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Eugenia Allegra,1 Ignazio La Mantia,2 Maria Rita Bianco,1 Gaetano Davide Drago,3 Maria Cristina Le Fosse,1 Alfio Azzolina,4 Calogero Grillo,2 Vincenzo Saita41Otolaryngology, Department of Health Science, University of Catanzaro, Catanzaro, Italy; 2Otolaryngology, "G.F Ingrassia" Department, University of Catania, Catania, Italy; 3Grand Hôpital de l’Est Francilien, Jossigny, France; 4Otolaryngology Unit, Cannizzaro Hospital, University of Catania, Catania, ItalyIntroduction: Total laryngectomy has important psychophysical and social consequences for patients’ quality of life because of the functional changes resulting from the removal of the larynx. Voice deprivation is perhaps the most relevant limiting factor in social relationships, increasing feelings of solitude and tending to drive individuals into social isolation. Multiple voice rehabilitation methods after total laryngectomy are available. This study aimed to determine the acoustic quality of the rehabilitated voice achieved with esophageal speech (ES) and tracheoesophageal speech (TES), and acoustic quality impacts on patients’ perceptions of their quality of life.Materials and methods: The patient inclusion criterion was the completion of a speech rehabilitation course with ES or TES at least 6 months after total laryngectomy. The voice acoustic analysis was carried out automatically by using the Multidimensional Voice Program. The following parameters were extracted: fundamental frequency (F0), Jitter% (Jitt), Shimmer% (Shim), and noise-to-harmonic ratio (NHR). Subjective voice evaluation was performed by using the following questionnaires: Voice Handicap Index (VHI), Voice-related Quality of Life (V-RQOL), and Voice Performance Questionnaire (VPQ).Results: The acoustic analysis showed a difference between ES and TES patients on all acoustic parameters; this difference was significant for F0 (133.09±2.4 and 119±3.3, respectively; p

Eugenia Allegra,1 Vincenzo Saita,2 Alfio Azzolina,2 Massimo De Natale,2 Maria Rita Bianco,1 Domenico Michele Modica,3 Aldo Garozzo1 1Otolaryngology, Department of Health Sciences, University of Catanzaro, Catanzaro, Italy; 2Otolaryngology Unit, Cannizzaro Hospital, Catania, Italy; 3Otolaryngology Unit, University of Palermo, Palermo, Italy Background: Laryngeal early glottic tumors can benefit from different treatment modalities, including transoral laser microsurgery, open partial horizontal laryngectomy (OPHL), and radiotherapy. However, the treatment of early glottic tumors with the involvement of the anterior commissure remains controversial. The studies about the role of anterior commissure involvement in oncologic outcomes in patients with early glottic cancer treated with supracricoid laryngectomy (SCL) are very few. For this reason, we conducted a retrospective study to evaluate local recurrence-free survival and specific survival in patients with and without involvement of the anterior commissure who underwent SCL with cricohyoidoepiglottopexy.Methods: This retrospective study has been carried out on patients with T1b–T2 glottic squamous cell carcinoma submitted to SCL with cricohyoidoepiglottopexy. The patients’ demographic and clinical data were collected, and the histological findings of the surgical specimens were reviewed to identify patients who had involvement of the anterior commissure.Results: A total of 72 patients were included in the study; two of them were female and 70 were male. The mean age at diagnosis was 61.5±8.0 SD years. In 26 of the 72 (36.2%) patients, anterior commissure was not pathologically involved (group A), while in 46 (63.8%) patients, it was involved (group B). The 5-year local recurrence-free survival rate was 96.1% and 93.48% in groups A and B, respectively, P=0.09. The 5-year disease-specific survival rate was 92.31% and 95.65% in groups A and B, respectively, P=0.057.Conclusion: SCL with cricohyoidoepiglottopexy seems to be an adequate treatment modality, even for T1b–T2 glottic tumors with anterior commissure involvement. Keywords: open partial horizontal laryngectomy, laryngeal cancer, supracricoid laryngectomy, cricohyoidoepiglottopexy

