Adjuvant and neoadjuvant chemotherapy for MSI early gastric cancer: a systematic review and meta-analysis.

Background: Perioperative chemotherapy (CT) is an established therapeutic approach for patients diagnosed with stage IB-III gastric cancer (GC). Objectives: This study aimed to investigate the efficacy of this approach in individuals with GC exhibiting high microsatellite instability (MSI-H). Design: A systematic review was conducted, including studies that provided data on (neo)adjuvant CT outcomes in patients with MSI-H GC. Methods: Systematic searches were conducted in PubMed, Cochrane Central of Controlled Trials, and Embase databases. Data were aggregated using hazard ratios (HRs) to compare overall survival between CT and surgery. Results: Data analysis from 23 studies, including 22,011 patients, revealed that the prevalence of MSI-H is 9.8%. Administration of adjuvant or perioperative CT did not significantly reduce the risk of death or relapse in patients with MSI-H GC (HR = 0.8, 95% CI 0.54-1.16; p = 0.24 and HR = 0.84, 95% CI 0.59-1.18; p = 0.31, respectively). Conclusion: Chemotherapy did not benefit patients diagnosed with MSI-H nonmetastatic GC but rather will be integrated with immune checkpoint inhibitors in the near future.

Molecular Tumor Board as a Clinical Tool for Converting Molecular Data Into Real-World Patient Care.

PURPOSE: The investigation of multiple molecular targets with next-generation sequencing (NGS) has entered clinical practice in oncology, yielding to a paradigm shift from the histology-centric approach to the mutational model for personalized treatment. Accordingly, most of the drugs recently approved in oncology are coupled to specific biomarkers. One potential tool for implementing the mutational model of precision oncology in daily practice is represented by the Molecular Tumor Board (MTB), a multidisciplinary team whereby molecular pathologists, biologists, bioinformaticians, geneticists, medical oncologists, and pharmacists cooperate to generate, interpret, and match molecular data with personalized treatments. PATIENTS AND METHODS: Since May 2020, the institutional MTB set at Fondazione IRCCS Istituto Nazionale Tumori of Milan met weekly via teleconference to discuss molecular data and potential therapeutic options for patients with advanced/metastatic solid tumors. RESULTS: Up to October 2021, among 1,996 patients evaluated, we identified >10,000 variants, 43.2% of which were functionally relevant (pathogenic or likely pathogenic). On the basis of functionally relevant variants, 711 patients (35.6%) were potentially eligible to targeted therapy according to European Society of Medical Oncology Scale for Clinical Actionability of Molecular Targets tiers, and 9.4% received a personalized treatment. Overall, larger NGS panels (containing >50 genes) significantly outperformed small panels (up to 50 genes) in detecting actionable gene targets across different tumor types. CONCLUSION: Our real-world data provide evidence that MTB is a valuable tool for matching NGS data with targeted treatments, eventually implementing precision oncology in clinical practice.

Adult neural precursors isolated from post mortem brain yield mostly neurons: an erythropoietin-dependent process.

This study was aimed at the isolation of neural precursor cells (NPCs) capable of resisting to a prolonged ischemic insult as this may occur at the site of traumatic and ischemic CNS injuries. Adult mice were anesthetized and then killed by cervical dislocation. The cadavers were maintained at room temperature or at 4°C for different time periods. Post mortem neural precursors (PM-NPCs) were isolated, grown in vitro and their differentiation capability was investigated by evaluating the expression of different neuronal markers. PM-NPCs differentiate mostly in neurons, show activation of hypoxia-inducible factor-1 and MAPK, and express both erythropoietin (EPO) and its receptor (EPO-R). The exposure of PM-NPCs to neutralizing antibodies to EPO or EPO-R dramatically reduced the extent of neuronal differentiation to about 11% of total PM-NPCs. The functionality of mTOR and MAPK is also required for the expression of the neuronal phenotype by PM-NPCs. These results suggest that PM-NPCs can be isolated from animal cadaver even several hours after death and their self-renewable capability is comparable to normal neural precursors. Differently, their ability to achieve a neural phenotype is superior to that of NPCs, and this is mediated by the activation of hypoxia-induced factor 1 and EPO signaling. PM-NPCs may represent good candidates for transplantation studies in animal models of neurodegenerative diseases.

