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Background: Oral cavity cancer is still an important public health problem throughout the world. Oral squamous cell carcinomas (OSCCs) can be quite aggressive and metastatic, with a low survival rate and poor prognosis. However, this is usually related to the clinical stage and histological grade, and molecular prognostic markers for clinical practice are yet to be defined. Heparanase (HPSE1) is an endoglycosidase associated with extracellular matrix remodeling, and although involved in several malignancies, the clinical implications of HPSE1 expression in OSCCs are still unknown. Methods: We sought to investigate HPSE1 expression in a series of primary OSCCs and further explore whether its overexpression plays a relevant role in OSCC tumorigenesis. mRNA and protein expression analyses were performed in OSCC tissue samples and cell lines. A loss-of-function strategy using shRNA and a gain-of-function strategy using an ORF vector targeting HPSE1 were employed to investigate the endogenous modulation of HPSE1 and its effects on proliferation, apoptosis, adhesion, epithelial-mesenchymal transition (EMT), angiogenesis, migration, and invasion of oral cancer in vitro . Results: We demonstrated that HPSE1 is frequently upregulated in OSCC samples and cell lines and is an unfavorable prognostic indicator of disease-specific survival when combined with advanced pT stages. Moreover, abrogation of HPSE1 in OSCC cells significantly promoted apoptosis and inhibited proliferation, migration, invasion, and epithelial-mesenchymal transition by significantly decreasing the expression of N-cadherin and vimentin. Furthermore, a conditioned medium of HPSE1-downregulated cells resulted in reduced vascular endothelial growth. Conclusion: Our results confirm the overexpression of HPSE1 in OSCCs, suggest that HPSE1 expression correlates with disease progression as it is associated with several important biological processes for oral tumorigenesis, and can be managed as a prognostic marker for patients with OSCC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Rodrigues, Lopes-Santos, Lacerda, Juste, Mariz, Cajazeiro, Giacobbe, Borges, Casarim, Callegari, Claret Arcadipane, Aprahamian, Salo, De Oliveira, Coletta, Augusto and Cervigne.)

Introduction: This study aimed to assess the feasibility and efficacy of office hysteroscopy to diagnose and treat the specific uterine pathologies frequently diagnosed and thought to be associated with female infertility., Material and Methods: Using office hysteroscopy, we examined the uterine cavity in women with primary or secondary infertility and evaluated the reproductive outcomes of those affected by one or more pathologies, including cervico-isthmic adhesions, intrauterine polyps and intrauterine adhesions. Additional patient characteristics considered were age and parity, uterine pathology, pain during hysteroscopy, and outcomes including spontaneous pregnancies achieved and time between treatment and pregnancy., Results: Reproductive outcomes of 200 patients affected by one or more uterine pathologies were evaluated. Cervico-isthmic adhesions were the most frequent findings in older women, with nearly 80% of them achieving pregnancy sooner than the others in our study. Spontaneous pregnancy rates following office hysteroscopy were 76%, 53% and 22% in women with cervico-isthmic adhesions, polyps (< 5 mm) and intrauterine adhesions, respectively., Conclusions: Office hysteroscopy is a feasible and highly effective diagnostic and therapeutic procedure for cervico-isthmic and intrauterine adhesions, as well as for small polyps, allowing the resolution of female infertility related to these pathologies, without trauma and with only minimal discomfort.

Purpose: Brain death (BD) is defined as the irreversible destruction of all brain functions. It is usually diagnosed through a clinical examination, but in certain circumstances, ancillary examinations (such as digital subtraction angiography (DSA), transcranial color Doppler (TCD), computed tomography angiography (CTA), magnetic resonance angiography (MRA), or radionuclide scanning) are required as confirmatory tests. In many countries, cervical color Doppler sonography (CCD) is not recognized as a valid test. The aim of our study is to assess its accuracy as a non-invasive, inexpensive, and easily available examination to determine cerebral circulatory arrest (CCA)., Methods: We performed a retrospective study in which 123 patients with clinical diagnosis of BD underwent bedside cervical color Doppler as an additional examination for CCA assessment. We compared these cervical color Doppler findings with the results of validated ancillary tests such as CTA, TCD, and DSA., Results: Cervical color Doppler exams showed a sensitivity of 78% (96/123 patients) in detecting CCA compared to standard ancillary tests. Twenty-seven patients showed a persistent diastolic flow in one or two of the four arterial vessels examined and thus considered as false negatives., Conclusion: Our results show that cervical color Doppler may become a reliable and safe technique in detecting CCA, which can shorten the time for declaring brain death. In particular, in patients lacking good bone windows at transcranial color Doppler, cervical color Doppler of the cervical internal carotids and vertebral arteries could be recommended to increase the sensitivity of transcranial color Doppler, or as an alternative bedside examination.

