Autophagic flux inhibition enhances cytotoxicity of the receptor tyrosine kinase inhibitor ponatinib

BACKGROUND: Despite reported advances, acquired resistance to tyrosine kinase inhibitors still represents a serious problem in successful cancer treatment. Among this class of drugs, ponatinib (PON) has been shown to have notable long-term efficacy, although its cytotoxicity might be hampered by autophagy. In this study, we examined the likelihood of PON resistance evolution in neuroblastoma and assessed the extent to which autophagy might provide survival advantages to tumor cells.METHODS: The effects of PON in inducing autophagy were determined both in vitro, using SK-N-BE(2), SH-SY5Y, and IMR-32 human neuroblastoma cell lines, and in vivo, using zebrafish and mouse models. Single and combined treatments with chloroquine (CQ)-a blocking agent of lysosomal metabolism and autophagic flux-and PON were conducted, and the effects on cell viability were determined using metabolic and immunohistochemical assays. The activation of the autophagic flux was analyzed through immunoblot and protein arrays, immunofluorescence, and transmission electron microscopy. Combination therapy with PON and CQ was tested in a clinically relevant neuroblastoma mouse model.RESULTS: Our results confirm that, in neuroblastoma cells and wild-type zebrafish embryos, PON induces the accumulation of autophagy vesicles-a sign of autophagy activation. Inhibition of autophagic flux by CQ restores the cytotoxic potential of PON, thus attributing to autophagy a cytoprotective nature. In mice, the use of CQ as adjuvant therapy significantly improves the anti-tumor effects obtained by PON, leading to ulterior reduction of tumor masses.CONCLUSIONS: Together, these findings support the importance of autophagy monitoring in the treatment protocols that foresee PON administration, as this may predict drug resistance acquisition. The findings also establish the potential for combined use of CQ and PON, paving the way for their consideration in upcoming treatment protocols against neuroblastoma

Humanoid Robot Use in Cognitive Rehabilitation of Patients with Severe Brain Injury: A Pilot Study

Severe acquired brain injury (SABI) is a major global public health problem and a source of disability. A major contributor to disability after SABI is limited access to multidisciplinary rehabilitation, despite evidence of sustained functional gains, improved quality of life, increased return to work, and reduced need for long-term care. Twelve patients with a diagnosis of SABI were enrolled and equally divided into two groups: experimental and control. Patients in both groups underwent intensive neurorehabilitation according to the severity of their disabilities (motor, psycho-cognitive, and sensory deficits). However, in the experimental group, the treatment was performed by using a humanoid robot. At baseline, the two groups differed significantly only in Severe Impairment Battery (SIB) scores. Results showed that the experimental treatment had a higher effect than the traditional one on quality of life and mood. In conclusion, this pilot study provides evidence of the possible effects of relational and cognitive stimulation in more severely brain-injured patients

Care models for mental health in a population of patients affected by COVID-19

Objective Emergency psychological interventions are needed in patients with COVID-19. During the pandemic, psychological counseling services have been provided using online platforms to address adverse psychological impacts and symptoms in patients and the general population. We investigated the effects of telepsychotherapy on emotional well-being and psychological distress in patients affected by COVID-19. Methods Forty-five Sicilian patients who had contracted COVID-19 joined "Telecovid Sicilia" from March to June 2020. Participants completed self-assessment questionnaires and psychological testing to measure levels of anxiety, presence of depressive symptoms, and altered circadian rhythm with consequent sleep disorders and psychological distress. Individual telepsychotherapy services were provided for 1 hour, twice a week, for 16 sessions in total. Results We enrolled 45 patients (42.2% women). We found significant changes between baseline and the end of follow-up in all outcome measures, especially depression (chi(2) (1) = 30.1; effect size [ES] = 0.82), anxiety (chi(2) (1) = 37.4; ES = 0.91), and paranoid ideation (chi(2) (1) = 5.6; ES = 0.35). The proportion of participants with sleep disorders decreased to 84.1% after intervention (chi(2) (1) = 58.6; ES = 1.14). Conclusion A telepsychotherapeutic approach showed promising effects on psychological symptoms, with significantly reduced patient anxiety and depression

Cortical Reorganization after Rehabilitation in a Patient with Conduction Aphasia Using High-Density EEG

Conduction aphasia is a language disorder occurred after a left-brain injury. It is characterized by fluent speech production, reading, writing and normal comprehension, while speech repetition is impaired. The aim of this study is to investigate the cortical responses, induced by language activities, in a sub-acute stroke patient affected by conduction aphasia before and after an intensive speech therapy training. The patient was examined by using High-Density Electroencephalogram (HD-EEG) examination, while was performing language tasks. the patient was evaluated at baseline and after two months after rehabilitative treatment. Our results showed that an intensive rehabilitative process, in sub-acute stroke, could be useful for a good outcome of language deficits. HD-EEG results showed that left parieto-temporol-frontal areas were more activated after 2 months of rehabilitation training compared with baseline. Our results provided evidence that an intensive rehabilitation process could contribute to an inter- and intra-hemispheric reorganization

Feasibility, Usability, and Customer Satisfaction of the Tele-COVID19 Project, Sicilian Model