Spatial epi-proteomics enabled by histone post-translational modification analysis from low-abundance clinical samples.

BACKGROUND: Increasing evidence linking epigenetic mechanisms and different diseases, including cancer, has prompted in the last 15 years the investigation of histone post-translational modifications (PTMs) in clinical samples. Methods allowing the isolation of histones from patient samples followed by the accurate and comprehensive quantification of their PTMs by mass spectrometry (MS) have been developed. However, the applicability of these methods is limited by the requirement for substantial amounts of material. RESULTS: To address this issue, in this study we streamlined the protein extraction procedure from low-amount clinical samples and tested and implemented different in-gel digestion strategies, obtaining a protocol that allows the MS-based analysis of the most common histone PTMs from laser microdissected tissue areas containing as low as 1000 cells, an amount approximately 500 times lower than what is required by available methods. We then applied this protocol to breast cancer patient laser microdissected tissues in two proof-of-concept experiments, identifying differences in histone marks in heterogeneous regions selected by either morphological evaluation or MALDI MS imaging. CONCLUSIONS: These results demonstrate that analyzing histone PTMs from very small tissue areas and detecting differences from adjacent tumor regions is technically feasible. Our method opens the way for spatial epi-proteomics, namely the investigation of epigenetic features in the context of tissue and tumor heterogeneity, which will be instrumental for the identification of novel epigenetic biomarkers and aberrant epigenetic mechanisms.

Weight regain after discontinuation of topiramate treatment in patients with migraine: a prospective observational study.

PURPOSE: To monitor weight regain after therapy discontinuation in patients with migraine experiencing weight loss during topiramate (TPM) treatment. METHODS: Patients with migraine without aura were enrolled in this observational prospective study. Weight, body mass index (BMI), waist circumference, systolic and diastolic blood pressure, plasma levels of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, leptin, and ghrelin, and homeostatic model assessment of insulin resistance (HOMA-IR) were evaluated before starting TPM (T1), at 3 (T2) and 6 (T3) months of treatment and 6 months after withdrawal of TPM (T4). Weight loss/regain was considered as a change of 5% of pre-TPM body weight. RESULTS: A total of 241 patients were analyzed. Of these, 87 (36%) patients experienced weight loss on TPM medication. During TPM therapy significant reductions in mean values of weight (p<0.001), BMI (p<0.001), waist circumference (p<0.01), HOMA-IR (p<0.01), and leptin (p<0.01) were observed. After TPM discontinuation, all of these parameters showed a clear trend to increase at T4, achieving pre-TPM values in 27 patients. Among potential predictors, only HOMA-IR before starting TPM (parameter estimate=1.36, effect size=0.75; p=0.006) was significantly associated with weight regain after therapy discontinuation. CONCLUSIONS: Loss of body weight is a reversible effect, which at 6 months after TPM discontinuation shows a clear trend to return to baseline values. HOMA-IR is the only predictive factor of weight regain.

Ear, nose and throat manifestations of mucocutaneous Leishmaniasis: a literature review.

Leishmaniasis comprises a group of diseases caused by a protozoan parasite belonging to the genus Leishmania and transmitted by the bite of infected female sand flies. Leishmaniasis is endemic in 88 countries and causes significant morbidity and mortality worldwide. Phenomena such as globalization and human migration, as well as the increased volume of international travel have extended its prevalence in developed countries. In addition, the incidence of leishmaniasis as an opportunistic disease has increased in recent years because of the growing number of patients with immune depression secondary to chronic illness, neoplasm, transplant and HIV infection, thereby constituting a public health problem. In humans, there are three possible clinical syndromes of leishmaniasis: cutaneous, mucocutaneous and visceral. Mucocutaneous disease is due to extension of local skin disease into the mucosal tissue via direct extension, bloodstream or lymphatics. Lesions interest mainly the oral and nasal mucosa and occasionally the laryngeal and pharyngeal mucosa. If not recognized and adequately treated, MCL may disfigure the patient because of the chronic local destruction of tissue of the nose, pharynx and palate. Because of the invariable involvement of the areas pertaining otorhinolaryngologists, it is important for ENT specialists and family physicians to have awareness of this condition and its clinical manifestations, particularly in presence of a history positive for travel to endemic areas. If mucocutaneous leishmaniasis is suspected, otorhinolaryngologic examination is very helpful in establishing a correct diagnosis, preventing inappropriate treatment.