Maria Rita Bianco, Alessandro La Boria, Teresa Franco, Pierpaolo Ferrise, Eugenia AllegraDepartment of Otolaryngology-Head and Neck Surgery, University of Catanzaro, Catanzaro, ItalyBackground: Lingual thyroid represents 90% of ectopic thyroid tissue localizations. The first case was described by Hickman in 1869. An ectopic thyroid is often asymptomatic, but pathological or physiological conditions inducing hyperproduction of thyroid-stimulating hormone can lead an ectopic thyroid to become symptomatic. Treatment of the symptomatic ectopic thyroid can be medical, with hormone-suppressing therapy, or surgical.Case presentation: A 17-year-old female presented to our outpatient clinic complaining of a sensation of a lump in her throat. Ear, nose, and throat (ENT) examination identified a swelling of the base of the tongue in the glossoepiglottic area. Thyroid scintigraphy showed a single contrast enhancement in the sublingual region, instead of in the normal anatomical position of the thyroid. She was treated surgically after failed hormone-suppressing therapy. An arteriography performed before the surgery showed vascular anomalies and was useful in surgical planning.Conclusion: Recognition of vascular anomalies in an ectopic thyroid is fundamental before surgical planning, therefore, accurate radiological study of the vasculature should always be planned before surgical treatment of this disease.Keywords: ectopic thyroid, arteriography, transoral approach, tongue

Patients who have undergone total laryngectomy (TL) are, in most cases, affected by lung disease due to smoking habits. Therefore, as part of the follow-up protocol for these patients, a spirometry test should be performed to adequately assess lung function. Current spirometers do not allow for spirometry tests in patients who breathe through a tracheostomy, as the patient cannot perform respiratory acts from the spirometer mouthpiece, which is designed to be used by mouth. We have, therefore, designed a device that allows the test to be performed through the tracheostoma. The device is made of biocompatible polymeric material, modeled using a 3-dimensional printer, reusable, and hermetically connected to the spirometer distally and to the tracheostoma proximally. The device was used on 5 patients who underwent TL and was found to be comfortable, safe, and valid for diagnostic purposes., Competing Interests: None., (© 2024 The Author(s). OTO Open published by Wiley Periodicals LLC on behalf of American Academy of Otolaryngology–Head and Neck Surgery Foundation.)

Background: Maternal mortality in the United States is rising and many deaths are preventable. Emergencies, such as postpartum hemorrhage, occur less frequently in non-teaching, rural, and urban low-birth volume hospitals. There is an urgent need for accessible, evidence-based, and sustainable inter-professional education that creates the opportunity for clinical teams to practice their response to rare, but potentially devastating events., Objective: To assess the feasibility of virtual simulation training for the management of postpartum hemorrhage in low-to-moderate-volume delivery hospitals., Study Design: The study occurred between December 2021 and March 2022 within 8 non-academic hospitals in the United States with low-to-moderate-delivery volumes, randomized to one of two models: direct simulation training and train-the-trainer. In the direct simulation training model, simulation faculty conducted a virtual simulation training program with participants. In the train-the-trainer model, simulation faculty conducted virtual lessons with new simulation instructors on how to prepare and conduct a simulation course. Following this training, the instructors led their own simulation training program at their respective hospitals. The direct simulation training participants and students trained by new instructors from the train-the-trainer program were evaluated with a multiple-choice questionnaire on postpartum hemorrhage knowledge and a confidence and attitude survey at 3 timepoints: prior to, immediately after, and at 3 months post-training. Paired t-tests were performed to assess for changes in knowledge and confidence within teaching models across time points. ANOVA was performed to test cross-sectionally for differences in knowledge and confidence between teaching models at each time point., Results: Direct simulation training participants ( n =22) and students of the train-the-trainer instructors ( n =18) included nurses, certified nurse midwives and attending physicians in obstetrics, family practice or anesthesiology. Mean pre-course knowledge and confidence scores were not statistically different between direct simulation participants and the students of the instructors from the train-the-trainer course (79%+/-13 versus 75%+/-14, respectively, P- value = .45). Within the direct simulation group, knowledge and confidence scores significantly improved from pre- to immediately post-training (knowledge score mean difference 9.81 [95% CI 3.23-16.40], P- value<.01; confidence score mean difference 13.64 [95% CI 6.79-20.48], P- value<.01), which were maintained 3-months post-training. Within the train-the-trainer group, knowledge and confidence scores immediate post-intervention were not significantly different compared with pre-course or 3-month post-course scores. Mean knowledge scores were significantly greater for the direct simulation group compared to the train-the-trainer group immediately post-training (89%+/-7 versus 74%+/-8, P- value<.01) and at 3-months (88%+/-7 versus 76%+/-12, P- value<.01). Comparisons between groups showed no difference in confidence and attitude scores at these timepoints. Both direct simulation participants and train-the-trainer instructors preferred virtual education, or a hybrid structure, over in-person education., Conclusion: Virtual education for obstetric simulation training is feasible, acceptable, and effective. Utilizing a direct simulation model for postpartum hemorrhage management resulted in enhanced knowledge acquisition and retention compared to a train-the-trainer model., Competing Interests: The authors have no conflicts of interest., (© 2024 The Authors.)