Aims and Objectives: To evaluate the diagnostic accuracy of mp-MRI correlating US/mp-MRI fusion-guided biopsy with systematic random US-guided biopsy in prostate cancer diagnosis., Materials and Methods: 137 suspected prostatic abnormalities were identified on mp-MRI (1.5T) in 96 patients and classified according to PI-RADS score v2. All target lesions underwent US/mp-MRI fusion biopsy and prostatic sampling was completed by US-guided systematic random 12-core biopsies. Histological analysis and Gleason score were established for all the samples, both target lesions defined by mp-MRI, and random biopsies. PI-RADS score was correlated with the histological results, divided in three groups (benign tissue, atypia and carcinoma) and with Gleason groups, divided in four categories considering the new Grading system of the ISUP 2014, using t test. Multivariate analysis was used to correlate PI-RADS and Gleason categories to PSA level and abnormalities axial diameter. When the random core biopsies showed carcinoma (mp-MRI false-negatives), PSA value and lesions Gleason median value were compared with those of carcinomas identified by mp-MRI (true-positives), using t test., Results: There was statistically significant difference between PI-RADS score in carcinoma, atypia and benign lesions groups (4.41, 3.61 and 3.24, respectively) and between PI-RADS score in Gleason < 7 group and Gleason > 7 group (4.14 and 4.79, respectively). mp-MRI performance was more accurate for lesions > 15 mm and in patients with PSA > 6 ng/ml. In systematic sampling, 130 (11.25%) mp-MRI false-negative were identified. There was no statistic difference in Gleason median value (7.0 vs 7.06) between this group and the mp-MRI true-positives, but a significant lower PSA median value was demonstrated (7.08 vs 7.53 ng/ml)., Conclusion: mp-MRI remains the imaging modality of choice to identify PCa lesions. Integrating US-guided random sampling with US/mp-MRI fusion target lesions sampling, 3.49% of false-negative were identified.

Introduction: Placental site trophoblastic tumor (PSTT) is a form of gestational trophoblastic disease that originates from the implantation of an intermediate trophoblast. It was described for the first time by Von F. Marchand in 1895 as belonging to chorioepithelioma sui generis, a pathological condition with many variations and a progressive degree of malignancy., Methods: We have conducted a literature review in MEDLINE about epidemiology, etiopathogenesis and clinical features of PSTT. Moreover, a case that occurred in our institution was reported., Results: Our research has highlighted that existing published data about PSTT are not uniform. The number of cases described in the literature has updated and the clinical features of selected "case series" of patients diagnosed with PSTT were showed. The etiopathogenesis was discussed. It was noted that current prognostic factors still allow important information regarding PSTT to be obtained, albeit fragmentary., Conclusions: The lack of uniformity in data collection seen so far has limited full knowledge of PSTT. For this reason, we suggest a model (PSTT model) that collects and unifies PSTT evidence as this would be useful to identify worldwide precise prognostic factors, which are still lacking. When PSTT is diagnosed, the proper procedure seems to be total hysterectomy, with sampling of pelvic lymph nodes and ovarian conservation. For advanced-stage diseases, (stage III and IV) a combination of surgery and polychemotherapy is suggested.

