Outcomes of a 3-Year Prospective Surveillance in Individuals at High Risk of Pancreatic Cancer.

INTRODUCTION: Pancreatic cancer (PC) surveillance of high-risk individuals (HRI) is becoming more common worldwide, aiming at anticipating PC diagnosis at a preclinical stage. In 2015, the Italian Registry of Families at Risk of Pancreatic Cancer was created. We aimed to assess the prevalence and incidence of pancreatic findings, oncological outcomes, and harms 7 years after the Italian Registry of Families at Risk of Pancreatic Cancer inception, focusing on individuals with at least a 3-year follow-up or developing events before. METHODS: HRI (subjects with a family history or mutation carriers with/without a family history were enrolled in 18 centers). They underwent annual magnetic resonance with cholangiopancreatography or endoscopic ultrasound (NCT04095195). RESULTS: During the study period (June 2015-September 2022), 679 individuals were enrolled. Of these, 524 (77.2%) underwent at least baseline imaging, and 156 (29.8%) with at least a 3-year follow-up or pancreatic malignancy/premalignancy-related events, and represented the study population. The median age was 51 (interquartile range 16) years. Familial PC cases accounted for 81.4% of HRI and individuals with pathogenic variant for 18.6%. Malignant (n = 8) and premalignant (1 PanIN3) lesions were found in 9 individuals. Five of these 8 cases occurred in pathogenic variant carriers, 4 in familial PC cases (2 tested negative at germline testing and 2 others were not tested). Three of the 8 PC were stage I. Five of the 8 PC were resectable, 3 Stage I, all advanced cases being prevalent. The 1-, 2-, and 3-year cumulative hazard of PC was 1.7%, 2.5%, and 3%, respectively. Median overall and disease-free survival of patients with resected PC were 18 and 12 months (95% CI not computable). Considering HRI who underwent baseline imaging, 6 pancreatic neuroendocrine neoplasms (1 resected) and 1 low-yield surgery (low-grade mixed-intraductal papillary mucinous neoplasm) were also reported. DISCUSSION: PC surveillance in a fully public health care system is feasible and safe, and leads to early PC or premalignant lesions diagnoses, mostly at baseline but also over time.

A Novel FLCN Variant in a Suspected Birt-Hogg-Dubè Syndrome Patient.

Subjects with pathogenic (PV) and likely pathogenic (LPV) FLCN variants have an increased risk of manifesting benign and malignant disorders that are related to Birt-Hogg-Dubé syndrome (BHDS): an autosomal dominantly inherited disorder whose severity can vary significantly. Renal cell carcinoma (RCC) development in BHD (Birt-Hogg-Dubé) patients has a very high incidence; thus, identifying this rare syndrome at early stages and preventing metastatic spread is crucial. Over the last decade, the advancement of Next Generation Sequencing (NGS) and the implementation of multigene panels for hereditary cancer syndromes (HCS) have led to a subsequent focus on additional genes and variants, including those of uncertain significance (VUS). Here, we describe a novel FLCN variant observed in a subject manifesting disorders that were suspected to be related to BHDS and with a family history of multiple cancers.

Clinical Impact of Next-Generation Sequencing Multi-Gene Panel Highlighting the Landscape of Germline Alterations in Ovarian Cancer Patients.

BRCA1 and BRCA2 are the most frequently mutated genes in ovarian cancer (OC) crucial both for the identification of cancer predisposition and therapeutic choices. However, germline variants in other genes could be involved in OC susceptibility. We characterized OC patients to detect mutations in genes other than BRCA1/2 that could be associated with a high risk of developing OC and permit patients to enter the most appropriate treatment and surveillance program. Next-generation sequencing analysis with a 94-gene panel was performed on germline DNA of 219 OC patients. We identified 34 pathogenic/likely pathogenic variants in BRCA1/2 and 38 in other 21 genes. The patients with pathogenic/likely pathogenic variants in the non-BRCA1/2 genes mainly developed OC alone compared to the other groups that also developed breast cancer or other tumors (p = 0.001). Clinical correlation analysis showed that the low-risk patients were significantly associated with platinum sensitivity (p < 0.001). Regarding PARP inhibitors (PARPi) response, the patients with pathogenic mutations in the non-BRCA1/2 genes had worse PFS and OS. Moreover, a statistically significantly worse PFS was found for every increase of one thousand platelets before PARPi treatment. To conclude, knowledge about molecular alterations in genes beyond BRCA1/2 in OC could allow for more personalized diagnostic, predictive, prognostic, and therapeutic strategies for OC patients.