Background and Objectives: In March 2020, COVID-19 pandemic affected the world. All countries, to limit viral transmission, imposed quarantine. This emergency exerted personal, social, economic, and psychological impact on people. For health systems, was needed to create alternative care pathways. Telemedicine can be helpful to reduce isolation, provide health care services, and monitor virus infections. Italian regions, including Sicily, have activated telemedicine services for management of patients with COVID-19. Objective: The purpose of study is to describe a Sicilian telemedicine model for management of COVID-19 patients, showing results on feasibility, usability and quality of service and patient satisfaction. Materials and Methods: This is a descriptive exploratory study on a telemedicine service for residents in Messina infected by COVID-19. It included monitoring of vital signs and specialist consultations (i.e., doctor, psychologists, social workers, and nutritionist biologists). Results: More than twenty percent (23.8%) of participants used tele-monitoring and tele-counselling services; 14.3% were only telemonitored. Participants judged positively telemedicine service (30% were quiet and 50% were very satisfied), as well as tool (70% were quiet and 10% were very satisfied). Telemonitoring had a low agreement (10% were slightly satisfied and 50% were neutral); tele-counselling had a high rate of satisfaction (40% quiet and 60% were very satisfied). Conclusions: This study showed that telemedicine model for Sicilian population affected by COVID-19 was feasible, easy to use and appreciated by patients. Our promising results allow us to assume that if in Sicily there was a return of the emergency, we would be ready to manage it This system can be the solution to remote management of these patients, to reduce isolation, provide health services, and monitor virus infections. The use of this technology should encourage future research to change the health care system and provides opportunities to ensure health and care for oneself and others

Class 1, 2 and 3 BRAF mutated metastatic colorectal cancer: a detailed clinical, pathological and molecular characterization

Purpose BRAF mutations are grouped in activating RAS-independent signaling as monomers (class 1 - V600E) or as dimers (class 2 - codons 597/601), and RAS-dependent with impaired kinase activity (class 3 - codons 594/596). While clinical, pathological and molecular features of V600E BRAF mutated metastatic colorectal cancer (mCRC) are well known, limited data are available from the two other classes. Experimental Design Data from 117 BRAF (92 class 1, 12 class 2, and 13 class 3) mutated mCRC patients were collected. 540 BRAF wt mCRC were included as control. Immunohistochemical profiling was performed to determine the consensus molecular subtypes (CMS), cytokeratins 7/20 profiles, tumor infiltrating lymphocytes (TILs) infiltration and BM1/BM2 categorization. OS and PFS were evaluated by Kaplan-Meier and log-rank test. Results Class 3 BRAF mutated mCRC were more frequently left sided (p=0.0028), pN0 (p=0.0159), and with no peritoneal metastases (p=0.0176) compared to class 1, whereas class 2 cases were similar to class 1. HR for OS, as compared to BRAF wt, was 2.38 (95%CI 1.61-3.54) for class 1, 1.90 (95% CI 0.85-4.26) for class 2 and 0.93 (95% CI 0.51-1.69) for class 3 (p<0.0001). Class 2 and 3 tumors were all assigned to CMS2-3. A higher median CD3/CD8 positive lymphocytes infiltration was observed in BRAF mutated class 2 (p= 0.033) compared to class 3 cases. Conclusions For the first time different clinical, pathological features and outcome data are reported according to the 3 BRAF mutation classes in mCRC. Specific targeted treatment strategies should be identified in the next future for such patients

Clinical nutrition in surgical oncology: Young AIOM-AIRO-SICO multidisciplinary national survey on behalf of NutriOnc research group

Malnutrition is a common condition in cancer patients which is usually associated with functional limitations, as well as increased morbidity and mortality. Based on the support of the young sections of Italian Association of Medical Oncology (AIOM), Italian Association of Radiotherapy and Clinical Oncology (AIRO) and Italian Society of Surgical Oncology (SICO) merged into the NutriOnc Research Group, we performed a multidisciplinary national survey with the aim to define the awareness of nutritional issues among healthcare professionals delivering anticancer care. The questionnaire was organized in four sections, as follows: Knowledge and practices regarding Nutritional Management of cancer patients; Timing of screening and assessment of Nutritional Status; Nutritional Treatment and prescription criteria; Immunonutrition and educational topics. The modules focused on esophagogastric, hepato-bilio-pancreatic and colorectal malignancies. Overall, 215 physicians completed the survey. As regards the management of Nutritional Status of cancer patients, many responders adopted the ERAS program (49.3%), while a consistent number of professionals did not follow a specific validated nutritional care protocol (41.8%), mainly due to lack of educational courses (14.5%) and financial support (15.3%). Nearly all the included institutions had a multidisciplinary team (92%) to finalize the treatment decision-making. Cancer patients routinely underwent nutritional screening according to 57.2% of interviewed physicians. The timing of nutritional assessment was at diagnosis (37.8%), before surgery (25.9%), after surgery (16.7%), before radiochemotherapy (13.5%) and after radiochemotherapy (7%). Most of the responders reported that nutritional status was assessed throughout the duration of cancer treatments (55.6%). An important gap between current delivery and need of nutritional assessment persists. The development of specific and defined care protocols and the adherence to these tools may be the key to improving nutritional support management in clinical practice