The aim of this single-center, prospective, randomized, parallel-group study was to compare Dienogest and Danazol as endometrial preparation in patients who have to undergo hysteroscopic surgery for submucous myomas. We enrolled 80 consecutive eligible patients, in reproductive age, affected by submucous myomas. Pre- and posttreatment characterization of endometrium was performed by hysteroscopic visual observation and histologic confirmation. The enrolled patients were randomly assigned to two groups: 40 were treated with 2 mg of Dienogest/die, 40 with 100 mg of Danazol/die, both orally for 5 weeks, starting on day 1 of menstruation. Posttreatment comparison of endometrial patterns showed a significant more marked effect of Dienogest, respect to Danazol, in atrophying endometrium ("normotrophic non-responders" versus "hypotrophic"-"atrophic", p = 0.028). Intraoperative data showed no significant difference between the two groups for cervical dilatation time (p = 0.326), while in the Dienogest group, we found a significant reduction of operative time (p = 0.001), infusion volume (p = 0.001), and severity of bleeding (p = 0.042). Moreover, Dienogest caused less side effects (p = 0.008). According to our data analysis, Dienogest, respect to Danazol, is more effective for the preparation of the endometrium in patients who have to undergo hysteroscopic surgery for submucous myomas, and causes less side effects.

Hysteroscopic surgery is indicated for the treatment of several intrauterine diseases. The surgeon needs to be aware of, and know how to prevent, possible complications related to these procedures. In the case of operative hysteroscopy, the systemic effects of low-viscosity fluid uptake must be considered in order to prevent the complications in the patient. We report on two unusual clinical signs of intravascular absorption syndrome (IAS) that developed during an operative hysteroscopy with glycine 1.5% as the fluid of distension. Based on our experience, we recommend that practitioners reduce operating times, monitor fluid balances, check electrolytes and kinetic heart rates, and monitor for symptoms including otorrhagia and nosebleed, in order to identify and possibly prevent IAS due to an overload of low-viscosity fluids.

Struma ovarii is an uncommon type of ovarian tumor derived by germinal cells, characterized by the predominance of thyroid tissue (> 50%); 90-95% of these formations are benign and mainly affect the left ovary, while in 6% of the cases struma ovarii is bilateral. The malignant transformation is a rare condition that often occurs after 50 years. In most instances, diagnosis of malignant struma ovarii is made postoperatively during histological analysis. This tumor appears to derive by one germinal cell through loss of heterozygosity of the androgen receptor gene and of the X chromosome. Clinical symptoms comprise abdominopelvic mass, lower abdominal pain, abnormal vaginal bleeding, and ascites (the occurrence of this condition has been observed in one-third of the cases). The patients with struma ovarii generally do not manifest symptoms related to thyroid hyperfunction, reported only in 8% of the cases, and due to hyperstimulation of the thyroid by auto-antibodies. Thyroid tissue of the struma ovarii, often embedded in a teratoma, may be papillary, follicular or with mixed pattern and it can include elements of mucinous cystoadenomas, Brenner's tumor or carcinoid or melanomas cells. Here the authors report their experience with an unusual case of Hashimoto thyroiditis onset after laparoscopic removal of struma ovarii.

In animal models of Alzheimer's disease (AD), mechanisms of cortical plasticity such as long-term potentiation (LTP) and long-term depression (LTD) are impaired. In AD patients, LTP-like cortical plasticity is abolished, whereas LTD seems to be preserved. Dopaminergic transmission has been hypothesized as a new player in ruling mechanisms of cortical plasticity in AD. We aimed at investigating whether administration of the dopamine agonist rotigotine (RTG) could modulate cortical plasticity in AD patients, as measured by theta burst stimulation (TBS) protocols of repetitive transcranial stimulation applied over the primary motor cortex. Thirty mild AD patients were tested in three different groups before and after 4 weeks of treatment with RTG, rivastigmine (RVT), or placebo (PLC). Each patient was evaluated for plasticity induction of LTP/LTD-like effects using respectively intermittent TBS (iTBS) or continuous TBS protocols. Short-latency afferent inhibition (SAI) protocol was performed to indirectly assess central cholinergic activity. A group of age-matched healthy controls was recruited for baseline comparisons. Results showed that at baseline, AD patients were characterized by impaired LTP-like cortical plasticity, as assessed by iTBS. These reduced levels of LTP-like cortical plasticity were increased and normalized after RTG administration. No effect was induced by RVT or PLC on LTP. LTD-like cortical plasticity was not modulated in any condition. Cholinergic activity was increased by both RTG and RVT. Our findings reveal that dopamine agonists may restore the altered mechanisms of LTP-like cortical plasticity in AD patients, thus providing novel implications for therapies based on dopaminergic stimulation.