Comprehensive analysis of DNA damage repair genes reveals pathogenic variants beyond BRCA and suggests the need for extensive genetic testing in pancreatic cancer.

BACKGROUND: Pancreatic cancer (PC) is a major cause of cancer death. In an effort to improve treatment strategies and outcomes, DNA damage repair (DDR) pathways have been introduced as a new target in PC and in other cancers, through the exploitation of synthetic lethality. Furthermore, genes involved in DDR are among the major determinants of cancer susceptibility. In addition to the well-known BRCA1 and BRCA2 genes, a plethora of other targets in the same pathways are now emerging. METHODS: We analyzed samples from 60 patients, affected by PC and already tested for BRCA, using a panel with 24 other cancer susceptibility genes. RESULTS: We detected 8 pathogenic or likely pathogenic mutations (13.3% of samples analyzed), 4 of which were found in non-BRCA genes (2 in ATM, 1 each in PALB2 and RAD50). Furthermore, 4 pathogenic or likely pathogenic mutations were found in patients without a personal or familial history of cancer. CONCLUSIONS: Our results suggest that genetic testing with a comprehensive gene panel should be perfomed in all patients with PC, in order to allow screening for PC and other gene-related cancers in all at risk family members and to assess patients' eligibility for emerging therapeutic options.

Sharing real-world experiences to optimize the management of olaparib toxicities: a practical guidance from an Italian expert panel.

Olaparib is the first poly(ADP-ribose) polymerase inhibitor approved as maintenance therapy of recurrent ovarian cancer (OC) patients with a BRCA mutation. To achieve the maximum clinical benefit, adherence to olaparib must be persistent. However, in clinical practice, this is challenged by the frequent suboptimal management of toxicities. In view of the expanding use of olaparib also in Italy, physicians must learn how to adequately and promptly manage drug toxicities not to unnecessarily interrupt or reduce the dose. The experts agreed that nausea,vomiting, anemia, and fatigue are the most frequent events experienced by OC patients on olaparib, and that these toxicities usually develop early during treatment, are mainly of grade 1-2 and transient and can be managed with simple non-pharmacological interventions. By sharing their real-world experiences, the panel prepared, for each toxicity, an algorithm organized by grade and besides the procedures indicated in the local label, included supportive care interventions based also on nutritional and lifestyle modifications and psycho-oncology consultation. Moreover, in view of the tablet entry into the Italian market, the full and reduced dosages of capsules and tablets were compared. This practical guidance is intended to be a tool to support especially less-experienced physicians in the management of these complex patients, with the aim to help preventing the worsening of patients' conditions and the unnecessary interruption/reduction of olaparib dosage, which may jeopardize treatment efficacy.

Surgical Efforts Might Mitigate Difference in Response to Neoadjuvant Chemotherapy in Stage IIIC-IV Unresectable Ovarian Cancer: A Case-Control Multi-institutional Study.

OBJECTIVE: The aim of the study was to evaluate outcomes of patients with unresectable advanced ovarian cancer experiencing complete response (CR) to neoadjuvant chemotherapy. METHODS: Data of consecutive patients undergoing neoadjuvant chemotherapy plus interval debulking surgery (IDS) were retrospectively reviewed in 4 Italian centers. Using a propensity-matching algorithm, we compared data of patients achieving CR with neoadjuvant chemotherapy (no macroscopic either microscopic residual disease (RD) at the time of IDS) with patients achieving partial response (PR). This latter group was stratified by the presence of RD (RD = 0 vs RD > 0). RESULTS: Overall, 193 had IDS after neoadjuvant chemotherapy: 25 (13%), 81 (41.9%), and 74 (38.3%) patients had CR, PR with RD of 0, and PR with RD of more than 0, respectively. In addition, 13 (6.7%) patients had no macroscopic disease detected at DS but just microscopic disease at pathological examination. For the study purpose, 25 patients achieving CR were matched (1:2) with 50 patients having PR and RD of 0 and 50 patients having PR and RD of more than 0. As the result of propensity matching, baseline characteristics were similar between groups. Comparing survival outcomes of patients having CR and PR with RD of 0, we observed that type of response to chemotherapy did not influence disease-free (hazard ratio = 1.53 [95% confidence interval = 0.88-2.66], P = 0.127) and overall (hazard ratio = 1.74 [95% confidence interval = 0.76-4.01], P = 0.189) survivals. Patients achieving CR experienced significantly better disease-free survival (P = 0.004) and a trend toward better overall survival (P = 0.06) than patients achieving PR with RD of more than 0 at IDS. CONCLUSIONS: Complete cytoreduction might mitigate the difference in response to neoadjuvant chemotherapy. The presence of RD at IDS is associated with worse survival outcomes.

