MiR-449a antagonizes EMT through IL-6-mediated trans-signaling in laryngeal squamous cancer.

MicroRNAs (miRNAs) are involved in post-transcriptional gene expression regulation and in mechanisms of cancer growth and metastases. In this light, miRNAs could be promising therapeutic targets and biomarkers in clinical practice. Therefore, we investigated if specific miRNAs and their target genes contribute to laryngeal squamous cell carcinoma (LSCC) development. We found a significant decrease of miR-449a in LSCC patients with nodal metastases (63.3%) compared with patients without nodal involvement (44%). The AmpliSeq Transcriptome of HNO-210 miR-449a-transfected cell lines allowed the identification of IL6-R as a potential target. Moreover, the downregulation of IL6-R and the phosphorylation reduction of the downstream signaling effectors, suggested the inhibition of the IL-6 trans-signaling pathway. These biochemical effects were paralleled by a significant inhibition of invasion and migration in vitro and in vivo, supporting an involvement of epithelial-mesenchymal transition. These findings indicate that miR-449a contributes to suppress the metastasization of LSCC by the IL-6 trans-signaling block and affects sensitivity to external stimuli that mimic pro-inflammatory conditions.

Prevalence of Scoliosis in Children and Adolescents with Cystic Fibrosis.

The prevalence of scoliosis in people with cystic fibrosis (CF) seems to be greater than in the normal population. Over the last two years, a screening for spinal deformities was carried out in patients with CF aged 5 to 18 years, followed up at the CF regional Centre in Parma (Italy). Forty-three patients (twenty-seven males, mean age: 11.8 ± 4.5 years) were enrolled in the study. Nine patients (20.9%) were diagnosed with scoliosis, with a mean Cobb angle of 20.8 ± 9.4 (12-38°). Five patients (11.6%) were diagnosed with a postural kyphosis attitude and one with pathological fixed kyphosis. All patients with scoliosis and postural kyphosis started daily physiotherapeutic scoliosis-specific exercises (PSSE). Compared to people without CF, the prevalence of scoliosis in our paediatric CF population seems to be higher and more present in males; the curves were thoracic and mostly right-sided. CF disease, hyposthenic postural attitude and sedentary lifestyle can contribute to the pathogenesis of this musculoskeletal alteration. Spinal deformities may negatively affect pulmonary function, resulting in disability, pain and a decreased quality of life. Since the prevention of musculoskeletal deformities is easier than restoration, in CF population targeted screening during growth and interventions, including regular physical exercise, are mandatory.

Management of nasal vestibule carcinomas: recommendations by the Oncological Committee of the Italian Society of Otorhinolaryngology - Head and Neck Surgery.

Objective: Squamous cell carcinoma of the nasal vestibule (NV SCC) is a head and neck malignancy for which there is no established consensus on most aspects of clinical management. The purpose of this document is to give updated recommendations that incorporate recent evidence on its clinical characteristics and the high efficacy of brachytherapy as primary treatment modality. Methods: A working group consisting of the members of the Scientific Committee for Oncology and Reconstructive Surgery of the Italian Society of Otorhinolaryngology Head and Neck Surgery and radiation oncologists expert in brachytherapy was formed to achieve a consensus. Results: Consensus was reached on a set of recommendations, proposing a refined anatomical definition of the nasal vestibule, a novel T staging system of the NV SCC, and brachytherapy as standard of care, with a new method for catheter implantation. Conclusions: The Committee emphasises the critical role of an accurate classification in clinical practice and encourages further research to validate the novel staging system and further improve treatment strategies. Where appropriate, it is recommended that patients be referred to centres with specific experience in brachytherapy for NV SCC.

A Retrospective Multicenter Italian Analysis of Epidemiological, Clinical and Histopathological Features in a Sample of Patients with Acinic Cell Carcinoma of the Parotid Gland.

