Integration of Smart Home and Building Automation Systems in Virtual Reality and Robotics-Based Technological Environment for Neurorehabilitation: A Pilot Study Protocol.

Technological innovation has revolutionized healthcare, particularly in neurological rehabilitation, where it has been used to address chronic conditions. Smart home and building automation (SH&BA) technologies offer promising solutions for managing chronic disabilities associated with such conditions. This single group, pre-post longitudinal pilot study, part of the H2020 HosmartAI project, aims to explore the integration of smart home technologies into neurorehabilitation. Eighty subjects will be enrolled from IRCCS San Camillo Hospital (Venice, Italy) and will receive rehabilitation treatment through virtual reality (VR) and robotics devices for 15 h per day, 5 days a week for 3 weeks in the HosmartAI Room (HR), equipped with SH&BA devices measuring the environment. The study seeks to optimize patient outcomes and refine rehabilitation practices. Findings will be disseminated through peer-reviewed publications and scientific meetings, contributing to advancements in neurological rehabilitation and guiding future research.

DNAJB1-PRKACA fusion neoantigens elicit rare endogenous T cell responses that potentiate cell therapy for fibrolamellar carcinoma.

Fibrolamellar carcinoma (FLC) is a liver tumor with a high mortality burden and few treatment options. A promising therapeutic vulnerability in FLC is its driver mutation, a conserved DNAJB1-PRKACA gene fusion that could be an ideal target neoantigen for immunotherapy. In this study, we aim to define endogenous CD8 T cell responses to this fusion in FLC patients and evaluate fusion-specific T cell receptors (TCRs) for use in cellular immunotherapies. We observe that fusion-specific CD8 T cells are rare and that FLC patient TCR repertoires lack large clusters of related TCR sequences characteristic of potent antigen-specific responses, potentially explaining why endogenous immune responses are insufficient to clear FLC tumors. Nevertheless, we define two functional fusion-specific TCRs, one of which has strong anti-tumor activity in vivo. Together, our results provide insights into the fragmented nature of neoantigen-specific repertoires in humans and indicate routes for clinical development of successful immunotherapies for FLC.

Telerehabilitation for Neurological Motor Impairment: A Systematic Review and Meta-Analysis on Quality of Life, Satisfaction, and Acceptance in Stroke, Multiple Sclerosis, and Parkinson's Disease.

Telerehabilitation (TR) seems to be a viable and feasible solution to face the rehabilitative challenges posed by neurological impairments and to improve patients' quality of life (QoL). This review aims to synthesize and analyze the evidence on the impact of physiotherapy intervention through TR on QoL in patients with stroke, Parkinson's disease (PD), and multiple sclerosis (MS), together with an evaluation of their satisfaction and technology acceptance levels. Through a systematic search of the literature and a screening process, treatment effects were assessed with meta-analyses using the standardized mean difference, setting the confidence interval at 95%. We included 28 studies in the review, which were analyzed for methodological quality, whereas 16 studies were included in the meta-analyses. The results suggest a significant improvement in QoL in patients who underwent TR. We were unable to perform analyses for satisfaction and technology acceptance outcomes due to insufficient data. Overall, motor TR has a positive impact on the QoL of patients with neurological diseases, especially in stroke patients; although caution is needed in the interpretation of the results due to the high heterogeneity found. For PD and MS, TR seems to yield comparable results to in-person treatment.

Telerehabilitation for Stroke: A Personalized Multi-Domain Approach in a Pilot Study.

Stroke, a leading cause of long-term disability worldwide, manifests as motor, speech language, and cognitive impairments, necessitating customized rehabilitation strategies. In this context, telerehabilitation (TR) strategies have emerged as promising solutions. In a multi-center longitudinal pilot study, we explored the effects of a multi-domain TR program, comprising physiotherapy, speech therapy, and neuropsychological treatments. In total, 84 stroke survivors (74 analyzed) received 20 tailored sessions per domain, addressing individual impairments and customized to their specific needs. Positive correlations were found between initial motor function, cognitive status, independence in activities of daily living (ADLs), and motor function improvement after TR. A lower initial health-related quality of life (HRQoL) perception hindered progress, but improved ADL independence and overall health status, and reduced depression correlated with a better QoL. Furthermore, post-treatment improvements were observed in the entire sample in terms of fine motor skills, upper-limb functionality, balance, independence, and cognitive impairment. This multi-modal approach shows promise in enhancing stroke rehabilitation and highlights the potential of TR in addressing the complex needs of stroke survivors through a comprehensive support and interdisciplinary collaboration, personalized for each individual's needs.

A scoping review of scientific concepts concerning motor recovery after stroke as employed in clinical trials.