Background : The aim of our multicenter retrospective study was to evaluate the long-term complications associated with primary and secondary tracheoesophageal puncture (TEP) in patients who underwent total laryngectomy (TL) for laryngeal cancer and were subsequently rehabilitated to phonatory function with tracheoesophageal speech (TES). Materials and Methods : To evaluate the long-term outcomes and complications of TEP, the following data were collected: mean time of prosthesis replacement, mean time of onset of complications, type of complications, and type of failure. Results : Complications occurred in 18 out of 46 patients (39.2%) with primary TEP and in 10 out of 30 patients (33.4%) with secondary TEP, out of a total of 76 enrolled patients. Common complications included prosthesis leakage, fistula leakage, granulation, and prosthesis extrusion. Prosthesis replacement due to fistula leakage or prosthesis extrusion was observed exclusively in the group of patients with primary TEP. Among the 28 patients (35.7%) who experienced complications, rehabilitation with TEP failed in 10 cases, primarily due to abandonment and spontaneous fistula closure. Conclusions : TEP, both primary and secondary, represents a valid option for vocal rehabilitation in patients undergoing TL. However, identifying prognostic factors that could influence the success of TEP would be beneficial to allow a targeted rehabilitation process.

Objective: In recent years, the number of open preservation surgeries for the treatment of laryngeal Cancer has increased. This surgery aims to maintain laryngeal function and ensure oncological radicality, thereby avoiding a total laryngectomy (TL) that could significantly impact the patient's quality of life. The purpose of this study was to assess the oncologic results of OPHL I and II and to identify prognostic factors that could impact patient survival and local failure rates. Methods: This study was conducted on 182 patients with laryngeal squamous cell carcinoma treated with OPHLs between 2005 and 2015. The survival rates of a group of patients treated with TL between 2004 and 2014 were taken into consideration to compare survival outcomes. Results: The disease-specific survival in pT2 and pT3 tumors in relation to the type of surgery showed no statistically significant difference between OPHLs and TL ( P  = .54 and P  = .63, respectively). The 5-year T-recurrence-free survival showed that pT4 tumors, perineural/vascular positive invasion, and OPHL IIb + ARY-treated tumors were associated with a higher risk of tumor recurrence ( P  < .0001, P  = .0005 and P  = .016 respectively). Conclusions: OPHLs represent an excellent alternative to TL considering the characteristics of the tumor and the general conditions of the patient., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

We focus on the new prognostic and predictive factors CD44, PDL1, and ATG7 in our study of surgical samples of patients with laryngeal squamous cell carcinoma (LSCC) using tissue microarray (TMA). Thirty-nine previously untreated patients affected by laryngeal carcinoma who then underwent surgical treatment were considered in this retrospective study. All surgical specimens were sampled, embedded in paraffin blocks, and stained with hematoxylin and eosin. A representative sample of the tumor was chosen and transferred into a new block of paraffin, the recipient block, to perform immunohistochemical analysis with the primary antibodies anti-CD44, PD-L1, and ATG7. At follow-up, 5-year disease-free survival (DFS) for negative and positive tumors was determined as 85.71% and 36% for CD44, 60% and 33.33% for PDL1, and 58.06% and 37.50% for ATG7, respectively. Multivariate analysis revealed that CD44 expression is an independent predictive factor of low-grade tumors ( p = 0.008), lymph node metastasis at the time of diagnosis, and AGT7 negativity. Thus, CD44 expression is a potential marker for more aggressive forms of laryngeal cancer.

