Guidelines for the diagnosis and treatment of cutaneous squamous cell carcinoma: a GRADE approach for evidence evaluation and recommendations by the Italian Association of Medical Oncology.

Cutaneous squamous cell carcinoma (CSCC) accounts for ∼20%-25% of all skin tumors. Its precise incidence is often challenging to determine due to limited statistics and its incorporation with mucosal forms. While most cases have a favorable prognosis, challenges arise in patients presenting with locally advanced or metastatic forms, mainly appearing in immunocompromised patients, solid organ transplantation recipients, or those facing social difficulties. Traditionally, chemotherapy and targeted therapy were the mainstays for advanced cases, but recent approvals of immunotherapeutic agents like cemiplimab and pembrolizumab have revolutionized treatment options. These guidelines, developed by the Italian Association of Medical Oncologists (AIOM) using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach, aim to guide clinicians in diagnosing, treating, and monitoring patients with CSCC, covering key aspects from primitive tumors to advanced stages, selected by a panel of experts selected by AIOM and other national scientific societies. The incorporation of these guidelines into clinical practice is expected to enhance patient care and address the evolving landscape of CSCC management.

Guidelines for the diagnosis and treatment of basal cell carcinoma: a GRADE approach for evidence evaluation and recommendations by the Italian Association of Medical Oncology.

Basal cell carcinoma (BCC) is the most common form of cancer, with a high impact on the public health burden and social costs. Despite the overall prognosis for patients with BCC being excellent, if lesions are allowed to progress, or in a small subset of cases harboring an intrinsically aggressive biological behavior, it can result in local spread and significant morbidity, and conventional treatments (surgery and radiotherapy) may be challenging. When a BCC is not amenable to either surgery or radiotherapy with a reasonable curative intent, or when metastatic spread occurs, systemic treatments with Hedgehog inhibitors are available. These guidelines were developed, applying the GRADE approach, on behalf of the Italian Association of Medical Oncologists (AIOM) to assist clinicians in treating patients with BCC. They contain recommendations with regard to the diagnosis, treatment and follow-up, from primitive tumors to those locally advanced or metastatic, addressing the aspects of BCC management considered as priorities by a panel of experts selected by AIOM and other national scientific societies. The use of these guidelines in everyday clinical practice should improve patient care.

Workplace health promotion: results of a combined multidisciplinary intervention over a long period - preliminary results.

OBJECTIVE: Obesity is a multifactorial disease that is one of the major public health problems. It is the result of the interaction between behavioral, social and endocrine-metabolic components. Already in the 80s, it was highlighted by the World Health Organization (WHO) that the workplace is an ideal setting for introducing health promotion programs. The aim of the present study was to implement a health promotion program among healthcare workers (HCWs) operating in an Emergency Hospital in Southern Italy, combining diet, sports activity and motivational support over a 24-month period. PATIENTS AND METHODS: Participants were HCWs operating in an Emergency Hospital in Southern Italy. The inclusion criteria were as follows: overweight or obesity, i.e., body mass index (BMI) >25 kg/m2, or waist circumference >102 cm (males), >88 cm (females); dyslipidemia without pharmacological treatment, i.e., total cholesterol >220 mg/dL, or high-density lipoprotein (HDL) cholesterol <35 mg/dL, or low-density lipoprotein cholesterol (LDL) >130 mg/dL, or triglycerides >200 mg/dL; fasting glucose levels >120 mg/dl and/or reduced tolerance to glucose or diabetes mellitus, without pharmacological treatment was determined through HbA1c. RESULTS: The analysis was conducted on 36 participants. Follow-up was performed after twelve (T12) and twenty-four months (T24). The average systolic blood pressure (SBP) and diastolic blood pressure (DBP) values decreased during the time period. The average BMI of both male and female HCWs was significantly reduced from T0 to T12 and from T0 to T24. The triglyceride levels gradually decreased, but not significantly, from T0 to T24. The average blood glucose values decreased from T0 to T12 and from T12 to T24. The number of subjects who started to perform physical activity increased significantly between T0 and T12 and between T0 and T24. CONCLUSIONS: The findings have led to a significant change in HCWs' lifestyles and body perceptions, as well as their ability to work.