The scientific literature on poststroke rehabilitation is remarkably vast. Over the last decades, dozens of rehabilitation approaches have been investigated. However, sometimes it is challenging to trace new experimental interventions back to some of the known models of motor control and sensorimotor learning. This scoping review aimed to investigate motor control models' diffusion among the literature on motor recovery after stroke. We performed a literature search on Medline, Cochrane, Web of Science, Embase, and Scopus databases. The last search was conducted in September 2023. This scoping review included full-text articles published in English in peer-reviewed journals that provided rehabilitation interventions based on motor control or motor learning frameworks for at least one individual with stroke. For each study, we identified the theoretical framework the authors used to design the experimental treatment. To this aim, we used a previously proposed classification of the known models of motor control, dividing them into the following categories: neuroanatomy, robotics, self-organization, and ecological context. In total, 2,185 studies were originally considered in this scoping review. After the screening process, we included and analyzed 45 studies: 20 studies were randomized controlled trials, 12 were case series, 4 were case reports, 8 were observational longitudinal pilot studies, and 1 was an uncontrolled trial. Only 10 studies explicitly declared the reference theoretical model. Considering their classification, 21 studies referred to the robotics motor control model, 12 to the self-organization model, 8 to the neuroanatomy model, and 4 to the ecological model. Our results showed that most of the rehabilitative interventions purposed in stroke rehabilitation have no clear theoretical bases on motor control and motor learning models. We suggest this is an issue that deserves attention when designing new experimental interventions in stroke rehabilitation.

How Lung Volume Recruitment Maneuvers Enhance Respiratory Function in Multiple Sclerosis Patients: A Quasi-Randomized Pilot Study.

Background and Objectives: In patients with multiple sclerosis (MS), a decrease in muscle strength can lead to limitations in pulmonary functions, potentially causing respiratory complications. To address these challenges, the lung volume recruitment (LVR) maneuver has emerged as a potential intervention. This study sought to evaluate the impact of a four-week LVR protocol on respiratory function in secondary progressive MS patients. Materials and Methods: In a quasi-randomized pre/post-controlled trial, 24 patients with secondary progressive MS were recruited. Participants aged 20-70 years with an EDSS score of 2 to 9 were alternately allocated to intervention (n = 12) or control groups (n = 12). The intervention group underwent a 4-week respiratory rehabilitation training focused on LVR, using a standardized cough machine treatment protocol twice daily. The control group received no respiratory intervention. Outcomes measured included forced vital capacity (FVC), maximal insufflation capacity (MIC), and peak cough flow (PCF), using turbine spirometry and other associated equipment. All measurements were taken at baseline (T0) and after 4 weeks (T1) by a blinded assessor. Results: For the intervention group, the mean difference pre/post-treatment in MIC (mL) was 0.45 (SD 1.13) (p = 0.02), and in MIC (%), it was 0.13 (SD 0.24) (p = 0.03). Compared to the control group (n = 10), the between-group mean difference for MIC (mL) was 0.54 (p = 0.02), and for MIC (%), it was 0.15 (p = 0.02). Conclusions: The short-term daily LVR protocol notably improved passive lung capacity, despite minimal changes in active lung capacity or cough force. The LVR maneuver offers promise for enhancing respiratory function, especially passive lung capacity, in secondary progressive MS patients. Further research should explore optimal treatment durations and frequencies for more extensive respiratory gains.

Language and gesture neural correlates: A meta-analysis of functional magnetic resonance imaging studies.

BACKGROUND: Humans often use co-speech gestures to promote effective communication. Attention has been paid to the cortical areas engaged in the processing of co-speech gestures. AIMS: To investigate the neural network underpinned in the processing of co-speech gestures and to observe whether there is a relationship between areas involved in language and gesture processing. METHODS & PROCEDURES: We planned to include studies with neurotypical and/or stroke participants who underwent a bimodal task (i.e., processing of co-speech gestures with relative speech) and a unimodal task (i.e., speech or gesture alone) during a functional magnetic resonance imaging (fMRI) session. After a database search, abstract and full-text screening were conducted. Qualitative and quantitative data were extracted, and a meta-analysis was performed with the software GingerALE 3.0.2, performing contrast analyses of uni- and bimodal tasks. MAIN CONTRIBUTION: The database search produced 1024 records. After the screening process, 27 studies were included in the review. Data from 15 studies were quantitatively analysed through meta-analysis. Meta-analysis found three clusters with a significant activation of the left middle frontal gyrus and inferior frontal gyrus, and bilateral middle occipital gyrus and inferior temporal gyrus. CONCLUSIONS: There is a close link at the neural level for the semantic processing of auditory and visual information during communication. These findings encourage the integration of the use of co-speech gestures during aphasia treatment as a strategy to foster the possibility to communicate effectively for people with aphasia. WHAT THIS PAPER ADDS: What is already known on this subject Gestures are an integral part of human communication, and they may have a relationship at neural level with speech processing. What this paper adds to the existing knowledge During processing of bi- and unimodal communication, areas related to semantic processing and multimodal processing are activated, suggesting that there is a close link between co-speech gestures and spoken language at a neural level. What are the potential or actual clinical implications of this work? Knowledge of the functions related to gesture and speech processing neural networks will allow for the adoption of model-based neurorehabilitation programs to foster recovery from aphasia by strengthening the specific functions of these brain networks.

