Circulating myomiRNAs as biomarkers in patients with Cushing's syndrome.

PURPOSE: Impairment of skeletal muscle mass and strength affects 40-70% of patients with active Cushing's syndrome (CS). Glucocorticoid excess sustains muscle atrophy and weakness, while muscle-specific microRNAs (myomiRs) level changes were associated with muscle organization and function perturbation. The aim of the current study is to explore changes in circulating myomiRs in CS patients compared to healthy controls and their involvement in IGFI/PI3K/Akt/mTOR pathway regulation in skeletal muscle. METHODS: C2C12, mouse myocytes, were exposed to hydrocortisone (HC), and atrophy-related gene expression was investigated by RT-qPCR, WB and IF to assess HC-mediated atrophic signalling. miRNAs were evaluated in HC-treated C2C12 by PCR Arrays. MyomiRs significantly overexpressed in C2C12 were investigated in 37 CS patients and 24 healthy controls serum by RT-qPCR. The anti-anabolic role of circulating miRNAs significantly upregulated in CS patients was explored in C2C12 by investigating the IGFI/PI3K/Akt/mTOR pathway regulation. RESULTS: HC induced higher expression of atrophy-related genes, miR-133a-3p, miR-122-5p and miR-200b-3p in C2C12 compared to untreated cells. Conversely, the anabolic IGFI/PI3K/Akt/mTOR signalling was reduced and this effect was mediated by miR-133a-3p. In CS patients miR-133a-3p and miR-200b-3p revealed higher circulating levels (p < 0.0001, respectively) compared to controls. ROC curves for miR-133a-3p (AUC 0.823, p < 0.0001) and miR-200b-3p (AUC 0.850, p < 0.0001) demonstrated that both myomiRs represent potential biomarkers to discriminate between CS and healthy subjects. Pearson's correlation analysis revealed that circulating levels of miR-133a-3p are directly correlated with 24 h urinary-free cortisol level (r = 0.468, p = 0.004) in CS patients. CONCLUSIONS: HC induces atrophic signals by miR-133a-3p overexpression in mouse myocytes and humans. Circulating miR-133a-3p is promising biomarkers of hypercortisolism.

Clinical application of the "sellar barrier's concept" for predicting intraoperative CSF leak in endoscopic endonasal surgery for pituitary adenomas with a machine learning analysis.

Background: Recently, it was defined that the sellar barrier entity could be identified as a predictor of cerebrospinal fluid (CSF) intraoperative leakage. The aim of this study is to validate the application of the sellar barrier concept for predicting intraoperative CSF leak in endoscopic endonasal surgery for pituitary adenomas with a machine learning approach. Methods: We conducted a prospective cohort study, from June 2019 to September 2020: data from 155 patients with pituitary subdiaphragmatic adenoma operated through endoscopic approach at the Division of Neurosurgery, Università degli Studi di Napoli "Federico II," were included. Preoperative magnetic resonance images (MRI) and intraoperative findings were analyzed. After processing patient data, the experiment was conducted as a novelty detection problem, splitting outliers (i.e., patients with intraoperative fistula, n = 11/155) and inliers into separate datasets, the latter further separated into training (n = 115/144) and inlier test (n = 29/144) datasets. The machine learning analysis was performed using different novelty detection algorithms [isolation forest, local outlier factor, one-class support vector machine (oSVM)], whose performance was assessed separately and as an ensemble on the inlier and outlier test sets. Results: According to the type of sellar barrier, patients were classified into two groups, i.e., strong and weak barrier; a third category of mixed barrier was defined when a case was neither weak nor strong. Significant differences between the three datasets were found for Knosp classification score (p = 0.0015), MRI barrier: strong (p = 1.405 × 10-6), MRI barrier: weak (p = 4.487 × 10-8), intraoperative barrier: strong (p = 2.788 × 10-7), and intraoperative barrier: weak (p = 2.191 × 10-10). We recorded 11 cases of intraoperative leakage that occurred in the majority of patients presenting a weak sellar barrier (p = 4.487 × 10-8) at preoperative MRI. Accuracy, sensitivity, and specificity for outlier detection were 0.70, 0.64, and 0.72 for IF; 0.85, 0.45, and 1.00 for LOF; 0.83, 0.64, and 0.90 for oSVM; and 0.83, 0.55, and 0.93 for the ensemble, respectively. Conclusions: There is a true correlation between the type of sellar barrier at MRI and its in vivo features as observed during endoscopic endonasal surgery. The novelty detection models highlighted differences between patients who developed an intraoperative CSF leak and those who did not.