The web of laughter: frontal and limbic projections of the anterior cingulate cortex revealed by cortico-cortical evoked potential from sites eliciting laughter.

According to an evolutionist approach, laughter is a multifaceted behaviour affecting social, emotional, motor and speech functions. Albeit previous studies have suggested that high-frequency electrical stimulation (HF-ES) of the pregenual anterior cingulate cortex (pACC) may induce bursts of laughter-suggesting a crucial contribution of this region to the cortical control of this behaviour-the complex nature of laughter implies that outward connections from the pACC may reach and affect a complex network of frontal and limbic regions. Here, we studied the effective connectivity of the pACC by analysing the cortico-cortical evoked potentials elicited by single-pulse electrical stimulation of pACC sites whose HF-ES elicited laughter in 12 patients. Once these regions were identified, we studied their clinical response to HF-ES, to reveal the specific functional target of pACC representation of laughter. Results reveal that the neural representation of laughter in the pACC interacts with several frontal and limbic regions, including cingulate, orbitofrontal, medial prefrontal and anterior insular regions-involved in interoception, emotion, social reward and motor behaviour. These results offer neuroscientific support to the evolutionist approach to laughter, providing a possible mechanistic explanation of the interplay between this behaviour and emotion regulation, speech production and social interactions. This article is part of the theme issue 'Cracking the laugh code: laughter through the lens of biology, psychology and neuroscience'.

Simultaneous stereo-EEG and high-density scalp EEG recordings to study the effects of intracerebral stimulation parameters.

BACKGROUND: Cortico-cortical evoked potentials (CCEPs) recorded by stereo-electroencephalography (SEEG) are a valuable tool to investigate brain reactivity and effective connectivity. However, invasive recordings are spatially sparse since they depend on clinical needs. This sparsity hampers systematic comparisons across-subjects, the detection of the whole-brain effects of intracortical stimulation, as well as their relationships to the EEG responses evoked by non-invasive stimuli. OBJECTIVE: To demonstrate that CCEPs recorded by high-density electroencephalography (hd-EEG) provide additional information with respect SEEG alone and to provide an open, curated dataset to allow for further exploration of their potential. METHODS: The dataset encompasses SEEG and hd-EEG recordings simultaneously acquired during Single Pulse Electrical Stimulation (SPES) in drug-resistant epileptic patients (N = 36) in whom stimulations were delivered with different physical, geometrical, and topological parameters. Differences in CCEPs were assessed by amplitude, latency, and spectral measures. RESULTS: While invasively and non-invasively recorded CCEPs were generally correlated, differences in pulse duration, angle and stimulated cortical area were better captured by hd-EEG. Further, intracranial stimulation evoked site-specific hd-EEG responses that reproduced the spectral features of EEG responses to transcranial magnetic stimulation (TMS). Notably, SPES, albeit unperceived by subjects, elicited scalp responses that were up to one order of magnitude larger than the responses typically evoked by sensory stimulation in awake humans. CONCLUSIONS: CCEPs can be simultaneously recorded with SEEG and hd-EEG and the latter provides a reliable descriptor of the effects of SPES as well as a common reference to compare the whole-brain effects of intracortical stimulation to those of non-invasive transcranial or sensory stimulations in humans.

Rehabilitation of focal hand dystonia in musicians: a systematic review of the studies. / Rehabilitación de la distonía focal de mano en músicos: una revisión sistemática de los estudios.