Objective: This study aimed to evaluate olfactory function in patients rehabilitated with oesophageal (ES) voice or tracheo-oesophageal (TES) prosthesis to further verify whether there were differences in smell alterations depending on voice rehabilitation modality., Methods: A total of 40 patients who had undergone total laryngectomy participated in the study. Speech rehabilitation was achieved through TES in 20 patients (Group A) or ES in 20 patients (Group B). Olfactory function was evaluated using the Sniffin' Sticks test., Results: At olfactory evaluation, in Group A, 4/20 patients (20%) were anosmic, whereas 16/20 patients (80%) were hyposmic; in Group B, 11/20 patients (55%) were anosmic whereas 9/20 patients (45%) were hyposmic. A significant difference (p = 0.04) was found at global objective evaluation., Conclusions: The study shows that the rehabilitation with TES contributes to maintaining a functioning, albeit limited, sense of smell., (Copyright © 2023 Società Italiana di Otorinolaringoiatria e Chirurgia Cervico-Facciale, Rome, Italy.)

Objective: Alterations of the olfactory function in patients affected by COVID-19 often have an early onset and a variable duration ranging from a few weeks to months. The aim of this study was to evaluate olfactory dysfunction persistence after recovery from COVID-19, and potential related clinical-demographic conditions., Patients and Methods: A total of 76 patients recovered from COVID-19 from at least 20 days with olfactory dysfunction during the infection were included in the study. For the subjective evaluation of olfactory function, a visual analogic scale (VAS) was used. The objective evaluation was performed with the use of the Sniffin' Sticks test., Results: Objective assessment of olfactory function revealed that 48 (63.16%) patients were found to be normosmic (TDI ≥ 30.5), 26 (34.21%) were hyposmic (TDI from 30.5 to 16.5) and two (2.63%) were anosmic (TDI ≤ 16.5) at the time of the evaluation. These results did not show a significant difference between subjective and objective tests (p = 0.45). Most patients recovered their sense of smell within the first two months after recovery while a portion (22.2%) still experienced olfactory alterations 4-6 months after SARS-CoV-2 infection. Patients who had not recovered their sense of smell had a significantly longer period of SARS-CoV-2 positivity compared to patients that fully recovered (36.07 ± 7.78 days vs. 29 ± 7.89 days; p = 0.04)., Conclusions: Our results suggest that the duration of the infection negatively correlates with the recovery of olfactory function.

Background: Obstructive Sleep Apnea (OSA) syndrome is a respiratory sleep disorder characterized by partial or complete episodes of upper airway collapse with reduction or complete cessation of airflow. Although the connection remains debated, several mechanisms such as intermittent hypoxemia, sleep deprivation, hypercapnia disruption of the hypothalamic-pituitary-adrenal axis have been associated with poor neurocognitive performance. Different treatments have been proposed to treat OSAS patients as continuous positive airway pressure (CPAP), mandibular advancement devices (MAD), surgery; however, the effect on neurocognitive functions is still debated. This article presents the effect of OSAS treatments on neurocognitive performance by reviewing the literature., Methods: We performed a comprehensive review of the English language over the past 20 years using the following keywords: neurocognitive performance and sleep apnea, neurocognitive improvement and CPAP, OSAS, and cognitive dysfunction. We included in the analysis papers that correlated OSA treatment with neurocognitive performance improvement. All validated tests used to measure different neurocognitive performance improvements were considered., Results: Seventy papers reported neurocognitive Performance improvement in OSA patients after CPAP therapy. Eighty percent of studies found improved executive functions such as verbal fluency or working memory, with partial neural recovery at long-term follow-up. One article compared the effect of MAD, CPAP treatment on cognitive disorders, reporting better improvement of CPAP and MAD than placebo in cognitive function., Conclusions: CPAP treatment seems to improve cognitive defects associated with OSA. Limited studies have evaluated the effects of the other therapies on cognitive function.

Chronic rhinosinusitis (CRS) is a significant health problem. It affects 5-12% of the general population. The causes that underlie the onset of CRS are not yet well known. However, many factors may contribute to its onset, such as environmental factors and the host's general condition. Medical treatment mainly uses local corticosteroids, nasal irrigation, and antibiotics. In recent years, a new therapeutic approach that employs the use of probiotics emerged. Probiotics have been extensively studied as a therapy for dysbiosis and inflammatory pathologies of various parts of the body. We aimed to examine the studies in vivo and in vitro and clinicals reports in the existing literature to update probiotics' role in rhinosinusitis chronic medical treatment.