BACKGROUND: The acinic cell carcinoma (AciCC) of the parotid gland is a rare tumor with an indolent behavior; however, a subgroup of this tumor presents an aggressive behavior with a tendency to recur. The aim of this multicenter study was to identify and stratify those patients with AciCC at high risk of tumor recurrence. METHODS: A retrospective study was carried out involving 77 patients treated with surgery between January 2000 and September 2022, in different Italian referral centers. Data about tumor characteristics and its recurrence were collected. The histological specimens and slides were independently reviewed by a senior pathologist coordinator (L.C.) and the institution's local head and neck pathologist. RESULTS: The patients' age average was 53.6 years, with a female prevalence in the group. The mean follow-up was 67.4 months (1-258, SD 59.39). The five-year overall survival (OS) was 83.2%. The 5-year disease-free survival (DFS) was 60% (95% CI 58.2-61.7). A high incidence of necrosis, extraglandular spread, lymphovascular invasion (LVI), atypical mitosis, and cellular pleomorphism was observed in the high-risk tumors compared to the low-risk ones. CONCLUSION: AciCC generally had an indolent behavior, optimal OS, DFS with few cervical node metastases, and rare distant relapses. This multicenter retrospective case series provides evidence of the need for clinical-epidemiological-histological stratification for patients at risk of poor outcomes. Our results suggest that the correct definition of high-risk AciCC should include tumor size, the presence of necrosis, extraglandular spread, LVI, atypical mitosis, and cellular pleomorphism.

Systematic Review of Management and Survival Outcome of Parotid Cancers with Lateral Skull Base Invasion.

Lateral skull base involvement from parotid cancers is a rare condition and is considered a poor prognostic indicator. The aim of this study was to systematically review the literature of parotid tumors with temporal bone invasion to analyze the survival outcome. A systematic literature review was performed in August 2022, without time limits, and 289 patients affected by parotid gland cancers and lateral skull base involvement were included. The most common symptoms in parotid tumors at the onset were indolent mass, facial weakness, pain, and hearing loss; the chi-square value is 23.1063, with a statistically significance (p = < 0.000121). The five most common histologies were adenoid cystic carcinoma, acinic cell carcinoma, mucoepidermoid carcinoma, adenocarcinoma, and squamous cell carcinoma. The facial nerve function after surgery showed statistically significance (functional vs. non-functional; chi-square was 91.7698, p = < 0.00001). Mean follow-up was 36.2 months (range 0.3-192). At the last follow-up, more patients died of disease (DOD; 60/289, 21%) than other causes (DOOC; 5/289, 2%). There is a statistically significant correlation between patients died for tumor (DOD) and patients died for other causes (DOOC) (p = < 0.0001), suggesting that the lateral skull base invasion negatively impacts on survival. Basing on the results of our systematic review, lateral skull base involvement from parotid recurrent/advance tumors should be considered a poor prognostic factor, as the majority of patients die due to this condition. It also would be necessary to have "clear"works, with full data (demographic, clinical, surgical data), and with a longer follow up, in order to assess the best treatment modality of these patients.

Submandibular gland involvement in oral cavity squamous cell carcinoma: a retrospective multicenter study.

BACKGROUND: The submandibular gland (SMG) is routinely excised during neck dissection. Given the importance of the SMG in saliva production, it is important to understand its involvement rate by cancer tissue and the feasibility of its preservation. METHODS: Retrospective data were collected from five academic centers in Europe. The study involved adult patients affected by primary oral cavity carcinoma (OCC) undergoing tumor excision and neck dissection. The main outcome analyzed was the SMG involvement rate. A systematic review and a meta-analysis were also conducted to provide an updated synthesis of the topic. RESULTS: A total of 642 patients were enrolled. The SMG involvement rate was 12/642 (1.9%; 95% CI 1.0-3.2) when considered per patient, and 12/852 (1.4%; 95% CI 0.6-2.1) when considered per gland. All the glands involved were ipsilateral to the tumor. Statistical analysis showed that predictive factors for gland invasion were: advanced pT status, advanced nodal involvement, presence of extracapsular spread and perivascular invasion. The involvement of level I lymph nodes was associated with gland invasion in 9 out of 12 cases. pN0 cases were correlated with a reduced risk of SMG involvement. The review of the literature and the meta-analysis confirmed the rare involvement of the SMG: on the 4458 patients and 5037 glands analyzed, the involvement rate was 1.8% (99% CI 1.1-2.7) and 1.6% (99% CI 1.0-2.4), respectively. CONCLUSIONS: The incidence of SMG involvement in primary OCC is rare. Therefore, exploring gland preservation as an option in selected cases would be reasonable. Future prospective studies are needed to investigate the oncological safety and the real impact on quality of life of SMG preservation.