INTRODUCTION: Focal hand dystonia in musicians is a task-specific movement disorder characterized by an involuntary loss of control and coordination of finger movements during instrumental playing. MATERIALS AND METHODS: Literature searches with the keywords 'dystonia' AND 'musician' AND 'finger' OR 'treatment' OR 'therapy' OR 'rehabilitation' were conducted in PubMed, EMBASE, Cochrane Library and Web of Science to perform the systematic review about the several strategies used to treat dystonia in musicians. The search was performed independently by two authors (R.C. and M.V.) from 6 April 2020 till 6 June 2020. The research identified a total of 423 articles. Seventy-seven selected articles were analysed by the reviewers. Thirty-six publications met the inclusion criteria and were included in the systematic review. RESULTS: The systematic review was performed to identify the main used treatments for dystonia in musicians. We defined the several techniques to better guide the physician to delineate a rehabilitation protocol adopting the better strategies described in the current literature. CONCLUSION: This systematic review tried to provide to the reader a complete overview of the literature of all possible different treatments for dystonia in musicians. A correct protocol could permit to improve the motor performance and the quality of life of musicians.

TITLE: Rehabilitación de la distonía focal de mano en músicos: una revisión sistemática de los estudios.Introducción. La distonía focal de la mano en los músicos es un trastorno del movimiento relacionado con una tarea específica, que se caracteriza por una pérdida involuntaria del control y la coordinación de los movimientos de los dedos al tocar un instrumento. Materiales y métodos. Se llevaron a cabo búsquedas bibliográficas con las palabras clave 'dystonia' (distonía) Y 'musician' (músico) Y 'finger' (dedo) O 'treatment' (tratamiento) O 'therapy' (terapia) O 'rehabilitation' (rehabilitación) en PubMed, EMBASE, Cochrane Library y Web of Science para realizar la revisión sistemática sobre las diversas estrategias usadas para tratar la distonía en los músicos. La búsqueda se realizó de forma independiente por dos autores (R.C. y M.V.) entre el 6 de abril de 2020 y el 6 de junio del mismo año. La investigación identificó un total de 423 artículos. Los encargados de la revisión analizaron 77 artículos que fueron previamente seleccionados. Treinta y seis publicaciones cumplieron con los criterios de inclusión y se incluyeron en la revisión sistemática. Resultados. La revisión sistemática se realizó para identificar los principales tratamientos utilizados para la distonía en músicos. Se definieron las diversas técnicas existentes para orientar mejor a los médicos a la hora de diseñar un protocolo de rehabilitación que adopte las mejores estrategias descritas en la bibliografía actual. Conclusión. Esta revisión sistemática intenta proporcionar al lector una mirada completa sobre todos los posibles tratamientos diferentes para la distonía en los músicos. Un protocolo correcto podría permitir mejorar el rendimiento motor y la calidad de vida de los músicos.

Rehabilitación de la distonía focal de mano en músicos: una revisión sistemática de los estudios / Rehabilitation of focal hand dystonia in musicians: a systematic review of the studies

Introducción: La distonía focal de la mano en los músicos es un trastorno del movimiento relacionado con una tarea específica, que se caracteriza por una pérdida involuntaria del control y la coordinación de los movimientos de los dedos al tocar un instrumento. Materiales y métodos: Se llevaron a cabo búsquedas bibliográficas con las palabras clave 'dystonia' (distonía) Y 'musician' (músico) Y 'finger' (dedo) O 'treatment' (tratamiento) O 'therapy' (terapia) O 'rehabilitation' (rehabilitación) en PubMed, EMBASE, Cochrane Library y Web of Science para realizar la revisión sistemática sobre las diversas estrategias usadas para tratar la distonía en los músicos. La búsqueda se realizó de forma independiente por dos autores (R.C. y M.V.) entre el 6 de abril de 2020 y el 6 de junio del mismo año. La investigación identificó un total de 423 artículos. Los encargados de la revisión analizaron 77 artículos que fueron previamente seleccionados. Treinta y seis publicaciones cumplieron con los criterios de inclusión y se incluyeron en la revisión sistemática. Resultados: La revisión sistemática se realizó para identificar los principales tratamientos utilizados para la distonía en músicos. Se definieron las diversas técnicas existentes para orientar mejor a los médicos a la hora de diseñar un protocolo de rehabilitación que adopte las mejores estrategias descritas en la bibliografía actual. Conclusión: Esta revisión sistemática intenta proporcionar al lector una mirada completa sobre todos los posibles tratamientos diferentes para la distonía en los músicos. Un protocolo correcto podría permitir mejorar el rendimiento motor y la calidad de vida de los músicos.(AU)