Lithopaidion, or stone child, is generally a single rare asymptomatic formation that evolves from an undiagnosed and untreated advanced abdominal pregnancy. The dead fetus is retained in the maternal abdominal cavity, which causes calcification. In this paper, we review the literature on the epidemiology, etiopathogenesis and clinical features of lithopaidion and report a unique case of lithokelyphos in a patient with an ectopic fallopian pregnancy. We propose a model to unify the data. The new word 'lithopaidion' can be utilized instead of lithopedion., (© 2014 S. Karger AG, Basel.)

Background: Abnormal uterine bleeding is defined as any alteration in the pattern or volume of menstrual blood flow, and it is preferably treated using hysterectomy, endometrial destruction or the levonorgestrel-releasing intrauterine system (Mirena(®) ). Recently, it has been demonstrated that studies of Mirena(®) were generally small and consequently imprecise., Aims: Our study was aimed at assessing the effects of a slow-release levonorgestrel (20 μg/day) intrauterine device in fertile and postmenopausal women experiencing abnormal uterine bleeding that did not respond to traditional medical management., Materials and Methods: A total of 40 women, of whom 24 were of reproductive capacity and 16 were postmenopausal, were enrolled in the trial. Removal of the intrauterine device was required for only 2 of the 24 fertile women and for only 3 of the 16 postmenopausal women. After 6 and 12 months of treatment, the remaining women were clinically evaluated and underwent ultrasound and hysteroscopy using biopsy specimens as a control. The EuroQol Group EQ-5D questionnaire was used for evaluation of quality of life., Results: The device showed good tolerability and efficacy. It resulted in a reduction in the endometrial mucosal thickness with a regression of bleeding and collateral effects, which were more evident after 12 months of treatment. A positive effect of the device on the woman's quality of life was demonstrated., Conclusions: The slow-release levonorgestrel intrauterine device may be a valid therapeutic tool for treating basic symptomatology and increasing quality of life in women with abnormal uterine bleeding., (© 2013 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.)

Background: Combining tDCS with robotic therapy is a new and promising form of neurorehabilitation after stroke, however the effectiveness of this approach is likely to be influenced by the relative timing of the brain stimulation and the therapy., Objective: To measure the kinematic and neurophysiological effects of delivering tDCS before, during and after a single session of robotic motor practice (wrist extension)., Methods: We used a within-subjects repeated-measurement design in 12 chronic (>6 months) stroke survivors. Twenty minutes of anodal tDCS was delivered to the affected hemisphere before, during, or after a 20-minute session of robotic practice. Sham tDCS was also applied during motor practice. Robotic motor performance and corticomotor excitability, assessed through transcranial magnetic stimulation (TMS), were evaluated pre- and post-intervention., Results: Movement speed was increased after motor training (sham tDCS) by ∼20%. Movement smoothness was improved when tDCS was delivered before motor practice (∼15%). TDCS delivered during practice did not offer any benefit, whereas it reduced speed when delivered after practice (∼10%). MEPs were present in ∼50% of patients at baseline; in these subjects motor practice increased corticomotor excitability to the trained muscle., Conclusions: In a cohort of stroke survivors, motor performance kinematics improved when tDCS was delivered prior to robotic training, but not when delivered during or after training. The temporal relationship between non-invasive brain stimulation and neurorehabilitation is important in determining the efficacy and outcome of this combined therapy.

Objective: To evaluate if labour induction and elective caesarean section could influence anxiety and depression in pregnant women., Methods: One hundred and sixteen consecutive pregnant women with uncomplicated singleton pregnancy at term, scheduled for these two obstetric procedures were enrolled. An anonymous questionnaire with two self-rating instruments STAI and HAM-A for anxiety and HAM-D for depression was administered., Results: Anxiety levels did not show significant differences while a light depressive mood was evidenced among pregnant women waiting for labour induction (p = 0.01)., Conclusions: An adequate psychological support could be considered a helpful tool for pregnant women scheduled for labour induction.