The Impact of Number of Cycles of Neoadjuvant Chemotherapy on Survival of Patients Undergoing Interval Debulking Surgery for Stage IIIC-IV Unresectable Ovarian Cancer: Results From a Multi-Institutional Study.

OBJECTIVES: Neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) may be a valuable treatment option in advanced ovarian cancer when primary cytoreduction is not feasible. However, a consensus on the ideal number of NACT cycles is still lacking. In the present investigation, we aimed to evaluate how number of cycles of NACT influenced patients' outcomes. METHODS: Data of consecutive patients undergoing NACT and IDS were retrospectively reviewed in 4 Italian centers, and survival outcomes were evaluated. RESULTS: Overall, 193 patients were included. Cycles of NACT were 3, 4, and at least 5 in 77 (40%), 74 (38%), and 43 (22%) patients, respectively. Patients undergoing 3 cycles experienced a similar disease-free survival (hazard ratio [HR], 1.12; 95% confidence interval [CI], 0.89-1.65; P = 0.20) but an improved overall survival (HR, 1.64; 95% CI, 1.05-2.4; P = 0.02) in comparison to patients receiving at least 4 cycles. Five-year overall survival was 46% and 31% for patients having 3 and at least 4 cycles. Ten-year overall survival was 26% and 18% for patients having 3 and at least 4 cycles (HR, 1.70; 95% CI, 1.13-2.55; P = 0.009). Using multivariate analysis, we observed that only Eastern Cooperative Oncology Group performance status correlated with overall survival (HR, 1.76; 95% CI, 1.2-2.49; P = 0.001). In addition, a trend toward worse overall survival was observed for patients with residual disease at IDS (HR, 1.29; 95% CI, 0.98-1.70; P = 0.06) and patients receiving at least 4 cycles (HR, 1.76; 95% CI, 0.95-3.22; P = 0.06). CONCLUSION: Our data underline the potential implication of number of cycles of NACT before IDS. Further prospective studies are warranted to assess this correlation.

Pazopanib plus weekly paclitaxel versus weekly paclitaxel alone for platinum-resistant or platinum-refractory advanced ovarian cancer (MITO 11): a randomised, open-label, phase 2 trial.

BACKGROUND: Inhibition of angiogenesis is a valuable treatment strategy for ovarian cancer. Pazopanib is an anti-angiogenic drug active in ovarian cancer. We assessed the effect of adding pazopanib to paclitaxel for patients with platinum-resistant or platinum-refractory advanced ovarian cancer. METHODS: We did this open-label, randomised phase 2 trial at 11 hospitals in Italy. We included patients with platinum-resistant or platinum-refractory ovarian cancer previously treated with a maximum of two lines of chemotherapy, Eastern Cooperative Oncology Group performance status 0-1, and no residual peripheral neurotoxicity. Patients were randomly assigned (1:1) to receive weekly paclitaxel 80 mg/m(2) with or without pazopanib 800 mg daily, and stratified by centre, number of previous lines of chemotherapy, and platinum-free interval status. The primary endpoint was progression-free survival, assessed in the modified intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01644825. This report is the final analysis; the trial is completed. FINDINGS: Between Dec 15, 2010, and Feb 8, 2013, we enrolled 74 patients: 37 were randomly assigned to receive paclitaxel and pazopanib and 37 were randomly assigned to receive paclitaxel only. One patient, in the paclitaxel only group, withdrew from the study and was excluded from analyses. Median follow-up was 16·1 months (IQR 12·5-20·8). Progression-free survival was significantly longer in the pazopanib plus paclitaxel group than in the paclitaxel only group (median 6·35 months [95% CI 5·36-11·02] vs 3·49 months [2·01-5·66]; hazard ratio 0·42 [95% CI 0·25-0·69]; p=0·0002). We recorded no unexpected toxic effects or deaths from toxic effects. Adverse events were more common in the pazopanib and paclitaxel group than in the paclitaxel only group. The most common grade 3-4 adverse events were neutropenia (11 [30%] in the pazopanib group vs one [3%] in the paclitaxel group), fatigue (four [11%] vs two [6%]), leucopenia (four [11%] vs one [3%]), hypertension (three [8%] vs none [0%]), raised aspartate aminotransferase or alanine aminotransferase (three [8%] vs none), and anaemia (two [5%] vs five [14%]). One patient in the pazopanib group had ileal perforation. INTERPRETATION: Our findings suggest that a phase 3 study of the combination of weekly paclitaxel plus pazopanib for patients with platinum-resistant or platinum-refractory advanced ovarian cancer is warranted. FUNDING: National Cancer Institute of Napoli and GlaxoSmithKline.