Structural changes in lung morphology detected by MRI after modulating therapy with elexacaftor/tezacaftor/ivacaftor in adolescent and adult patients with cystic fibrosis.

INTRODUCTION: Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) improves CFTR function in cystic fibrosis (CF) patients homozygous or heterozygous for F508del mutation. The aim of the study was to evaluate the response to ELX/TEZ/IVA treatment both clinically and morphologically in terms of bronchiectasis, bronchial wall thickening, mucus plugging, abscess and consolidations. METHODS: We retrospectively collected data from CF patients followed at Parma CF Centre (Italy) treated by ELX/TEZ/IVA between March and November 2021. Post-treatment changes in respiratory function, quality of life, sweat chloride concentration, body mass index, pulmonary exacerbations and lung structure by chest magnetic resonance imaging (MRI) were assessed. T2-and T1-weighted sequences were acquired with a 20 min-long scanning protocol on a 1.5T MRI scanner (Philips Ingenia) without administration of intravenous contrast media. RESULTS: 19 patients (32.5 ± 10.2 years) were included in the study. After 6 months of treatment with ELX/TEZ/IVA, MRI showed significant improvements in the morphological score (p < 0.001), with a reduction in bronchial wall thickening (p < 0.001) and mucus plugging (p 0.01). Respiratory function showed significant improvement in predicted FEV1% (58.5 ± 17.5 vs 71.4 ± 20.1, p < 0.001), FVC% (79.0 ± 11.1 vs 88.3 ± 14.4, p < 0.001), FEV1/FVC (0.61 ± 0.16 vs 0.67 ± 0.15, <0.001) and LCI2.5% (17.8 ± 4.3 vs 15.8 ± 4.1 p < 0.005). Significant improvement was found in body mass index (20.6 ± 2.7 vs 21.9 ± 2.4, p < 0.001), pulmonary exacerbations (2.3 ± 1.3 vs 1.4 ± 1.3 p 0.018) and sweat chloride concentration (96.5 ± 36.6 vs 41.1 ± 16.9, p < 0.001). CONCLUSIONS: Our study confirms the efficacy of ELX/TEZ/IVA in CF patients not only from a clinical point of view but also in terms of morphological changes of the lungs.

Impact of Epstein Barr Virus Infection on Treatment Opportunities in Patients with Nasopharyngeal Cancer.

Chemical, physical, and infectious agents may induce carcinogenesis, and in the latter case, viruses are involved in most cases. The occurrence of virus-induced carcinogenesis is a complex process caused by an interaction across multiple genes, mainly depending by the type of the virus. Molecular mechanisms at the basis of viral carcinogenesis, mainly suggest the involvement of a dysregulation of the cell cycle. Among the virus-inducing carcinogenesis, Epstein Barr Virus (EBV) plays a major role in the development of both hematological and oncological malignancies and importantly, several lines of evidence demonstrated that nasopharyngeal carcinoma (NPC) is consistently associated with EBV infection. Cancerogenesis in NPC may be induced by the activation of different EBV "oncoproteins" which are produced during the so called "latency phase" of EBV in the host cells. Moreover, EBV presence in NPC does affect the tumor microenvironment (TME) leading to a strongly immunosuppressed status. Translational implications of the above-mentioned statements are that EBV-infected NPC cells can express proteins potentially recognized by immune cells in order to elicit a host immune response (tumor associated antigens). Three immunotherapeutic approaches have been implemented for the treatment of NPC including active, adoptive immunotherapy, and modulation of immune regulatory molecules by use of the so-called checkpoint inhibitors. In this review, we will highlight the role of EBV infection in NPC development and analyze its possible implications on therapy strategies.

Cost-effectiveness of 5 fraction and partial breast radiotherapy for early breast cancer in the UK: model-based multi-trial analysis.