Modified hyoid suspension technique in the treatment of multilevel related obstructive sleep apnea.

OBJECTIVE: Using the Hörmann technique of hyoid suspension in sleep apnea surgery, a steel wire is placed through the thyroid cartilage and slung around the hyoid bone. However, we experienced thyroid cartilage fracture by steel wire traction. A modification is presented to avoid thyroid cartilage fracture. STUDY DESIGN: Case series with chart review. SETTING: University hospital. SUBJECTS AND METHODS: Twenty-seven patients affected by obstructive sleep apnea syndrome underwent Hörmann hyoid suspension. In 2 patients, the steel wire caused a fracture of the thyroid cartilage. The technique was therefore modified in 25 subsequent patients. The wire is threaded through an adaptation titanium miniplate placed on the surface of the thyroid cartilage. RESULTS: The apnea-hypopnea index decreased from 43.1 to 10.9/h. Nineteen patients (76%) met the criteria for a successful outcome. No complications related to this modification were noted. CONCLUSIONS: The Hörmann hyoid suspension is a procedure that advances the hyoid bone to expand the airway, and its effectiveness has been proven previously. The modified hyoid suspension presented here promises similar results without the risk of serious complications such as thyroid cartilage fracture.

Acquired middle ear cholesteatoma in children with cleft palate: experience from 18 surgical cases.

OBJECTIVES: To review an institutional experience with the surgical management of middle ear cholesteatoma in children with cleft palate. MATERIALS AND METHODS: We analyzed retrospectively 18 children diagnosed with cleft palate who underwent surgery for acquired middle ear cholesteatoma between 2000 and 2007. The following data were recorded: age, sex, history of ventilation tube insertion, status of the contralateral ear, cholesteatoma location and extension, and surgical technique involved. Cholesteatoma recidivism, stable mastoid cavity and hearing levels were the main outcomes measured. RESULTS: Follow-up ranged from 5 to 12 years (mean 8 years). Twelve children underwent planned staged canal wall up mastoidectomy: a residual cholesteatoma was found and removed during the second-look procedure in 2 ears (16.6%); two children (16.6%) showed a recurrent cholesteatoma and required conversion to canal wall down mastoidectomy. A modified Bondy technique was chosen in two children with an epitympanic cholesteatoma with an intact tympano-ossicular system, while in the remaining four subjects a canal wall down mastoidectomy was performed because of an irreparable erosion of the postero-superior canal wall: no cases of recurrent cholesteatoma were observed in these 6 children; revision mastoidectomy was needed in one patient for cavity granulation. A postoperative air-bone gap result of 0-20dB was achieved in 11 children (61.1%); in 5 cases (27.7%) postoperative air-bone gap was between 21 and 30dB, while in 2 (11.1%) was >30dB. Bone conduction thresholds remained unaffected in all cases. CONCLUSIONS: Our results indicate that most cleft palate children with cholesteatoma can be managed with a canal wall up mastoidectomy with low complication rates. In extensive disease with large erosion of the canal wall as well in presence of a retraction pocket in the contralateral ear, a canal wall down mastoidectomy should be considered. In epitympanic cholesteatomas with an intact tympano-ossicular system and mesotympanum free of disease, the modified Bondy procedure is an effective surgical option. As in the general pediatric population, improvement or preservation of hearing can be obtained in most patients.