Introduction: Focal hand dystonia in musicians is a task-specific movement disorder characterized by an involuntary loss of control and coordination of finger movements during instrumental playing. Materials and methods: Literature searches with the keywords ‘dystonia’ AND ‘musician’ AND ‘finger’ OR ‘treatment’ OR ‘therapy’ OR ‘rehabilitation’ were conducted in PubMed, EMBASE, Cochrane Library and Web of Science to perform the systematic review about the several strategies used to treat dystonia in musicians. The search was performed independently by two authors (R.C. and M.V.) from 6 April 2020 till 6 June 2020. The research identified a total of 423 articles. Seventy-seven selected articles were analysed by the reviewers. Thirty-six publications met the inclusion criteria and were included in the systematic review. Results: The systematic review was performed to identify the main used treatments for dystonia in musicians. We defined the several techniques to better guide the physician to delineate a rehabilitation protocol adopting the better strategies described in the current literature. Conclusion: This systematic review tried to provide to the reader a complete overview of the literature of all possible different treatments for dystonia in musicians. A correct protocol could permit to improve the motor performance and the quality of life of musicians.(AU)

Immune checkpoint inhibitor associated vitiligo and its impact on survival in patients with metastatic melanoma: an Italian Melanoma Intergroup study.

BACKGROUND: Checkpoint inhibitors in melanoma can lead to self-immune side-effects such as vitiligo-like depigmentation (VLD). Beyond the reported association with favorable prognosis, there are limited data regarding VLD patient features and their echo on the therapeutic outcomes. METHODS: To assess the association between VLD and a series of clinical and biological features as well as therapeutic outcomes, we built an observational cohort study by recruiting patients who developed VLD during checkpoint inhibitors. RESULTS: A total of 148 patients from 15 centers (101 men, median age 66 years, BRAF mutated 23%, M1c 42%, Eastern Cooperative Oncology Group (ECOG) status 0/1 99%, normal lactate dehydrogenase 74%) were enrolled. VLD was induced by ipilimumab, programmed cell death-1 (PD-1) inhibitors, and their combination in 32%, 56%, and 12%, respectively. The median onset was 26 weeks and it was associated with other skin and nonskin toxicities in 27% and 28%, respectively. After 3 years of VLD onset, 52% (95% confidence interval 39% to 63%) were progression free and 82% (95% confidence interval 70% to 89%) were still alive. The overall response rate was 73% with 26% complete response. Univariable analysis indicated that BRAF V600 mutation was associated with a better overall survival (P = 0.028), while in multivariable analysis a longer progression-free survival was associated with BRAF V600 (P = 0.093), female sex (P = 0.008), and M stage other than 1a (P = 0.024). When VLD occurred, there was a significant decrease of white blood cell (WBC) count (P = 0.05) and derived WBC-to-lymphocytes ratio (dWLR; P = 0.003). A lower monocyte count (P = 0.02) and dWLR (P = 0.01) were also reported in responder patients. CONCLUSIONS: Among VLD population, some features might help to identify patients with an effective response to immunotherapy, allowing clinicians to make more appropriate choices in terms of therapeutic options and duration.

Anticancer innovative therapy: Highlights from the ninth annual meeting.