PURPOSE: We estimated the cost-effectiveness of 4 radiotherapy modalities to treat early breast cancer in the UK. In a subgroup of patients eligible for all modalities, we compared whole-breast (WB) and partial breast (PB) radiotherapy delivered in either 15 (WB15F, PB15F) or 5 fractions (WB5F, PB5F). In a subgroup ineligible for PB radiotherapy, we compared WB15F to WB5F. METHODS: We developed a Markov cohort model to simulate lifetime healthcare costs and quality-adjusted life years (QALYs) for each modality. This was informed by the clinical analysis of two non-inferiority trials (FAST Forward and IMPORT LOW) and supplemented with external literature. The primary analysis assumed that radiotherapy modality influences health only through its impact on locoregional recurrence and radiotherapy-related adverse events. RESULTS: In the primary analysis, PB5F had the least cost and greatest expected QALYs. WB5F had the least cost and the greatest expected QALYs in those only eligible for WB radiotherapy. Applying a cost-effectiveness threshold of £15,000/QALY, there was a 62% chance that PB5F was the cost-effective alternative in the PB eligible group, and there was a 100% chance that WB5F was cost-effective in the subgroup ineligible for PB radiotherapy. CONCLUSIONS: Hypofractionation to 5 fractions and partial breast radiotherapy modalities offer potentially important benefits to the UK health system.

1000 Days: The "WeCare Generation" Program-The Ultimate Model for Improving Human Mental Health and Economics: The Study Protocol.

INTRODUCTION: The COVID-19 pandemic stressed the necessity of a new resilience of the human population and health system. The "WeCare Generation" program is a new proposal of territorial intervention, with a new paradigm, on the diseases of the human body and mind. BACKGROUND: In recent decades, the independent strands of investigation on brain plasticity and early trauma consequences have demonstrated that traumatic experiences in the period from pregnancy to the age of 3 years have an enormous impact on an individual's future development, and both physical and mental health. Research shows that adverse child experiences (ACEs) are associated with a strong risk of conditions such as: harmful alcohol use, smoking, illicit drug use, high body-mass index, depression, anxiety, interpersonal violence, cancer, type 2 diabetes, cardiovascular diseases, stroke respiratory diseases and, as a consequence, to a high financial cost in Italy and also across Europe (1-9% GDP) and the USA (total annual costs estimated to be USD 581 billion in Europe and USD 748 billion in North America). All this suggests that an early intervention on that traumatized-slice of population leads to multiplied savings. METHODS: A multi-center, randomized, controlled trial was designed. The parents of the future neonatal population (from pregnancy to delivery) with trauma will be enrolled, and randomized to treatment, or control arm. The article describes in detail how the primary outpoint (cost to the national health system), and some secondary outpoints, will be collected. DISCUSSION: An overall rate of return on investment (ROI) statistically significant 13.0% per annum with an associated benefit/cost ratio (BCR) of 6.3 is expected as the primary outcome of the "WeCare Generation" program. Our proposed model predicts a new medical paradigm aiming to empower new generations, with a strong return on economy and health.

Hindbrain insulin controls feeding behavior.

OBJECTIVE: Pancreatic insulin was discovered a century ago, and this discovery led to the first lifesaving treatment for diabetes. While still controversial, nearly one hundred published reports suggest that insulin is also produced in the brain, with most focusing on hypothalamic or cortical insulin-producing cells. However, specific function for insulin produced within the brain remains poorly understood. Here we identify insulin expression in the hindbrain's dorsal vagal complex (DVC), and determine the role of this source of insulin in feeding and metabolism, as well as its response to diet-induced obesity in mice. METHODS: To determine the contribution of Ins2-producing neurons to feeding behavior in mice, we used the cross of transgenic RipHER-cre mouse and channelrhodopsin-2 expressing animals, which allowed us to optogenetically stimulate neurons expressing Ins2 in vivo. To confirm the presence of insulin expression in Rip-labeled DVC cells, in situ hybridization was used. To ascertain the specific role of insulin in effects discovered via optogenetic stimulation a selective, CNS applied, insulin receptor antagonist was used. To understand the physiological contribution of insulin made in the hindbrain a virogenetic knockdown strategy was used. RESULTS: Insulin gene expression and presence of insulin-promoter driven fluorescence in rat insulin promoter (Rip)-transgenic mice were detected in the hypothalamus, but also in the DVC. Insulin mRNA was present in nearly all fluorescently labeled cells in DVC. Diet-induced obesity in mice altered brain insulin gene expression, in a neuroanatomically divergent manner; while in the hypothalamus the expected obesity-induced reduction was found, in the DVC diet-induced obesity resulted in increased expression of the insulin gene. This led us to hypothesize a potentially divergent energy balance role of insulin in these two brain areas. To determine the acute impact of activating insulin-producing neurons in the DVC, optic stimulation of light-sensitive channelrhodopsin 2 in Rip-transgenic mice was utilized. Optogenetic photoactivation induced hyperphagia after acute activation of the DVC insulin neurons. This hyperphagia was blocked by central application of the insulin receptor antagonist S961, suggesting the feeding response was driven by insulin. To determine whether DVC insulin has a necessary contribution to feeding and metabolism, virogenetic insulin gene knockdown (KD) strategy, which allows for site-specific reduction of insulin gene expression in adult mice, was used. While chow-fed mice failed to reveal any changes of feeding or thermogenesis in response to the KD, mice challenged with a high-fat diet consumed less food. No changes in body weight were identified, possibly resulting from compensatory reduction in thermogenesis. CONCLUSIONS: Together, our data suggest an important role for hindbrain insulin and insulin-producing cells in energy homeostasis.