Psychological factors and barriers to donating and receiving milk from human milk banks: A review.

Human milk banks (HMBs), established in the early 20th century, aimed to provide safe breast milk for infants with challenges obtaining it. The spread of infections since the 1980s resulted in strict regulations and screening in HMBs, to ensure the safety of donated milk. Several social and personal factors discourage mothers from practicing breastfeeding, making donated milk a viable alternative because of its protective and immunity-enhancing properties. However, psychological barriers can affect the decision to donate or receive donated milk. To identify psychological factors related to donating and receiving human milk from HMBs, we searched PubMed to identify studies reporting psychological factors in donating and receiving milk and excluding studies not reporting psychological factors. The search identified 28 articles meeting the inclusion criteria. Eligible studies from various countries spanned from 1995 to 2023 and focused on psychological factors influencing milk donation and receiving. Most studies were descriptive-qualitative. Factors facilitating or hindering milk donation and reception included perceptions, psychological aspects, and previous experiences. Positive factors for donors included the desire to help other mothers, support from health care professionals, and personal well-being. Negative factors included breast milk exclusivity and discomfort caused by health checks. For recipients, awareness of donated milk benefits was a positive factor, whereas fear regarding safety was negative. The altruistic motivation to help other mothers drove many women to donate. Proper awareness and support from health care professionals and families can help women understand the value of milk donation and support their personal and identity reintegration, especially in cases of the loss of a child.

The Relationship between Language and Technology: How Screen Time Affects Language Development in Early Life-A Systematic Review.

Screen time refers to the amount of time a child is exposed to a screen, that is, television, computer, smartphone, or any other digital medium. Prolonged screen time in the first years of life may affect a child's cognitive abilities, especially language acquisition. A systematic review was conducted, following the PRISMA-P guidelines, with the aim to explore the available literature relating to the impact of screen time on children's language development. This review identified 18 articles. The articles reviewed showed that prolonged screen time and exposure to screens in the first 2 years of life can negatively affect language development and communication skills, in terms of comprehension and vocabulary range. In addition, overexposure to screens in the early years can affect overall cognitive development, especially attention to environmental stimuli, social experiences, problem solving, and communication with others, e.g., the alternance of rhythms and roles in a conversation. In conclusion, our systematic review supports the idea that preschool screen time has negative effects on children's cognitive and language development. Television seems to be the medium most detrimental to children's skills, as it is used in a passive manner and is often characterised by language and content that do not suit the child's processing mode. Future studies should increasingly focus on the digital media that children possess at an early age, such as mobile phones and tablets, and on how children relate to the online world, such as social networks.

Case report: Post-COVID new-onset neurocognitive decline with bilateral mesial-temporal hypometabolism in two previously healthy sisters.

Background: Long coronavirus disease (COVID) is increasingly recognized in adults and children; however, it is still poorly characterized from a clinical and diagnostic perspective, particularly in the younger populations. Case presentation: We described the story of two sisters-with high social and academic performance before their severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-who reported severe neurocognitive problems, initially classified as psychologic pandemic distress and eventually found to have significant brain hypometabolism. Conclusions: We provided a detailed clinical presentation of neurocognitive symptoms in two sisters with long COVID associated with brain hypometabolism documented in both sisters. We believe that the evidence of objective findings in these children further supports the hypothesis that organic events cause persisting symptoms in a cohort of children after SARS-CoV-2 infection. Such findings highlight the importance of discovering diagnostics and therapeutics.