The Ninth Annual Conference of "Anticancer Innovative Therapy", organized by Fondazione IRCCS Istituto Nazionale dei Tumori di Milano (Fondazione IRCCS INT) and hosted by Hotel Michelangelo, was held in Milan on 25 January 2019. Cutting-edge science was presented in two main scientific sessions: i) pre-clinical evidences and new targets, and ii) clinical translation. The Keynote lecture entitled "Cancer stem cells (CSCs): metabolic strategies for their identification and eradication" presented by M. Lisanti, was one of the highlights of the conference. One key concept of the meeting was how the continuous advances in our knowledge about molecular mechanisms in various fields of research (cancer metabolism reprogramming, epigenetic regulation, transformation/invasiveness, and immunology, among others) are driving cancer research towards more effective personalized antineoplastic strategies. Specifically, recent preclinical data on the following topics were discussed: 1. Polycomb group proteins in cancer; 2. A d16HER2 splice variant is a flag of HER2 addiction across HER2-positive cancers; 3. Studying chromatin as a nexus between translational and basic research; 4. Metabolomic analysis in cancer patients; 5. CDK4-6 cyclin inhibitors: clinical activity and future perspectives as immunotherapy adjuvant; and 6. Cancer stem cells (CSCs): metabolic strategies for their identification and eradication. In terms of clinical translation, several novel approaches were presented: 1. Developing CAR-T cell therapies: an update of preclinical and clinical development at University of North Carolina; 2. Vγ9Vδ2 T-cell activation and immune suppression in multiple myeloma; 3. Predictive biomarkers for real-world immunotherapy: the cancer immunogram model in the clinical arena; and 4. Mechanisms of resistance to immune checkpoint blockade in solid tumors. Overall, the pre-clinical and clinical findings presented could pave the way to identify novel actionable therapeutic targets to significantly enhance the care of persons with cancer.

ENT involvement and orobuccal movements' disorders in Pandas patients: assessment and rehabilitations tools.

OBJECTIVE: PANDAS are known as the spectrum of autoimmune pathologies related to a previous or current infection by group A beta-hemolytic streptococcus (SBEGA), dealing with several neuropsychiatric manifestations that mainly affect pediatric age. The main features consist of behavioral disease or movement disease characterized by acute-onset, presenting especially through infant period or adolescence. Specific manifestations, occurring during the progression of the disease, are the presence of otorhinolaryngologic symptoms (ENT) and orofacial movement disorders associated with temporomandibular joint pain. PATIENTS AND METHODS: We enrolled 130 children (5-15 years) with a clinical diagnosis of PANDAS between 2012 and 2018. Participants were assessed using ENT specific parameters, PSG to examine respiratory disorders and conventional audiological evaluation. Descriptive and comparative statistical analyses were performed with a control group of 51 healthy patients. RESULTS: The prevalence of ENT symptoms associated was significantly detected in 88 patients of 130 in Group A (relative frequency (%) 67.6; p=0.041) and in 51 patients of 130 in the control Group B (relative frequency (%) 39.2; p=0.063). In relation to prevalence of SDB, 54 subjects have presented nocturnal respiratory obstructive symptoms from mild to severe (relative frequency (%) 61.3; p=0.033) vs. 20 patients of Group B (relative frequency (%) 39.2; p=0.055). The obstructive severity average type was correlated to the consensual adenotonsillar development (size 3-4), (relative frequency (%) 45.4; p=0.047). The audiological deficits found were mostly of transmissive type with OME correlated and linked to the presence of occasional episodes of AOM. The four PANDAS patients who presented orobuccal dystonia (relative frequency (%) 4.54; p=0.091) achieved an improvement of the algic symptoms through the exercises of self-rehabilitation. CONCLUSIONS: Findings from our study show that respiratory diseases, characterizing a group of patients with pandas, are the direct consequences of the malformed or hypertrophic condition and suggesting in these conditions surgical therapy as an approaching tool.

Innovative therapy, monoclonal antibodies, and beyond: Highlights from the eighth annual meeting.