Objectives: Alteration of smell and taste has been reported in patients with coronavirus disease 2019 (COVID-19). The incidence and clinical-symptomatic manifestation of COVID-19 is different between northern and southern Italy. This study aims to evaluate the onset of alteration of smell and taste in asymptomatic and symptomatic patients in Sicily (extreme south of Italy)., Methods: This prospective cross-sectional study was performed on asymptomatic and symptomatic COVID-19 patients tested for severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) from May 1 to May 15, 2020. A questionnaire was used for evaluating the prevalence of smell and taste disorders in COVID-19 patients before performing nasopharyngeal swab., Results: Of the total 292 patients, 242 (83.2%) were negative for SARS-CoV-2 and 50 were positive (16.8%). Twenty-six of the 50 (52%) SARS-CoV-2 positive patients reported smell/taste disorders. Twenty-eight of the 50 (57.1%) SARS-CoV-2 positive patients were hospitalized (group A), and 22 (42.9%) were nonhospitalized (group B). The mean age in group A and group B was 45.4 ± 13.7 years and 57.0 ± 15.0, respectively ( P = .007). The symptoms reported by hospitalized patients were fever (71.4%), cough (64.2%), fatigue (82.1%), and dyspnea (100%), while in nonhospitalized patients, the most reported symptoms were sore throat (72.7%), rhinorrhea (77.2%), and altered smell (81.8%). Anosmia/hyposmia reported in group A and group B was 28.5% and 81.8%, respectively ( P = .001)., Conclusion: These preliminary results indicate that the majority of SARS-Cov-2 positive patients in southern Italy did not require hospitalization and presented with milder symptoms or no symptoms and the alterations in smell and taste occurred.

Background and Objectives : Laryngeal cancer is one of the most common cancers in the upper aerodigestive tract, and tobacco and alcohol habits are the most relevant risk factors. The role of these risk factors in the incidence of laryngeal carcinomas is well known, yet only a few studies have been conducted on their role as risk factors of prognosis. The aim of the study was to assess the impact of clinical-demographic data on overall survival (OS), disease-free survival (DFS), and disease-specific survival (DSS) in patients with advanced-stage laryngeal cancer (Stage III-IV) who underwent total laryngectomy. Materials and Methods : This retrospective study was carried out on patients with Stage III-IV laryngeal squamous cell carcinoma treated with total laryngectomy between 2004 and 2014. For each patient, clinical and anamnestic data were collected and collated in a database, including alcohol and smoking habits. Results : Considering the variable age, family history, alcohol, grading, subsite, stage, pT stage, pN stage, and adjuvant therapy, no statistical significance was found for five-year OS. Smoking was the only variable that was statistically significant ( p = 0.0043). A relevant difference was noted in the five-year DFS between pN-negative and pN-positive tumors (74.3% vs. 55.26%, respectively; p = 0.056), and a statistically significant difference was found between non- and ≤20 cigarettes/day smokers and heavy smokers (77.78% vs. 53.66%, respectively; p = 0.021). The five-year disease-specific survival rate was 68.83%, and a significant difference was detected for the smoking and pN stage variables. Heavy smokers (43.90% died vs. 16.67% of the non- and ≤20 cigarettes/day smokers; p = 0.0057) and pN-positive (42.1% died vs. 20.51% of the pN-negative patients; p = 0.042) patients had a worse prognosis. Conclusion : Smoking in our study was found to be an important independent risk factor for worse OS and DSS in patients with advanced laryngeal cancer.

Background: A possible oncogenic role of human papillomavirus (HPV) in head and neck cancers (mainly oropharynx tumors) has been suggested. This significant association has been considered true for oropharynx tumors; however, the association between HPV infection and laryngeal carcinomas is yet to be established. The aim of this study was to evaluate the relationship between p16 expression and long-term overall, disease-free, and disease-specific survival (OS, DF, and DSS, respectively) in patients surgically treated for laryngeal carcinoma., Materials and Methods: Seventy-four previously untreated laryngeal carcinoma patients who underwent surgical treatment were considered for this retrospective study. The tissue specimens were processed for immunohistochemical p16 protein (surrogate HPV marker) detection., Results: Survival analysis of the p16 expression of the primary tumor showed that the 5-year OS rates were 90% and 29.7% for the p16-positive and negative groups, respectively ( P = .003). The 5-year DFS and DSS also differed between both groups ( P < .001), whereas the 5-year DSS seemed to be related to tumor/lymph node classification and p16 expression. However, only p16 expression was identified as an independent prognostic factor associated with OS and DSS., Conclusions: Surgically treated p16-positive laryngeal cancer patients may represent a subset of patients with a better prognosis than their p16-negative counterparts.