From an Empty Stomach to Anxiolysis: Molecular and Behavioral Assessment of Sex Differences in the Ghrelin Axis of Rats.

Ghrelin, a stomach-produced hormone, is well-recognized for its role in promoting feeding, controlling energy homeostasis, and glucoregulation. Ghrelin's function to ensure survival extends beyond that: its release parallels that of corticosterone, and ghrelin administration and fasting have an anxiolytic and antidepressant effect. This clearly suggests a role in stress and anxiety. However, most studies of ghrelin's effects on anxiety have been conducted exclusively on male rodents. Here, we hypothesize that female rats are wired for higher ghrelin sensitivity compared to males. To test this, we systematically compared components of the ghrelin axis between male and female Sprague Dawley rats. Next, we evaluated whether anxiety-like behavior and feeding response to endogenous or exogenous ghrelin are sex divergent. In line with our hypothesis, we show that female rats have higher serum levels of ghrelin and lower levels of the endogenous antagonist LEAP-2, compared to males. Furthermore, circulating ghrelin levels were partly dependent on estradiol; ovariectomy drastically reduced circulating ghrelin levels, which were partly restored by estradiol replacement. In contrast, orchiectomy did not affect circulating plasma ghrelin. Additionally, females expressed higher levels of the endogenous ghrelin receptor GHSR1A in brain areas involved in feeding and anxiety: the lateral hypothalamus, hippocampus, and amygdala. Moreover, overnight fasting increased GHSR1A expression in the amygdala of females, but not males. To evaluate the behavioral consequences of these molecular differences, male and female rats were tested in the elevated plus maze (EPM), open field (OF), and acoustic startle response (ASR) after three complementary ghrelin manipulations: increased endogenous ghrelin levels through overnight fasting, systemic administration of ghrelin, or blockade of fasting-induced ghrelin signaling with a GHSR1A antagonist. Here, females exhibited a stronger anxiolytic response to fasting and ghrelin in the ASR, in line with our findings of sex differences in the ghrelin axis. Most importantly, after GHSR1A antagonist treatment, females but not males displayed an anxiogenic response in the ASR, and a more pronounced anxiogenesis in the EPM and OF compared to males. Collectively, female rats are wired for higher sensitivity to fasting-induced anxiolytic ghrelin signaling. Further, the sex differences in the ghrelin axis are modulated, at least partly, by gonadal steroids, specifically estradiol. Overall, ghrelin plays a more prominent role in the regulation of anxiety-like behavior of female rats.

Astrocytes derived from ASD individuals alter behavior and destabilize neuronal activity through aberrant Ca2+ signaling.