The eighth annual conference of "Innovative therapy, monoclonal antibodies, and beyond" was held in Milan on Jan. 26, 2018, and hosted by Fondazione IRCCS-Istituto Nazionale dei Tumori (Fondazione IRCCS INT). The conference was divided into two main scientific sessions, of i) pre-clinical assays and novel biotargets, and ii) clinical translation, as well as a third session of presentations from young investigators, which focused on recent achievements within Fondazione IRCCS INT on immunotherapy and targeted therapies. Presentations in the first session addressed the issue of cancer immunotherapy activity with respect to tumor heterogeneity, with key topics addressing: 1) tumor heterogeneity and targeted therapy, with the definition of the evolutionary Index as an indicator of tumor heterogeneity in both space and time; 2) the analysis of cancer evolution, with the introduction of the TRACERx Consortium-a multi-million pound UK research project focused on non-small cell lung cancer (NSCLC); 3) the use of anti-estrogen agents to boost immune recognition of breast cancer cells; and 4) the high degree of functional plasticity within the NK cell repertoire, including the expansion of adaptive NK cells following viral challenges. The second session addressed: 1) the effectiveness of radiotherapy to enhance the proportion of patients responsive to immune-checkpoint blockers (ICBs); 2) the use of MDSC scores in selecting melanoma patients with high probability to be responsive to ICBs; and 3) the relevance of the gut microbiome as a predictive factor, and the potential of its perturbation in increasing the immune response rate to ICBs. Overall, a picture emerged of tumor heterogeneity as the main limitation that impairs the effectiveness of anti-cancer therapies. Thus, the choice of a specific therapy based on reproducible and selective predictive biomarkers is an urgent unmet clinical need that should be addressed in order to increase the proportion of long-term responding patients and to improve the sustainability of novel drugs.

Innovative Therapy, Monoclonal Antibodies and Beyond.

The seventh Edition of "Innovative Therapy, Monoclonal Antibodies and Beyond" Meeting took place in Milan, Italy, on January 27, 2017. The two sessions of the meeting were focused on: 1) Preclinical assays and novel biotargets; and 2) monoclonal antibodies, cell therapies and targeted molecules. Between these two sessions, a lecture entitled "HLA-antigens modulation and response to immune checkpoint inhibitor immunotherapy" was also presented. Despite the impressive successes in cancer immunotherapy in recent years, the response to immune based interventions occurs only in a minority of patients (∼20%). Several basic and translational mechanisms of resistance to immune checkpoint blockers (ICBs) were discussed during the meeting: 1. the impact of tumor microenvironment on the activity of immune system; 2. strategies to inhibit the cross-talk between extracellular matrix and myeloid-derived suppressor cells (MDSC) in the preclinical setting; 3. microRNA expression as a biomarker and as a target of therapy in non-small cell lung cancer (NSCLC); 4. the significance of complement activation pathways in response to immune checkpoint inhibitors; 5. the immunosuppressive activity of the microbiota by inducing IL-17 producing cells; and 6. modulation of HLA antigens as possible markers of response to ICB therapy. In order to overcome the deficiency in active anti-tumor T cells, several clinically applicable combination strategies were also discussed: 1. strategies to enhance the anticancer effects of immunogenic cell death inducing-chemotherapy; 2. the use of CAR T-cells in solid tumors; 3. the use of combination strategies involving oncolytic viruses and ICBs; 4. combinations of new ICBs with anti-PD-1/CTLA-4 therapy; and 4. combinations of targeted therapies and ICBs in melanoma. Overall, this conference emphasized the many novel strategies that are being investigated to improve the overall patient response to cancer immunotherapy. Optimization of biomarkers to accurately select patients who will respond to immunotherapy, coupled with combination strategies to improve long term patient survival remain critical challenges in the immuno-oncology field.

An outbreak of Clostridium difficile PCR ribotype 027 in Spain: risk factors for recurrence and a novel treatment strategy.

