-PI, GIPR overexpression does not appear to affect acromegalic patients’ clinical features. In STC-1 cells transfected with GIP promoter-driven luciferase vector, IGF-1 but not GH induced dose-dependent increase in luciferase activity. Conclusions We demonstrate that GIPR mediates the GH-PI in a significant proportion of gsp− acromegalic patients. In these cases, the stimulatory effect of IGF-1 on GIP promoter support the hypothesis of a functional GH/IGF-1/GIP axis. Further studies based on larger cohorts and the development of a stable transgenic model with inducible GIPR overexpression targeted to pituitary somatotroph lineage will be mandatory to establish the real role of GIPR in the pathogenesis of somatotropinomas.
Papillary craniopharyngiomas harbor the BRAF V600E mutation, which paves the way for using BRAF inhibitor molecules to treat tumors refractory to standard therapies. Single case reports confirmed the ...efficacy of targeted therapy. However, most reports were limited by the short follow-up. We describe the long-term course of a patient treated with dual-agent BRAF and MEK inhibitors and review the available literature.
A 75-year-old male patient had recurrence of a papillary craniopharyngioma after transsphenoidal surgery and Gamma Knife radiosurgery. Review of the pathologic specimen confirmed the presence of the BRAF V600E mutation. Because of the few therapeutic options, we decided to initiate BRAF/MEK inhibitor combined therapy for six months. Rapid reduction of the tumor occurred, but three months after quitting combined medical therapy the tumor recurred. BRAF/MEK inhibitor therapy was resumed and the tumor again showed a marked reduction. The second course was maintained for 20 months and the tumor showed another recurrence within three months, which, again, responded to a third course of targeted therapy.
Our study confirms the excellent response of papillary craniopharyngioma to combined BRAF and MEK inhibitors. However, rapid tumor recurrence is the rule when medical therapy is stopped. Resistance to a second and third course of targeted therapy did not occur, suggesting that tumor mutations affecting the response to drugs seems an uncommon event in papillary craniopharyngioma. The exact role of targeted therapy in the treatment algorithm of papillary craniopharyngiomas has still to be refined.
Thyrotropin (TSH)-secreting pituitary adenoma (TSHoma) is a rare cause of TSH-dependent hyperthyroidism. The first therapeutic option is surgery. Medical treatment with somatostatin analogs is also ...effective. To obviate the need for lifelong drug therapy, gamma knife radiosurgery (GKRS) might be considered in selected patients. We report the largest series of patients with TSHoma treated by GKRS at a single center.
This study was a retrospective analysis of 18 consecutive patients with TSHoma treated by GKRS between 1994 and 2022. Normalization of hyperthyroidism, when present at the time of surgery, and control of tumor growth were the main outcomes of the study.
The median follow-up after GKRS treatment was 114 months (IQR, 57-213 months; range 17-285 months). No patients had growth of the residual tumor after GKRS. Remission of hyperthyroidism occurred in 9 of the 11 (81.8%) patients who were hyperthyroid before GKRS. The probability of hyperthyroidism remission three years after GKRS was 59.1% (95% CI 27.9-90.3%). No major side effects occurred after GKRS. One patient out of the 15 patients (6.7%) with normal baseline adrenal function and follow-up longer than 3 years developed new onset hypoadrenalism, while hypogonadism did not occur in the 13 patients with baseline normal function.
Our study shows that GKRS is an effective and safe adjuvant treatment for selected patients with residual or recurring TSHoma. The option of GKRS as an alternative treatment to lifelong medical treatment with somatostatin analogs should be thoroughly discussed with the patients.
Background: It has been reported that KRAS mutations (and to a lesser extent KRAS mutations with the BRAF V600E mutation) negatively affect response to anti-epidermal growth factor receptor (EGFR) ...mAbs in metastatic colorectal cancer (mCRC) patients, while the biological impact of the EGFR pathway represented by PI3K/PTEN/AKT on anti-EGFR treatment is still not clear.
Patients and methods: We analysed formalin-fixed samples from a cohort of 32 mCRC patients treated with cetuximab by means of EGFR immunohistochemistry, EGFR and PTEN FISH analysis, and KRAS, BRAF, PI3KCA, and PTEN genomic sequencing.
Results: Ten (31%) of 32 patients showed a partial response to cetuximab and 22 (69%) did not nonresponder (NR). EGFR immunophenotype and FISH-based gene status did not predict an anti-EGFR mAb response, whereas KRAS mutations (24%) and PI3K pathway activation, by means of PI3KCA mutations (13%) or PTEN mutation (10%)/loss (13%), were significantly restricted to, respectively, 41% and 37% of NRs.
Conclusion: These findings suggested that KRAS mutations and PI3KCA/PTEN deregulation significantly correlate with resistance to cetuximab. In line with this, patients carrying KRAS mutations or with activated PI3K profiles can benefit from targeted treatments only by switching off molecules belonging to the downstream signalling of activated EGFR, such as mammalian target of rapamycin.
•Fatigue behavior of asphalt mortars containing RAP aggregate was investigated.•The influence of fine aggregate particles and aging on fatigue was studied.•Relationship between fatigue law ...parameters, aging and mix conditions was found.•Parameter A shows a decreasing linear trend with the increase of volume particles.•Parameter B follows an increasing linear trend with the volume aggregate particles.