Eye Movement Desensitization and Reprocessing (EMDR) as a Possible Evidence-Based Rehabilitation Treatment Option for a Patient with ADHD and History of Adverse Childhood Experiences: A Case Report Study.

BACKGROUND: Children with Attention Deficit Hyperactivity Disorder (ADHD) having a history of adverse childhood experiences (ACEs) could be very difficult to treat with standard psychotherapeutic approaches. Some children diagnosed with ADHD may have Post-Traumatic Stress Disorder (PTSD) or have had experienced a significant traumatic event. Trauma and PTSD could exacerbate ADHD core symptoms and be a risk factor of poor outcome response. OBJECTIVE: to report for the first time the history of a patient with ADHD and ACE successfully treated with an EMDR approach. CONCLUSION: EMDR could be a promising treatment for ADHD children with a history of traumatic experiences in addition to pharmacological treatments.

Specific Learning Disorders (SLD) and Behavior Impairment: Comorbidity or Specific Profile?

INTRODUCTION: Specific Learning Disorder (SLD) is a neurodevelopmental disorder characterized by difficulties in perceiving and processing verbal and non-verbal information. It is usually accompanied by impaired academic skills leading to school dropout and emotional disturbances, resulting in significant distress and behavioral problems. METHODS: A cognitive, academic, and emotional-behavioral assessment was performed at T0 and T1 in children and adolescents with SLD. Participants received psychotherapy and speech therapy treatment from T0 to T1. RESULTS: In SLD, the most compromised cognitive functions were working memory and writing skills. An impact on academic abilities was found. Children and adolescents with SLD experience greater anxiety and depression levels compared to their control peers. CONCLUSIONS: SLD may adversely influence psychological well-being. To counteract such a consequence, more specific cognitive and academic skill-oriented strategies should be taken into consideration.

Prevalence of a BRCA2 Pathogenic Variant in Hereditary-Breast-and-Ovarian-Cancer-Syndrome Families with Increased Risk of Pancreatic Cancer in a Restricted Italian Area.

PVs and LPVs in BRCA1/2 genes are correlated to a high risk of developing breast cancer and/or ovarian cancer (Hereditary Breast and Ovarian Cancer syndrome, HBOC); additionally, in recent years, an increasing number of BRCA 1/2 variants have been identified and associated with pancreatic cancer. Epidemiologic studies have highlighted that inherited factors are involved in 10% to 20% of PCs, mainly through deleterious variants of BRCA2. The frequency of BRCA1/2 germline alterations fluctuates quite a lot among different ethnic groups, and the estimated rate of PVs/LPVs variants in Italian HBOC families is not very accurate, according to different reports. The aim of our study is to describe the prevalence of a BRCA2 PV observed in a selected cohort of HBOC patients and their relatives, whose common origin is the eastern coast of Emilia Romagna, a region of Italy. This study provides insight into the frequency of the variant detected in this area and provides evidence of an increased risk of pancreatic and breast cancer, useful for genetic counseling and surveillance programs.

Impact of the time interval between primary or interval surgery and adjuvant chemotherapy in ovarian cancer patients.

Introduction: Primary debulking surgery (PDS), interval debulking surgery (IDS), and platinum-based chemotherapy are the current standard treatments for advanced ovarian cancer (OC). The time to initiation of adjuvant chemotherapy (TTC) could influence patient outcomes. Methods: We conducted a multicenter retrospective cohort study of advanced (International Federation of Gynecology and Obstetrics (FIGO) stage III or IV) OC treated between 2014 and 2018 to assess progression-free survival (PFS) and overall survival (OS) in relation to TTC. All patients underwent a germline multigene panel for BRCA1/2 evaluation. Results: Among the 83 patients who underwent PDS, a TTC ≥ 60 days was associated with a shorter PFS (hazard ratio (HR) 2.02, 95% confidence interval (CI) 1.04-3.93, p = 0.038), although this association lost statistical significance when adjusting for residual disease (HR 1.52, 95% CI 0.75-3.06, p = 0.244, for TTC and HR 2.73, 95% CI 1.50-4.96, p = 0.001, for residual disease). Among 52 IDS patients, we found no evidence of an association between TTC and clinical outcomes. Ascites, type of chemotherapy, or germline BRCA1/2 mutational status did not influence TTC and were not associated with clinical outcomes in PDS or IDS patients. Discussion: In conclusion, longer TTC seems to negatively affect prognosis in patients undergoing PDS, especially those with residual disease.