Background and objectives : Transoral laser microsurgery (TLM) is widely accepted for its advantages, which consist of a brief hospital stay, rapid functional recovery, low management costs and the fact that it can be easily repeated in cases of recurrence. However, a high incidence of positive or narrow surgical margins has been reported in the literature, even if controversy still exists on the prognostic significance of positive resection margins. The aim of the study was to evaluate the utility of toluidine blue staining in defining the resection margins of early glottic cancer (T1a-T2) treated with TLM. Materials and Methods : This retrospective study was conducted on patients with early glottic cancer (T1a-T2) managed by TLM. A group of patients treated between 2010 and 2014 underwent toluidine blue staining (TB group) of the lesions before starting the cordectomy by TLM, and a group of patients treated by TLM between 2006 and 2009 was considered the control group. Results : A total of 44 subjects were included in this study: 41 were men, and 3 were women. The mean age was 58 ± 9.0 years (median 59.0, range 41-77). Twenty-three of the 44 patients were included in the TB group and 21 in the case control group. In the TB group, only the positivity of the deep margin was a predictor of local recurrence ( p = 0.037), while in the control group, positive or close margins and the type of cordectomy were predictive factors of local recurrence ( p = 0.049). Considering the TB group and control cases, the 5-year local recurrence-free survival was 95.6% and 80.9%, respectively ( p = 0.14). Conclusions : From this first study, toluidine blue staining seems to be a useful modality to improve the rate of the negative resection margins of early glottic cancer (T1a-T2) treated by TLM.

Neuronal differentiation involves extensive modification of biochemical and morphological properties to meet novel functional requirements. Reorganization of the mitochondrial network to match the higher energy demand plays a pivotal role in this process. Mechanisms of neuronal differentiation in response to nerve growth factor (NGF) have been largely characterized in terms of signaling, however, little is known about its impact on mitochondrial remodeling and metabolic function. In this work, we show that NGF-induced differentiation requires the activation of autophagy mediated by Atg9b and Ambra1, as it is disrupted by their genetic knockdown and by autophagy blockers. NGF differentiation involves the induction of P-AMPK and P-CaMK, and is prevented by their pharmacological inhibition. These molecular events correlate with modifications of energy and redox homeostasis, as determined by ATP and NADPH changes, higher oxygen consumption (OCR) and ROS production. Our data indicate that autophagy aims to clear out exhausted mitochondria, as determined by enhanced localization of p62 and Lysotracker-red to mitochondria. In addition, we newly demonstrate that NGF differentiation is accompanied by increased mitochondrial remodeling involving higher levels of fission (P-Drp1) and fusion proteins (Opa1 and Mfn2), as well as induction of Sirt3 and the transcription factors mtTFA and PPARγ, which regulate mitochondria biogenesis and metabolism to sustain increased mitochondrial mass, potential, and bioenergetics. Overall, our data indicate a new NGF-dependent mechanism involving mitophagy and extensive mitochondrial remodeling, which plays a key role in both neurogenesis and nerve regeneration.

TGF-β pathway is generally associated with the processes of metastasis, angiogenesis and EMT in cancer. Very little is known, however, about the role of TGF-β in cancer drug resistance. In this work, we show a specific activation of the TGF-β pathway in consequence of chemotherapeutic treatment in in vivo and in vitro models of colorectal carcinoma. 5-Fluorouracil (5FU) was able to stimulate the activation of SMAD3 and the transcription of specific genes such as ACVRL1, FN1 and TGFB1. On the other hand, the specific inhibition of TGF-βRI was able to repress the 5FU-induced genes transcription and to restore the sensitivity of chemoresistant cells to the toxic action of the drug, by decreasing the expression of BCL2L1 and ID1 genes. The role of the TGF-β molecule in the chemoresistant colon carcinoma cells' response to 5FU was further demonstrated by conditioned medium (CM) experiments: CM from 5FU-treated chemoresistant cells was able to protect chemosensitive cells against the toxic action of 5FU. In conclusion, these findings showed the pivotal role of TGF-β pathway in colon cancer mechanisms of drug resistance suggesting new possible approaches in diagnosis and treatment of colon cancer patients., Competing Interests: The authors declare that no potential conflicts of interests exist.