An outbreak of Clostridium difficile infection (CDI) caused by ribotype 027 (B1/NAP1) began in our hospital in November 2014, and produced 141 episodes in the following months. The aim of this study is to describe this outbreak, assess risk factors for recurrence of CDI-027 and to analyze the implementation of a novel treatment strategy. This is a prospective study of all patients with CDI-027, from November 2014 to November 2015. The epidemiological data were collected daily for each patient. We compared clinical characteristics and treatment between patients with and without recurrence of CDI-027. Interestingly, liver cirrhosis was present in 22% of the patients, and most of them received prophylaxis for hepatic encephalopathy with rifaximin. Patients were also taking antimicrobial drugs (93.6%) and proton pump inhibitors (80.1%). Overall, 27 (23.5%) patients had a first recurrence of CDI-027. Liver cirrhosis increased the risk of recurrence (44.4% vs 14.8%). Patients treated with a prolonged oral vancomycin regimen vs the conventional regimen (oral metronidazole or 10 days of vancomycin) had fewer recurrences (8.6 versus 44.7% [p ≤ 0.01]; OR, 0.91; 95% CI, 0.028-0.294) and less attributable mortality (0% versus 7.1%; p = 0.058). We report an outbreak of CDI-027, mainly in patients with liver cirrhosis. Recurrence of CDI-027 was more common in those patients. A novel approach involving high-dose prolonged vancomycin taper as a first-line treatment, together with a bundle of outbreak measures, seemed to reduce the number of cases of CDI-027, recurrences, and attributable mortality. Nevertheless, this approach warrants further investigation.

Criterion values for urine-specific gravity and urine color representing adequate water intake in healthy adults.

Growing evidence suggests a distinction between water intake necessary for maintaining a euhydrated state, and water intake considered to be adequate from a perspective of long-term health. Previously, we have proposed that maintaining a 24-h urine osmolality (UOsm) of ⩽500 mOsm/kg is a desirable target for urine concentration to ensure sufficient urinary output to reduce renal health risk and circulating vasopressin. In clinical practice and field monitoring, the measurement of UOsm is not practical. In this analysis, we calculate criterion values for urine-specific gravity (USG) and urine color (UCol), two measures which have broad applicability in clinical and field settings. A receiver operating characteristic curve analysis performed on 817 urine samples demonstrates that a USG ⩾1.013 detects UOsm>500 mOsm/kg with very high accuracy (AUC 0.984), whereas a subject-assessed UCol⩾4 offers high sensitivity and moderate specificity (AUC 0.831) for detecting UOsm >500 m Osm/kg.

Radiotherapy and immunotherapy: Can this combination change the prognosis of patients with melanoma brain metastases?

Brain metastases are a common occurrence in patients with melanoma. Prognosis is poor. Radiotherapy is the main local treatment for brain metastases. Recently, immunotherapy (i.e. immune checkpoints inhibitors) showed a significant impact on the prognosis of patients with metastatic melanoma, also in the setting of patients with brain metastases. Despite various possible treatments, survival of patients with melanoma brain metastases is still unsatisfactory; new treatment modalities or combination of therapies need to be explored. Being immunotherapy and radiotherapy alone both efficient in the treatment of melanoma brain metastases, the combination of these two therapies seems logical. Moreover radiotherapy can improve the efficacy of immunotherapy and the immune system plays a relevant role in the action of radiotherapy. Preclinical data support this combination. Clinical data are more contradictory. In this review, we will discuss available therapies for melanoma brain metastases, focusing on the preclinical and clinical available data supporting the possible synergism between radiotherapy and immunotherapy.

Baseline neutrophils and derived neutrophil-to-lymphocyte ratio: prognostic relevance in metastatic melanoma patients receiving ipilimumab.