Objective: Cortico-cortical circuits originating from the posterior parietal cortex (PPC) of the intact left hemisphere (LH) may become hyperexcitable in patients with hemispatial neglect due to a right hemispheric (RH) stroke., Methods: In the current randomized, double-blind, sham-controlled study, we investigated safety and efficacy of continuous theta-burst stimulation (cTBS) in 10 sessions over 2 weeks applied over the intact PPC of the LH in subacute ischemic stroke patients. Severity of neglect was assessed through the standardized Behavioral Inattention Test (BIT). We also measured, by means of bifocal transcranial magnetic stimulation (TMS), how cTBS modified the excitability of the parieto-frontal functional connections in the intact LH., Results: We found that 2 weeks of cTBS, but not sham cTBS, were effective in improving neglect symptoms as measured by BIT score. BIT scores improved by 16.3% after 2 weeks of cTBS and 22.6% at 1 month follow-up. We also found that hyperexcitability of LH parieto-frontal circuits was reduced following treatment with real but not sham cTBS., Conclusion: These findings suggest that a 2-week course of cTBS over the LH PPC may be a potential effective strategy in accelerating recovery from visuospatial neglect in subacute stroke patients, possibly counteracting the hyperexcitability of LH parieto-frontal circuits., Classification of Evidence: This study provides Class III evidence that left posterior parietal cortex theta-burst stimulation improves hemispatial neglect for up to 2 weeks after treatment.

Purpose: In the chronic phase of stroke brain plasticity plays a crucial role for further motor control improvements. This study aims to assess the brain plastic reorganizations and their association with clinical progresses induced by a robot-aided rehabilitation program in chronic stroke patients., Methods: 7 stroke patients with an upper limb motor impairment in chronic phase underwent a multi-modal evaluation before starting and at the end of a 12-week upper-limb neurorehabilitation program. Fugl-Meyer Assessment (FMA) Scale scores and performance indices of hand movement performance (isometric pinch monitored through a visual feedback) were collected. Cerebral reorganizations were characterized by 32-channel electroencephalography (EEG) focusing on ipsilesional and contralesional resting state properties investigating both bipolar derivations overlying the middle cerebral artery territory and the primary somatosensory sources (S1) obtained through the Functional Source Separation (FSS) method. Power Spectral Density (PSD) and interhemispheric coherence (IHCoh) at rest were measured and correlated with clinical and hand control robot-induced improvements., Results: After the robotic rehabilitation we found an improvement of FMAS scores and hand motor control performance and changes of brain connectivity in high frequency rhythms (24-90 Hz). In particular, the improvement of motor performance correlated with the modulation of the interhemispheric S1 coherence in the high beta band (24-33 Hz)., Conclusions: Recently it has been shown that an upper limb robot-based rehabilitation improves motor performance in stroke patients. We confirm this potential and demonstrate that a robot-aided rehabilitation program induces brain reorganizations. Specifically, interhemispheric connectivity between primary somatosensory areas got closer to a 'physiological level' in parallel with the acquisition of more accurate hand control.

Recording of slow spontaneous fluctuations at rest using functional magnetic resonance imaging (fMRI) allows distinct long-range cortical networks to be identified. The neuronal basis of connectivity as assessed by resting-state fMRI still needs to be fully clarified, considering that these signals are an indirect measure of neuronal activity, reflecting slow local variations in de-oxyhaemoglobin concentration. Here, we combined fMRI with multifocal transcranial magnetic stimulation (TMS), a technique that allows the investigation of the causal neurophysiological interactions occurring in specific cortico-cortical connections. We investigated whether the physiological properties of parieto-frontal circuits mapped with short-latency multifocal TMS at rest may have some relationship with the resting-state fMRI measures of specific resting-state functional networks (RSNs). Results showed that the activity of fast cortico-cortical physiological interactions occurring in the millisecond range correlated selectively with the coupling of fMRI slow oscillations within the same cortical areas that form part of the dorsal attention network, i.e., the attention system believed to be involved in reorientation of attention. We conclude that resting-state fMRI ongoing slow fluctuations likely reflect the interaction of underlying physiological cortico-cortical connections.