Reactive astrocytes and activated microglia are the key players in several pathophysiologic modifications of the central nervous system. We used the spared nerve injury (SNI) of the sciatic nerve to induce glial maladaptive response in the ventral horn of lumbar spinal cord and examine its role in the remodeling of the tripartite synapse plasticity. Imaging the ventral horn revealed that SNI was associated with both an early microglial and astrocytic activation, assessed, respectively, by analysis of Iba1 and GFAP expression. Microglia, in particular, localized peculiarly surrounding the motor neurons somata. Perineuronal astrocytes, which play a key role in maintaining the homeostasis of neuronal circuitry, underwent a substantial phenotypic change following peripheral axotomy, producing reactive gliosis. The gliosis was associated with the reduction of glial aminoacid transporters (GLT1 and GlyT1) and increase of neuronal glutamate transporter EAAC1. Although the expression of GABAergic neuronal marker GAD65/67 showed no change, glutamate increase, as demonstrated by HPLC analysis, shifted the excitatory/inhibitory balance as showed by the net increase of the glutamate/GABA ratio. Moreover, endogenous NGF levels were altered in SNI animals and not restored by the intrathecal NGF administration. This treatment reverted phenotypic changes associated with reactive astrocytosis, but failed to modify microglia activation. These findings on one hand confirm the correlation between gliopathy and maladaptive plasticity of the spinal synaptic circuitry, on the other hand add new data concerning the complex peculiar behavior of different glial cells in neuronal degenerative processes, defining a special role of microglia in sustaining the inflammatory response.

Background: Many brain areas participate to supraspinal control of nociception. In these regions, few studies have investigated the role of glial cells in supraspinal plasticity and the effect of 7-day intrathecal nerve growth factor-like (BB14®, Blueprint Biotech, Milano, Italy) treatment., Methods: In male Sprague-Dawley rats, we evaluated by immunohistochemistry the morphological and molecular rearrangement of neuroglial network occurring in several supraspinal brain regions involved in pain processing following spared nerve injury (SNI) of the sciatic nerve. In particular, the medial prefrontal cortex, the amygdala (Amy), the nucleus accumbens (Acb), the thalamus and the periaqueductal gray were analysed., Results: Despite the modifications occurring in the dorsal horn of spinal cord following SNI, no significant changes in the Iba1 and glial fibrillary acidic protein (GFAP) expression were detected in all the analysed supraspinal regions, except for the Amy, showing a remarkable GFAP increase. Interestingly, neuropathic rats also displayed a significant increase of glial transporters (GTs) in all the supraspinal regions. Finally, the analysis of vesicular glutamate transporter 1 (vGLUT1) and vesicular gamma-aminobutyric acid (GABA) transporter (vGAT) expression revealed a significant enhancement of glutamatergic/GABAergic ratio in all selected brain regions of SNI animals, except for Acb. Both glial activation in the Amy and alteration of GTs and vGLUT/vGAT levels observed in neuropathic animals were largely reversed by BB14® treatment., Conclusions: All together, these data strengthen the role of supraspinal neuroglial network plasticity in the establishment of neuropathic pain syndrome. The hallmark is represented by the divergence between glial reaction confined to Amy and the widespread changes in the GT distribution and glutamate/GABA ratio detected in the other supraspinal region., (© 2012 European Federation of International Association for the Study of Pain Chapters.)