The role of OCT- angiography in predicting anatomical and functional recovery after endoscopic endonasal pituitary surgery: A 1-year longitudinal study.

PURPOSE: The purpose of this study was to investigate the changes in structural spectral-domain optical coherence tomography (SD-OCT), OCT Angiography (OCTA) parameters, and visual acuity, 1 year after endoscopic endonasal approach for the removal of an intra-suprasellar pituitary adenoma compressing optic chiasm and compare outcomes with 48 hours postoperative data. METHODS: Sixteen eyes of eight patients (4 males, 4 females, mean age 52 ± 11 years) were enrolled in this prospective study. The primary outcome was to evaluate the changes over time before and after surgery, analyzing the Best Corrected Visual Acuity (BCVA), Ganglion Cell Complex (GCC), Retinal Nerve Fiber Layer (RNFL) thicknesses, the retinal vessel density (VD) of Superficial Capillary Plexus (SCP), Deep Capillary Plexus (DCP), Radial Peripapillary Capillary (RPC) and the Foveal Avascular Zone (FAZ). The secondary outcome was to identify potential biomarkers that could predict visual acuity changes after 1-year follow-up. RESULTS: When comparing SD-OCT and OCTA measurements obtained after 1 year with those observed 48 hours after surgery, GCC and RNFL were significantly improved. After a significant reduction at 48 hours, GCC thickness showed a significant increase at 1 year after surgery (p = 0.007), while a significant restoration of RNFL thickness was found at 1 year (p = 0.005), as well as the VD of SCP, DCP, and RPC values. FAZ area did not change over time. BCVA significantly improved at each time after surgery (p = 0.037, p = 0.013). A statistically significant correlation was found between the preoperative BCVA, VD of SCP, DCP, RPC, and the postoperative BCVA at 1 year (p = 0.017, p = 0.029, p = 0.031, p = 0.023). CONCLUSION: SD-OCT and OCTA provide helpful information to identify the retinal structural and vascular improvements 1 year after surgery. OCTA parameters could serve as potential predictive markers for visual acuity recovery at long-term follow-up.

Reporte de un caso: embarazo gemelar con un feto vivo y mola completa / Case report: twin pregnancy with a live fetus and complete mole

RESUMEN La coexistencia de una mola completa y un feto vivo es una condición infrecuente que puede evolucionar con múltiples complicaciones tanto maternas como fetales; entre ellas aborto, preeclampsia, hipertiroidismo, metrorragia, parto pretérmino y enfermedad trofoblástica gestacional persistente. No existe consenso internacional respecto al manejo de esta condición, aun conociéndose el mal pronóstico para el feto y los elevados riesgos maternos asociados. El siguiente es un reporte de un caso clínico de embarazo gemelar con feto vivo y mola completa, diagnosticado a las 12+1 semanas. Luego de realizar consejería, y en contexto de la legislación chilena en el año 2015, se decide continuar con el embarazo. La paciente es monitorizada en policlínico de alto riesgo obstétrico con controles seriados de b-HCG, ecografía fetal y RNM pélvica. Desde las 13 semanas presenta hipertensión arterial que se maneja con antihipertensivos orales; posteriormente, a las 20+2 semanas, desarrolla un cuadro de preeclampsia severa por lo que, en conjunto con la paciente, se decide realizar histerectomía en bloque. Dada la persistencia de valores de b-HCG elevados a las 12 semanas post interrupción del embarazo, se decide tratamiento con metotrexato. El caso fue analizado en Comité de Ginecología Oncológica donde se decidió seguimiento con b-HCG, lográndose la negativización a las 38 semanas post metotrexato. Se confirmaron valores negativos de b-HCG por 6 meses, tras lo cual fue dada de alta.