The cellular mechanisms of autism spectrum disorder (ASD) are poorly understood. Cumulative evidence suggests that abnormal synapse function underlies many features of this disease. Astrocytes regulate several key neuronal processes, including the formation of synapses and the modulation of synaptic plasticity. Astrocyte abnormalities have also been identified in the postmortem brain tissue of ASD individuals. However, it remains unclear whether astrocyte pathology plays a mechanistic role in ASD, as opposed to a compensatory response. To address this, we combined stem cell culturing with transplantation techniques to determine disease-specific properties inherent to ASD astrocytes. We demonstrate that ASD astrocytes induce repetitive behavior as well as impair memory and long-term potentiation when transplanted into the healthy mouse brain. These in vivo phenotypes were accompanied by reduced neuronal network activity and spine density caused by ASD astrocytes in hippocampal neurons in vitro. Transplanted ASD astrocytes also exhibit exaggerated Ca2+ fluctuations in chimeric brains. Genetic modulation of evoked Ca2+ responses in ASD astrocytes modulates behavior and neuronal activity deficits. Thus, this study determines that astrocytes derived from ASD iPSCs are sufficient to induce repetitive behavior as well as cognitive deficit, suggesting a previously unrecognized primary role for astrocytes in ASD.

Patients affected by squamous cell carcinoma of the head and neck: A population particularly prone to developing severe forms of COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the recent Coronavirus Disease 2019 (COVID-19) pandemic, which has spread all over the world over the past year. Comorbidities appear to affect the prognosis of patients with such diseases, but the impact of cancer on the course of SARS-CoV2 has remained largely elusive. The aim of the present study is to analyze the outcome of patients affected by squamous cell carcinoma of the head and neck (SCCHN) and a number of their comorbidities, if infected with SARS-CoV2. The clinical data of 100 patients affected by SCCHN, who were undergoing treatment or who had finished their oncologic treatment in the past 6 months, were retrospectively collected and analysed. For each patient, the Charlson Comorbidity Index (CCI) was calculated to provide a score assessing the real weight of comorbidities on the patient's outcome at the time of diagnosis. It was discovered that these patients, besides the SCCHN, frequently presented at diagnosis with several other comorbidities, including hypertension, type 2 diabetes, cardiac arrhytmia, chronic obstructive pulmonary disease and various forms of vasculopathy (and thus a poor CCI). This feature suggest that, given the high frequency of various comorbidities in patients with SCCHN, additional SARS-CoV2 infection could have particularly devastating consequences.

Emergencies in oncology: an overview and practical suggestions.

Oncologic emergencies are clinical situations that can lead to death in a short time (24-48 hours) if not quickly faced. In the clinical practice of the medical oncologist, such situations do not infrequently occur. The onset of oncologic emergencies may depend on the presence of cancer itself, the therapies carried out to counteract cancer, or the patient's predisposition to develop such events. Mediastinal syndrome, spinal cord compression, endocranial hypertension, pancytopenia, metabolic syndromes, deep vein thrombosis, pulmonary thromboembolism, disseminated intravascular coagulation and the massive pericardial effusion are the main medical emergencies in oncology occurring in clinical practice. It is essential to recognize the aforementioned situations early in order to treat them promptly, thus avoiding serious consequences. This paper is aimed at presenting an overview on the topic, offering practical suggestions useful in daily clinical practice.

Neutron and photon out-of-field doses at cardiac implantable electronic device (CIED) depths.

The accuracy of an out-of-field dose from an Elekta Synergy accelerator calculated using the X-ray Voxel Monte Carlo (XVMC) dose algorithm in the Monaco treatment planning system (TPS) for both low-energy (6 MV) and high-energy (15 MV) photons at cardiac implantable electronic device (CIED) depths was investigated through a comparison between MCNPX simulated out-of-field doses and measured out-of-field doses using three high spatial and sensitive active detectors. In addition, total neutron equivalent dose and fluence at CIED depths of a 15-MV dose from an Elekta Synergy accelerator were calculated, and the corresponding CIED relative neutron damage was quantified. The results showed that for 6-MV photons, the XVMC dose algorithm in Monaco underestimated out-of-field doses in all off-axis distances (average errors: -17% at distances X < 10 cm from the field edge and -31% at distances between 10 < X ≤ 16 cm from the field edge), with an increasing magnitude of underestimation for high-energy (15 MV) photons (up to 11%). According to the results, an out-of-field photon dose at a shallower CIED depth of 1 cm was associated with greater statistical uncertainty in the dose estimate compared to a CIED depth of 2 cm and clinical depth of 10 cm. Our results showed that the relative neutron damage at a CIED depth range for 15 MV photon is 36% less than that reported for 18 MV photon in the literature.

Key role for hypothalamic interleukin-6 in food-motivated behavior and body weight regulation.