Pediatric cochlear implantation: an update.

Deafness in pediatric age can adversely impact language acquisition as well as educational and social-emotional development. Once diagnosed, hearing loss should be rehabilitated early; the goal is to provide the child with maximum access to the acoustic features of speech within a listening range that is safe and comfortable. In presence of severe to profound deafness, benefit from auditory amplification cannot be enough to allow a proper language development. Cochlear implants are partially implantable electronic devices designed to provide profoundly deafened patients with hearing sensitivity within the speech range. Since their introduction more than 30 years ago, cochlear implants have improved their performance to the extent that are now considered to be standard of care in the treatment of children with severe to profound deafness. Over the years patient candidacy has been expanded and the criteria for implantation continue to evolve within the paediatric population. The minimum age for implantation has progressively reduced; it has been recognized that implantation at a very early age (12-18 months) provides children with the best outcomes, taking advantage of sensitive periods of auditory development. Bilateral implantation offers a better sound localization, as well as a superior ability to understand speech in noisy environments than unilateral cochlear implant. Deafened children with special clinical situations, including inner ear malformation, cochlear nerve deficiency, cochlear ossification, and additional disabilities can be successfully treated, even thogh they require an individualized candidacy evaluation and a complex post-implantation rehabilitation. Benefits from cochlear implantation include not only better abilities to hear and to develop speech and language skills, but also improved academic attainment, improved quality of life, and better employment status. Cochlear implants permit deaf people to hear, but they have a long way to go before their performance being comparable to that of the intact human ear; researchers are looking for more sophisticated speech processing strategies as well as a more efficient coupling between the electrodes and the cochlear nerve with the goal of dramatically improving the quality of sound of the next generation of implants.

Factors associated with the efficacy of mandibular advancing device treatment in adult OSA patients.

The aim of this study was to evaluate the anthropometric, demographic, occlusal and cephalometric characteristics of a group of adult obstructive sleep apnea (OSA) patients treated with mandibular advancement devices (MADs) and to determine the factors associated with treatment efficacy. Twenty-three consecutive patients with mild to severe OSA (polysomnographically diagnosed [T0]) were recruited for this prospective study; they were treated with a Silensor(®) appliance, and a polysomnographic exam with the MAD in situ was performed 2 to 3 months later (T1) to evaluate MAD's efficacy. Based on apnea-hypopnea index (AHI) differences between the T0 and T1 values, patients were classified into two groups: completely recovered and not completely recovered patients. The differences in anthropometric, demographic, occlusal and cephalometric parameters between the two groups were analyzed, and significant parameters verified. The sample showed these prevalent characteristics: deep bite, crossbite, tooth wear, dental and skeletal Class II, mesofacial mandibular vertical growth pattern, low position of the hyoid bone, longer soft palate length. The transverse diameters of upper maxilla had the greatest impact on T0 AHI. The factors associated with MAD efficacy were: age under 55 years, distance between the hyoid bone and the mandibular plane (H-MP) less than 20 mm, divergence of mandibular vertical growth pattern (SN^MP) less than 29°.

Metabolic epilepsy: an update.

Inborn errors of metabolism comprise a large class of genetic diseases involving disorders of metabolism. Presentation is usually in the neonatal period or infancy but can occur at any time, even in adulthood. Seizures are frequent symptom in inborn errors of metabolism, with no specific seizure types or EEG signatures. The diagnosis of a genetic defect or an inborn error of metabolism often results in requests for a vast array of biochemical and molecular tests leading to an expensive workup. However a specific diagnosis of metabolic disorders in epileptic patients may provide the possibility of specific treatments that can improve seizures. In a few metabolic diseases, epilepsy responds to specific treatments based on diet or supplementation of cofactors (vitamin-responsive epilepsies), but for most of them specific treatment is unfortunately not available, and conventional antiepileptic drugs must be used, often with no satisfactory success. In this review we present an overview of metabolic epilepsies based on various criteria such as treatability, age of onset, seizure type, and pathogenetic background.