ABSTRACT The coexistence of a complete mole and an alive fetus is a rare condition that can evolve with multiple complications both maternal and fetal; among them abortion, preeclampsia, hyperthyroidism, uterine bleeding, preterm labor and persistent gestational trophoblastic disease. There is no international consensus regarding the management of this condition, despite the poor prognosis for the fetus and the associated high maternal risks. The following is a report of a clinical case of twin pregnancy with live fetus and complete mole, diagnosed at 12+1 weeks. After counseling, and in the context of Chilean legislation in 2015, it is decided to continue with pregnancy. The patient is monitored in a high-risk pregnancy outpatient clinic with follow ups b-HCG, fetal ultrasound and pelvic MRI. From 13 weeks, the patient presents high blood pressure that is managed with oral antihypertensives; and later, with 20+2 weeks, developed severe preeclampsia which is why, in conjunction with patient, it was decided to perform a block hysterectomy. Given the persistence of elevated b-HCG values at 12 weeks post-termination of pregnancy, treatment with methotrexate was decided. The case was analyzed in the local Committee of Oncological Gynecology, in which it was decided to follow the b-HCG curve, achieving negative values at 38 weeks post-methotrexate. Negative values of b-HCG were confirmed for 6 months, after which it was discharged.

Bilateral hypertrophy of masseteric and temporalis muscles, our fifteen patients and review of literature.

OBJECTIVE: The association of bilateral hypertrophy of temporalis and masseteric muscles is a rare clinical entity. The origin of the condition is unclear, causing cosmetic problems, pain, and functional impairment. PATIENTS AND METHODS: In this paper we analyzed 15 patients treated at the Department of Maxillo-Facial Surgery of the University of Naples Federico II, from 2000 to 2013, for temporalis and/or masseteric muscle hypertrophy, and in particular, a rare case of a patient with a marked bilateral swelling of the temporalis and masseteric region, in conjunction with a review of the literature. RESULTS: Fourteen patients have not any kind of postoperatively problems. The last patient had been aware of the swelling for many years and complained of recurrent headaches. We adopted a new protocol fort this patients and the patient was very pleased with the treatment results, and reported a reduction in headaches and a continuation of his well-being, in addition to greater self-confidence. The last follow-up was performed three years after the first treatment, and the patient showed a complete resolution of his symptoms, and just a small increase of the swelling. CONCLUSIONS: The treatment of temporalis and masseteric hypertrophy with Botulin toxin could be an effective option compared to conservative treatment or surgical intervention, although the review of the literature shows that this is only a temporary treatment. In fact, surgery still remains the best option. The treatment must be repeated every 4/6 months for 2-3 consecutive years before having stable benefits. To overcome this problem, an association with a bite treatment allowed us to achieve more lasting and more stable results over time without a recurrence of symptoms between the treatments. Furthermore, this association has enabled us to obtain a more rapid reduction of the hypertrophy.

Facial osteomas: fourteen cases and a review of literature.

OBJECTIVE: Osteomas are benign tumors that frequently affect the cranio-facial region, especially the temporal bones, jaw and sinus. This lesion very rarely involves the maxillary bones. The aim of our study is to describe our surgical case series and to evaluate the diagnosis and management of peripheral craniofacial osteomas with a review of the literature. PATIENTS AND METHODS: We retrospectively analyzed a series of 14 patients that underwent surgery for the removal of a cranio-facial osteoma, 10 cases were peripheral osteoma of the lower jaw and 4 were peripheral osteomas of the upper jaw. The 14 patients included 8 females and 6 males, with a mean age of 42 years. The median follow up period was 48 months. RESULTS: All patients received a total surgical removal and we did not have any intraoperative complications with optimal cosmetic and functional results. Pain resolved in all cases and a single case postoperative dysesthesia occurred. NO recurrence has been detected at last follow-up visit. CONCLUSIONS: Osteomas must be well identified and differentiated from other solid diseases of the bone and should be treated if symptomatic. The elective treatment is surgical removal, resulting in a complete resolution of the pathology.

At the heart of the arterial baroreflex: a physiological basis for a new classification of carotid sinus hypersensitivity.

The aim of this review is to provide an update of the current knowledge of the physiological mechanisms underlying reflex syncope. Carotid sinus syncope will be used as the classical example of an autonomic reflex with relatively well-established afferent, central and efferent pathways. These pathways, as well as the pathophysiology of carotid sinus hypersensitivity (CSH) and the haemodynamic effects of cardiac standstill and vasodilatation will be discussed. We will demonstrate that continuous recordings of arterial pressure provide a better understanding of the cardiovascular mechanisms mediating arterial hypotension and cerebral hypoperfusion in patients with reflex syncope. Finally we will demonstrate that the current criteria to diagnose CSH are too lenient and that the conventional classification of carotid sinus syncope as cardioinhibitory, mixed and vasodepressor subtypes should be revised because isolated cardioinhibitory CSH (asystole without a fall in arterial pressure) does not occur. Instead, we suggest that all patients with CSH should be thought of as being 'mixed', between cardioinhibition and vasodepression. The proposed stricter set of criteria for CSH should be evaluated in future studies.