BACKGROUND: Clinical responses to ipilimumab are variable in terms of onset, magnitude and duration. Upfront identification of patients who are more likely or unlikely to benefit from treatment is a major need. PATIENTS AND METHODS: Prospectively collected data from 720 advanced melanoma patients treated with ipilimumab 3 mg/kg within the Italian expanded access program were analyzed. The derived neutrophil-to-lymphocyte ratio (dNLR) was calculated from baseline peripheral blood cell counts, and receiver operating characteristic curve was used to evaluate the best cutoff for this marker. Patients were stratified according to dichotomized baseline absolute neutrophil counts (ANC), dNLR and their combination. The prognostic values of ANC and dNLR for survival were assessed using multivariate Cox proportional hazard models. A subgroup analysis including LDH in the models was also carried out. RESULTS: The median follow-up was 16.5 months. The optimal cutoff for dNLR was 3. Baseline ANC and dNLR were significantly associated with the outcome of ipilimumab-treated melanoma patients, in terms of disease progression and death (P < 0.0001 for all). Furthermore, for each elevated variable, prognosis worsened. Patients with both ANC ≥ 7500 and dNLR ≥ 3 had a significantly and independently increased risk of death [hazard ratio(HR) = 5.76; 95% confidence interval (CI) 4.29-7.75] and of progression (HR = 4.10; 95% CI 3.08-5.46) compared with patients with both lower ANC and dNLR. Patients with one of the two factors elevated displayed an intermediate risk of progression and death. The 1- and 2-year survival rates were 2% and 0%, respectively, for patients with ANC ≥ 7500 and dNLR ≥ 3, and 43% and 24%, respectively, for patients with both lower ANC and dNLR. CONCLUSIONS: Although these findings need to be confirmed and validated, we suggest that a neutrophil-based index may help risk-group stratification and assist disease-management strategies. Furthermore, the potential predictive value of this index for response to ipilimumab should be investigated in randomized clinical trials.

Parasympathetic nervous system involvement in food allergy: description of a paediatric case.

The latest research data emphasize the interaction between the nervous and the immune systems. It has been demonstrated that the central nervous system (CNS) can be involved secondarily due to blood brain barrier (BBB) disruption via pro-inflammatory cytokines released in allergy. More recently it was demonstrated that the parasympathetic nervous system (PNS) could also be equally involved in models of peripheral inflammation such as food allergy; although this last clinical presentation has rarely been described. Herein, the authors report the case of a five-year-old Caucasian female who was admitted to our Pediatric Acute and Emergency Operative Unit for cyclic vomiting. Her vomiting, which was preceded by objective torque vertigo, headache and weakness, had been recurring with constant frequency every two months since she was 3 years old. After a complex diagnostic flow-chart, it was found that this spectrum of neurologic symptoms was due to a food allergy syndrome, which postulates some etiopathogenic hypotheses to explain the relationship between the two mentioned diseases.

Congenital muscular dystrophy and epilepsy: a prospective case series of pediatric patients.

Congenital Muscular Dystrophies (CMDs) can be considered as a heterogeneous group of diseases characterized by marked weakness, generalized hypotonia and joint contractures. They are divided into pure and classical forms, without ocular and cerebral involvement, and complex forms, which are associated with cerebral abnormalities. Seizures have rarely been described in the pure forms while they seem to occur more frequently in complex forms. The aim of our study was to evaluate the incidence of seizure in CMD. Herein, the authors describe 16 cases of congenital muscular dystrophy (CMD) associated with different kinds of epileptic events, in order to study the pathogenic connection between the two clinical manifestations. In all described patients we reviewed the clinical, neurophysiologic, and neuroimaging data to determine any associations with epilepsy. The patients were divided into two groups: 14 cases with merosin positive CMD in one group and 2 patients with Walker Warburg syndrome (WWS) in the second group. In our study we found that in the first group, one benign myoclonic epilepsy (BME), one benign febrile convulsions had occurred. Also in one patient, the EEG revealed a moderately high voltage slow background with diffuse sharp waves reaching 300mV in amplitude with no clinical signs. In the merosin positive CMD patients, the presence of two different epileptic diseases, benign myoclonic epilepsy (BME) in one and febrile convulsion with tonic clinic seizures, may represent a new expression of merosine-positive congenital muscular disease (PCMD) in which the deficiency of an undiscovered muscular protein with a cerebral isoform may be the cause of epileptic events in this group of patients.