The role of the purinergic system in the modulation of pain mechanisms suggests that it might be promising target for treating neuropathic pain. In this study we evaluated the effects of two different dialdehydic compounds: a modified stable adenosine (2-[1-(6-amminopurin-9-il)-2-osso-etossi]prop-2-enale, named MED1101), and oxidized ATP (Ox-ATP), in two different neuropathic pain rat models: the sciatic spared nerve injury (SNI) and paclitaxel evoked painful peripheral neuropathy (pPPN). Neuropathic animals were divided in groups as follows: (a) treated with intraperitoneal (i.p.) MED1101 or Ox-ATP for 21 days; (b) receiving vehicle (VEH) and (c) control (CTR) rats. The allodynic and hyperalgesic behavior was investigated by Von Frey filament test and thermal Plantar test, respectively. We evaluated by immunocytochemistry the astrocytic (GFAP) and microglial (Iba1) response on lumbar spinal cord sections. In either experimental models and using either substances, treated animals showed reduced allodynia and thermal hyperalgesia paralleled by a significant reduction of glial reaction in the spinal cord. These data prompt to hypothesize a potential role of dialdehydes as analgesic agent in chronic neuropathic pain and a possible role as anti-gliotic molecules., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Peptidomimetics hold a great promise as therapeutic agents for neurodegenerative disorders. We previously described a Nerve Growth Factor (NGF)-like peptide, now named BB14, which was found to act as a strong TrkA agonist and to be effective in the sciatic nerve injury model of neuropathic pain. In this report we present the effects of BB14 in reducing reactive astrocytosis and reverting neuroplastic changes of the glutamate/GABAergic circuitry in the lumbar spinal cord following spared nerve injury (SNI) of the sciatic nerve. Immunohistochemical analysis of spinal cord sections revealed that SNI was associated with increased microglial (Iba1) and astrocytic (GFAP) responses, indicative of reactive gliosis. These changes were paralleled by (i) decreased glial aminoacid transporters (GLT1 and GlyT1) and increased levels of (ii) neuronal glutamate transporter EAAC1, (iii) neuronal vesicular GABA transporter (vGAT) and (iv) the GABAergic neuron marker GAD65/67. A remarkable increase of the Glutamate/GABA ratio and the reduction of glutathione (GSH) levels were also indicative of modifications of glial function in neuroprotection. All these molecular changes were found to be linked to an alteration of endogenous NGF metabolism, as demonstrated by decreased levels of mature NGF, increase of proNGF and increased activity of NGF-degrading methallo-proteinases (MMPs). Biochemical alterations and SNI-related neuropathic behavior, characterized by allodynia and hyperalgesia, were reversed by 7-days i.t. administration of the NGF-like peptide BB14, as well as by increasing endogenous NGF levels by i.t. infusion of GM6001, a MMPs inhibitor. All together, while confirming the correlation between reactive astrogliosis and perturbation of synaptic circuitry in the SNI model of peripheral nerve injury, these data strongly support the beneficial effect of BB14 in reducing reactive astrogliosis and restoring synaptic homeostasis under pathological conditions linked to alteration of NGF availability and signaling, thereby suggesting a potential role of BB14 as a therapeutic agent., (Copyright © 2011. Published by Elsevier Inc.)

Neuronal death has been reported to involve mitochondrial dysfunction and cell cycle reentry. In this report, we used Nerve Growth Factor (NGF)-differentiated PC12 cells to investigate mechanisms linking mitochondrial dysfunction and cell cycle activation during neuronal death induced by NGF withdrawal and/or oxidative stress. We found that loss of survival following H(2) O(2) -induced oxidative stress or NGF deprivation was preceded by a decrease in mitochondrial membrane potential (ΔΨm), increase in reactive oxygen species (ROS), and up-regulation of cyclin D1 and phosphorylation (Ser-780) of protein retinoblastoma (P-pRb), without an increase of proliferation rates. Treatment with H(2) O(2) , but not NGF deprivation, also induced the phosporylation (Ser-10) of p27(kip1) and the appearance of a cleaved P-p27(kip1) fragment of about 15 kDa. The extent of cell cycle activation appeared to be inversely correlated to the duration of toxic stimuli (pulse/continuous). H(2) O(2) -induced mitogenic responses appeared to be mediated by induction of P-MAPK and P-Akt and were blocked by p38MAPK and JNK inhibitors as well as by the CDK inhibitor flavopiridol (Flav) and by sodium selenite (Sel), a component of selenoproteins, including glutathione peroxidases. Inhibition of p38MAPK and JNK, instead, did not affect cyclin D1 changes following NGF deprivation. Finally, both Flav hydrochloride and Sel partially prevented mitochondrial dysfunction and cell death following NGF withdrawal or H(2) O(2) toxicity, but not during oxidative stress in the absence of NGF. Taken together, these data suggest that H(2) O(2) -induced oxidative stress can determine distinct patterns of mitogenic responses as a function of mitochondrial dysfunction depending on 1) intensity/duration of stress stimuli and/or 2) presence of NGF., (Copyright © 2011 Wiley-Liss, Inc.)