Background: A single session of isolated repetitive movements of the thumb can alter the response to transcranial magnetic stimulation (TMS), such that the related muscle twitch measured post-training occurs in the trained direction. This response is attributed to transient excitability changes in primary motor cortex (M1) that form the early part of learning. We investigated; (1) whether this phenomenon might occur for movements at the wrist, and (2) how specific TMS activation patterns of opposing muscles underlie the practice-induced change in direction., Methods: We used single-pulse suprathreshold TMS over the M1 forearm area, to evoke wrist movements in 20 healthy subjects. We measured the preferential direction of the TMS-induced twitch in both the sagittal and coronal plane using an optical goniometer fixed to the dorsum of the wrist, and recorded electromyographic (EMG) activity from the flexor carpi radialis (FCR) and extensor carpi radialis (ECR) muscles. Subjects performed gentle voluntary movements, in the direction opposite to the initial twitch for 5 minutes at 0.2 Hz. We collected motor evoked potentials (MEPs) elicited by TMS at baseline and for 10 minutes after training., Results: Repetitive motor training was sufficient for TMS to evoke movements in the practiced direction opposite to the original twitch. For most subjects the effect of the newly-acquired direction was retained for at least 10 minutes before reverting to the original. Importantly, the direction change of the movement was associated with a significant decrease in MEP amplitude of the antagonist to the trained muscle, rather than an increase in MEP amplitude of the trained muscle., Conclusions: These results demonstrate for the first time that a TMS-twitch direction change following a simple practice paradigm may result from reduced corticospinal drive to muscles antagonizing the trained direction. Such findings may have implications for training paradigms in neurorehabilitation.

Visuospatial abilities are preferentially mediated by the right hemisphere. Although this asymmetry of function is thought to be due to an unbalanced interaction between cerebral hemispheres, the underlying neurophysiological substrate is still largely unknown. Here, using a method of trifocal transcranial magnetic stimulation, we show that the right, but not left, human posterior parietal cortex exerts a strong inhibitory activity over the contralateral homologous area by a short-latency connection. We also clarify, using diffusion-tensor magnetic resonance imaging, that such an interaction is mediated by direct transcallosal projections located in the posterior corpus callosum. We argue that this anatomo-functional network may represent a possible neurophysiological basis for the ongoing functional asymmetry between parietal cortices, and that its damage could contribute to the clinical manifestations of neglect.

Background: Muscle vibration modifies corticomotor excitability in healthy subjects and reduces muscle tonus in stroke patients., Objective: This study examined whether repeated muscle vibration (rMV) applied over the flexor carpi radialis (FCR) and biceps brachii (BB) can induce long-lasting changes, using transcranial magnetic stimulation (TMS), in patients with chronic stroke., Methods: Thirty hemiparetic patients who offered at least minimal wrist and elbow isometric voluntary contractions were randomly assigned to either an experimental group, which received rMV in addition to physiotherapy (rMV + PT), or a control group that underwent PT alone. The following parameters of the FCR, BB, and extensor digitorum communis (EDC) were measured through TMS before, and 1 hour, 1 week, and 2 weeks after the end of intervention: resting motor threshold (RMT), map area, map volume, short-interval intracortical inhibition (SICI), and intracortical facilitation (ICF). Muscle tonus and motor function were assessed on the same day as TMS., Results: Pre-post analysis revealed a reduction in RMT and an increase in motor map areas occurred in the vibrated muscles only in the rMV + PT group, with an increase in map volumes of all muscles. Moreover, SICI increased in the flexors and decreased in the extensor. These neurophysiological changes lasted for at least 2 weeks after the end of rMV + PT and paralleled the reduction in spasticity and increase in motor function. A significant correlation was found between the degree of spasticity and the amount of intracortical inhibition., Conclusion: rMV with PT may be used as a nonpharmacological intervention in the neurorehabilitation of mild to moderate hemiparesis.