Posterior Fossa Tumor Rehabilitation: An Up-to-Date Overview.

This narrative review highlights the latest achievements in the field of post-surgical rehabilitation of posterior fossa tumors. Studies investigating the effects of cognitive rehabilitation programs have been considered, following a comprehensive literature search in the scientific electronic databases: Pubmed, Scopus, Plos One, and ScienceDirect. This review investigates the effects of cognitive remediation, with specific highlights for single cognitive domains. The results revealed that in spite of the increasing number of children who survive into adulthood, very few studies investigated the effects of rehabilitation programs in this specific population. This study details new, promising therapeutic opportunities for children after brain surgery. More research in this filed is needed to identify the most effective protocols for clinical use.

Developmental Coordination Disorder and Joint Hypermobility in Childhood: A Narrative Review.

Children with developmental coordination disorder (DCD) and joint hypermobility could present an overlap of symptoms and motor functional difficulties. The link between these two clinical conditions has not yet been clarified. Recent studies reported a high incidence (30-50%) of motor delay in children who are referred to hypermobility and of enhanced joint hypermobility in children with DCD. The aim of this study was to provide a critical review of the literature outlining the association between DCD or limited motor performance and joint hypermobility. Studies were eligible for inclusion if they were written in English and human-based. All the studies were first selected, looking for the presence of a clinical association between developmental coordination disorder or motor performance and hyperlaxity and reporting details of outcome. After a review of the full texts, 16 articles for a total of 1898 children met the inclusion criteria. In general, there was evidence of a higher incidence of motor delay or DCD in children who are referred to hypermobility and of enhanced joint hypermobility in children with DCD with similar range of functional difficulties. These results could influence the way to support children with rehabilitation and the type of intervention according to the prevalence of one of the two conditions.

Case Report: A BRCA2 Mutation Identified Through Next-Generation Sequencing in a Birt-Hogg-Dubè Syndrome Family.

Birt-Hogg-Dubé syndrome (BHDS) is a rare autosomal dominant inherited disorder caused by a mutation in folliculin (FLCN) gene transmitted via germline autosomal dominant pattern. Patients with this syndrome have an increased susceptibility to renal cell carcinoma, lung cysts, spontaneous pneumothorax, and benign skin hamartomas, and its diagnosis is not easy and consequently underestimated. Several mutations have been identified in FLCN gene, among which the majority of alterations are frameshift (insertion/deletion), nonsense, or splice-site mutations that generally produce unfunctional truncated FLCN proteins. Our aim is to present a case of a BHDS family whose proband is a 56-year-old patient who has been experiencing multiple disorders, has an FLCN genetic mutation, and has also been identified to have a pathogenic variant in BRCA2 gene. Our further purpose is to emphasize the importance of the next-generation sequencing (NGS) approach to identify potential multiple germline mutations in complex and rare oncologic disorders, allowing strict and more targeted cancer screening programs.

The Virtual Challenge: Virtual Reality Tools for Intervention in Children with Developmental Coordination Disorder.

This narrative review highlights the latest achievements in the field of tele-rehabilitation: Virtual Reality (VR) and Augmented Reality (AR) serious games aimed at restoring and improving cognitive functions could be effectively used in Developmental Coordination Disorder Training. Studies investigating the effects of the abovementioned tech applications on cognitive improvement have been considered, following a comprehensive literature search in the scientific electronic databases: Pubmed, Scopus, Plos One, ScienceDirect. This review investigates the effects of VR and AR in improving space/motor skills through mental images manipulation training in children with developmental coordination disorders. The results revealed that in spite of the spreading of technology, actually only four studies investigated the effects of VR/AR tools on mental images manipulation. This study highlights new, promising VR and AR based therapeutic opportunities for digital natives now available, emphasizing the advantages of using motivational reward-oriented tools, in a playful therapeutic environment. However, more research in this filed is needed to identify the most effective virtual tool set for clinical use.