Fatigue cracking is one of the primary failure mechanisms in asphalt pavements and it predominantly occurs within the mortar phase. For this reason, in recent years, a number of studies were carried out by various researchers to better understand the fatigue mechanism in such a critical mixture phase. In the present work, time sweep tests were performed in strain control mode on asphalt mortars prepared with three volume percentages of fine aggregate at different aging conditions. In particular, two different asphalt mortars were used: one containing Recycled Asphalt Pavement (RAP) materials and the other one composed of the same RAP aggregate skeleton without the aged binder. The influence of the different aging conditions, the presence of the aged binder and the addition of fine aggregate particles on the fatigue resistance of the mortars were evaluated. Moreover, a relationship between the parameters of the obtained fatigue laws and the different aging and mix design conditions was found. The proposed relationship can be easily used to predict the fatigue resistance of a mortar composed of a specific volume concentration of aggregate particles and recycled material. The potential extension of the proposed relationship to mixtures may eventually result in the implementation of a simple analysis tool for practitioner limiting the need for more sophisticated and expensive fatigue tests on asphalt mixtures.
•Performing Dynamic Shear Rheometer tests on mortars containing RAP.•Back-calculating the rheological properties of bituminous blends from mortars.•Determining the maximum amount of RAP in SMA ...mixture in terms of fatigue resistance.•Validating the procedure on fatigue using Linear Amplitude Sweep tests.
This paper presents a simple method to determine the amount of Reclaimed Asphalt Pavement (RAP) that can be added to Stone Matrix Asphalt (SMA) mixtures without compromising the fatigue resistance. Dynamic Shear Rheometer tests (DSR) on binder and mortars composed with fine RAP particles, called Selected Recycled Asphalt Pavement (SRAP) are used together with the Nielsen model to back-calculate the norm of the complex modulus of the bituminous blend of fresh and RAP binder. Fatigue properties are derived from parameter G*sinδ and Linear Amplitude Sweep tests. The analysis indicates that a limiting SRAP binder content of 23% can be included in SMA mixtures with satisfactory fatigue performance.
Abstract The calcaneus is a desirable site for harvesting autologous bone for use in foot surgery. However, fracture of the calcaneus is a serious complication associated with bone harvesting from ...this site. Currently it is unknown how much bone may be safely harvested from the calcaneus without inducing a fracture. The purpose of this study was to investigate the effect of progressive bone removal from the calcaneus onto the mechanical stress redistribution of the foot, and therefore on the increase in fracture risk. Different loads were applied on the talus to evaluate the calcaneus stress distribution at different situations. Because of the potential increase in mechanical stress in the calcaneus, secondary to contraction of the Achilles tendon, we also evaluated the mechanical behavior properties of the foot with increasing traction force in the Achilles tendon. A three-dimensional (3D) finite element (FE) model developed from CT images obtained from a healthy individual was used to compute displacement, tension and compression stresses in six situations, including intact foot, and five depth of the bone block removed, with a maximum depth of 7.5 mm. The results from these simulations indicated that when the maximum load was applied at the Achilles tendon, the tension stress increased from 42.16 MPa in the intact foot to 86.28 MPa with maximum bone harvesting. Furthermore, as the volume of bone extracted from the calcaneus increases, there is a redistribution of stresses that differs significantly from the intact foot. In fact, although the maximum stress was not significantly affected by increasing the volume of bone harvested—except when increasing the Achilles tendon force-, stresses did increase in areas of the calcaneus is vulnerable to injury, leading to an increase in fracture risk.
Summary EGFR overexpression in salivary gland carcinomas provides the rational for the investigation of anti-EGFR treatments in recurrent and/or metastatic salivary gland cancers (RMSGCs). The ...activity of cetuximab in terms of clinical benefit rate (CBR) defined as the occurrence of objective response (CR or PR) or stable disease (SD) for ⩾6 months was investigated. From April to December 2005, 30 patients 23 adenoid cystic carcinoma (ACC) and 7 non-ACC were treated with cetuximab at 400 mg/m2 /week followed by 250 mg/m2 /week until progression, major toxicity or voluntary discontinuation. EGFR expression and gene status were retrospectively analyzed by immunocytochemistry and fluorescence in situ hybridization, respectively. A median of 14 courses of cetuximab (range 5–54) were infused. Skin toxicity was the main adverse event. Cetuximab provides a CBR in 50% (95% CL, 31 to 69%) of cases. None tumor sample showed EGFR gene amplification and an increased EGFR copy number was observed in 12% of samples, all ACC. Skin rash ⩾G2, EGFR overexpression and EGFR copy number were not statistically correlated to CB. In RMSGCs further evaluations of EGFR targeting agents are advisable and should take place by appropriate tumor biological selection, differentiating ACC from non-ACC.
ObjectiveTo describe demographic and hormonal characteristics, comorbidities (diabetes mellitus and hypertension), therapeutic procedures and their effectiveness, as well as predictors of morbidity ...and mortality in a nationwide survey of Italian acromegalic patients.DesignRetrospective multicenter epidemiological study endorsed by the Italian Society of Endocrinology and performed in 24 tertiary referral Italian centers. The mean follow-up time was 120 months.ResultsA total of 1512 patients, 41% male, mean age: 45±13 years, mean GH: 31±37 μg/l, IGF1: 744±318 ng/ml, were included. Diabetes mellitus was reported in 16% of cases and hypertension in 33%. Older age and higher IGF1 levels at diagnosis were significant predictors of diabetes and hypertension. At the last follow-up, 65% of patients had a controlled disease, of whom 55% were off medical therapy. Observed deaths were 61, with a standardized mortality ratio of 1.13 95% (confidence interval (CI): 0.87–1.46). Mortality was significantly higher in the patients with persistently active disease (1.93; 95% CI: 1.34–2.70). Main causes of death were vascular diseases and malignancies with similar prevalence. A multivariate analysis showed that older age, higher GH at the last follow-up, higher IGF1 levels at diagnosis, malignancy, and radiotherapy were independent predictors of mortality.ConclusionsPretreatment IGF1 levels are important predictors of morbidity and mortality in acromegaly. The full hormonal control of the disease, nowadays reached in the majority of patients with modern management, reduces greatly the disease-related mortality.
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