The pro-inflammatory role of interleukin-6 (IL-6) is well-characterized. Blockade of IL-6, by Tocilizumab, is used in patients with rheumatoid arthritis and those diagnosed with cytokine storm. However, brain-produced IL-6 has recently emerged as a critical mediator of gut/adipose communication with the brain. Central nervous system (CNS) IL-6 is engaged by peripheral and central signals regulating energy homeostasis. IL-6 is critical for mediating hypophagia and weight loss effects of a GLP-1 analog, exendin-4, a clinically utilized drug. However, neuroanatomical substrates and behavioral mechanisms of brain IL-6 energy balance control remain poorly understood. We propose that the lateral hypothalamus (LH) is an IL-6-harboring brain region, key to food intake and food reward control. Microinjections of IL-6 into the LH reduced chow and palatable food intake in male rats. In contrast, female rats responded with reduced motivated behavior for sucrose, measured by the progressive ratio operant conditioning test, a behavioral mechanism previously not linked to IL-6. To test whether IL-6, produced in the LH, is necessary for ingestive and motivated behaviors, and body weight homeostasis, virogenetic knockdown by infusion of AAV-siRNA-IL6 into the LH was utilized. Attenuation of LH IL-6 resulted in a potent increase in sucrose-motivated behavior, without any effect on ingestive behavior or body weight in female rats. In contrast, the treatment did not affect any parameters measured (chow intake, sucrose-motivated behavior, locomotion, and body weight) in chow-fed males. However, when challenged with a high-fat/high-sugar diet, the male LH IL-6 knockdown rats displayed rapid weight gain and hyperphagia. Together, our data suggest that LH-produced IL-6 is necessary and sufficient for ingestive behavior and weight homeostasis in male rats. In females, IL-6 in the LH plays a critical role in food-motivated, but not ingestive behavior control or weight regulation. Thus, collectively these data support the idea that brain-produced IL-6 engages the hypothalamus to control feeding behavior.

Electrochemotherapy as a First Line Treatment in Recurrent Squamous Cell Carcinoma of the Oral Cavity and Oropharynx PDL-1 Negative and/or with Evident Contraindication to Immunotherapy: A Randomized Multicenter Controlled Trial.

BACKGROUND: A significant proportion of patients with head and neck squamous cell carcinoma (HNSCC) have advanced-stage disease (stages III to IVB) that do not respond to therapy despite aggressive, site-specific multimodality therapy. A great number of them will develop disease recurrence, with up to 60% risk of local failure and up to 30% risk of distant failure. Therapy can be very demanding for the patient especially when important anatomical structures are involved. For these reasons, therapies that preserve organ functionality in combination with effective local tumor control, like electrochemotherapy (ECT), are of great interest. Until few months ago, systemic cetuximab + platinum-based therapy + 5-fluorouracil represented the standard treatment for HNSCC relapses with a median overall survival of 10.1 months and an objective response rate of 36%. Recently the results of KEYNOTE-048 study were published and a new combination of monoclonal antibody named pembrolizumab and chemotherapy emerged as standard first line therapy of recurrent or metastatic tumor that overexpress tissue PDL-1 (Programmed Death 1 ligand). Nevertheless, a variable percentage from 10 to 15% of patients with recurrent/metastatic disease have a tumor that does not overexpress tissue PDL-1, and therefore, according to the results of the KEYNOTE-048 study, does not benefit from replacement of cetuximab with pembrolizumab. These patients will be treated with the "gold standard": cetuximab, cisplatin/carboplatin and 5-fluorouracil. AIM: To verify whether electrochemotherapy performed with bleomycin of HNSCC relapses of the oral cavity and oropharynx (single relapse on T) is able to lead to an increase in the objective response rate in comparison with the systemic treatment with cetuximab + platinum-based therapy + 5-fluorouracil in patients with PDL-1 negative tumors. METHODS: The phase IIb study involves the enrolment of 96 patients who meet the inclusion criteria (48 in the control arm and 48 in the treatment arm). The control arm involves the treatment of HNSCC with systemic treatment (cetuximab + platinum-based therapy + 5-fluorouracil). The treatment arm involves the ECT with bleomycin. The primary objective is to verify the objective response rate of patients in the control arm compared to the treatment arm.