Advances in trans-sphenoidal pituitary surgery.

Pituitary surgery is a continuous evolving speciality of the neurosurgeons' armamentarium, requiring precise anatomical knowledge, technical skills and integrated appreciation of the pituitary pathophysiology. Actually, it could be considered the result of a close cooperation between different specialists, i.e. the ophthalmologist, the neuroradiologist, the endocrinologist, the neurosurgeon, the pathologist, etc. In this teamwork environment each member plays his own role, offering his contribute to the final result; every effort is performed to provide patients with the best possible procedure, individually measured. The endoscopic pituitary surgery performed by means of a transsphenoidal approach perfectly fits this scenario, being though advocated as the result of an evolutionary process rather than a revolutionary one. The "pure" endoscopic transsphenoidal surgery - consisting of a whole procedure performed with the endoscope alone and without the use of any transsphenoidal retractor - offers some advantages due to the endoscope itself: a superior close-up view of the relevant anatomy, very important at the tumor/gland interface and an enlarged working angle are provided with an increased panoramic vision inside the surgical area. Results in terms of mass removal, relief of clinical symptoms, cure of the underlying disease and complication rate are similar to those reported in the major microsurgical series but patient compliance is by far better.

Clinic blood pressure, ambulatory blood pressure and cardiac structural alterations in nonagenarians and in centenarians.

scant information is available on the alterations in cardiac structure and function characterizing very elderly people as well as on their relationships to clinic and ambulatory blood pressure (BP) values. In 106 subjects aged 95.3 ± 3.7 years (mean ± standard deviation, 89 nonagenarians and 17 centenarians) in good clinical conditions and living in the municipal house in Milan, we measured, along with standard clinical and laboratory variables, clinic BP, 24-h ambulatory BP and echocardiographic parameters. Forty-five of the recruited subjects were normotensive individuals, whereas 61 were treated hypertensive patients. Subjects with an age greater than 90 years showed clinic systolic (SBP) and diastolic BP (DBP) both within the normal range, with values that for clinic SBP were slightly lower than the corresponding 24-h SBP (120.8 ± 15.9 vs 128.0 ± 16.3 mmHg) and for DBP slightly higher (69.7 ± 8.8 vs 64.9 ± 8.0 mmHg). Daytime average mean BP was slightly lower than night-time average mean BP, indicating the attenuation of the BP reduction during night-time. Left ventricular mass index (LVMI) was increased and significantly related to both 24-h and clinic BP values (r = 0.24, p < 0.04 and r = 0.20, p < 0.05). Thus in nonagenarians and centenarians, abnormalities in left ventricular pattern are of frequent detection and may be related both to the ageing process and to BP load.

The supraorbital approach for recurrent or residual suprasellar tumors.

BACKGROUND: Suprasellar tumors can be removed through a variety of approaches including conventional frontotemporal craniotomies, the transsphenoidal route, or the supraorbital (SO) eyebrow craniotomy. Herein we assess the utility of the SO route for recurrent or residual suprasellar tumors previously treated by an alternative route. MATERIAL AND METHODS: A retrospective analysis of all consecutive patients who underwent an SO approach for removal of a recurrent/residual tumor was undertaken. RESULTS: Between December 2007 and February 2010, 11 patients underwent an SO craniotomy for a recurrent or growing residual tuberculum sellae meningioma (n=7) or craniopharyngioma (n=4). All 11 patients had prior craniotomies, 5 had transsphenoidal surgery, 6 had radiation treatment, and 1 had chemotherapy. In the last 5 cases, the endoscope was used in addition to the microscope for intraoperative visualization. 3 patients underwent decompression of multicystic craniopharyngiomas and the remaining 8 patients had tumor debulking, all achieving 70% or more tumor removal. Of 9 patients with preoperative visual deterioration, 6 (67%) had improvement and no patient had visual worsening. No new adenohypophysis or neurohypophysis dysfunction was noted. One patient had a postoperative CSF leak requiring reoperation. CONCLUSION: The SO approach should be considered as a safe and effective alternative route for recurrent or residual suprasellar tumors previously treated by conventional craniotomy or TS surgery. It typically offers a simplified trajectory that minimizes scar tissue from prior approaches and provides excellent access for optic apparatus decompression. Endoscopy is helpful to visualize hidden tumor remnants and maximize safe tumor removal.