Efficacy of non-immersive virtual reality-based telerehabilitation on postural stability in Parkinson's disease: a multicenter randomized controlled trial.

BACKGROUND: The implementation of regular prolonged, and effective rehabilitation in people with Parkinson's disease is essential for ensuring a good quality of life. However, the continuity of rehabilitation care may find barriers related to economic, geographic, and social issues. In these scenarios, telerehabilitation could be a possible solution to guarantee the continuity of care. AIM: To investigate the efficacy of non-immersive virtual reality-based telerehabilitation on postural stability in people with Parkinson's disease, compared to at-home self-administered structured conventional motor activities. DESIGN: Multicenter randomized controlled trial. SETTING: Five rehabilitation hospitals of the Italian Neuroscience and Rehabilitation Network. POPULATION: Individuals diagnosed with Parkinson's disease. METHODS: Ninety-seven participants were randomized into two groups: 49 in the telerehabilitation group (non-immersive virtual reality-based telerehabilitation) and 48 in the control group (at-home self-administered structured conventional motor activities). Both treatments lasted 30 sessions (3-5 days/week for, 6-10 weeks). Static and dynamic balance, gait, and functional motor outcomes were registered before and after the treatments. RESULTS: All participants improved the outcomes at the end of the treatments. The primary outcome (mini-Balance Evaluation Systems Test) registered a greater significant improvement in the telerehabilitation group than in the control group. The gait and endurance significantly improved in the telerehabilitation group only, with significant within-group and between-group differences. CONCLUSIONS: Our results showed that non-immersive virtual reality-based telerehabilitation is feasible, improves static and dynamic balance, and is a reasonably valuable alternative for reducing postural instability in people with Parkinson's disease. CLINICAL REHABILITATION IMPACT: Non-immersive virtual reality-based telerehabilitation is an effective and well-tolerated modality of rehabilitation which may help to improve access and scale up rehabilitation services as suggested by the World Health Organization's Rehabilitation 2030 agenda.

Treatment of High-Risk Neuroblastoma with Dinutuximab and Chemotherapy Administered in all Cycles of Induction.

Administration of chemoimmunotherapy using concurrent chemotherapy and an anti-GD2 monoclonal antibody (mAb), dinutuximab (DIN), demonstrated efficacy for the treatment of relapsed and refractory neuroblastoma. Chemoimmunotherapy, using a humanized anti-GD2 mAb, demonstrated a signal of activity in a phase 2 study for the treatment of patients with newly diagnosed high-risk neuroblastoma (HRNBL). In this single-institution retrospective study, patients with HRNBL received an Induction chemotherapy regimen plus DIN in all Induction cycles. Toxicity and response data were abstracted from the electronic medical record. Toxicities were graded by CTCAE v.5.0. The end of Induction (EOI) objective response rate was determined using the Revised International Neuroblastoma Response Criteria. Twenty-seven patients with HRNBL (23 newly diagnosed, 16 females, median age 3.9 years) started Induction chemoimmunotherapy from 27 January 2017 to 28 December 2022. All patients received DIN with all cycles of Induction therapy, and all but one patient completed Induction therapy. The most common non-hematologic grade ≥ 3 toxicities included fever (44%), hypoxemia (20%), and hypoalbuminemia (11%). End of Induction responses included eighteen with a complete response (CR), seven with a partial response (PR), one with progressive disease (PD), and zero with a minor response or stable disease. Twenty-six of twenty-seven patients (96%) completed all Induction cycles and were evaluable for a response. The EOI response of PR or better in the evaluable cohort was 96%. Dinutuximab was well tolerated with all Induction cycles, demonstrated an encouraging EOI response rate, and should be evaluated in a randomized study.

Clinical Response to a PARP Inhibitor and Chemotherapy in a Child with BARD1-Mutated Refractory Neuroblastoma: A Case Report.

Despite advances in the treatment of high-risk neuroblastoma, approximately half of these patients die from the disease. Targeted therapy based on synthetic lethality associated with homologous recombination deficiency (HRD) caused by germline mutations in homologous recombination repair genes has shown great efficacy in several adult solid tumors. Here we report the first successful treatment of a pediatric patient with refractory neuroblastoma and a germline pathogenic mutation in BARD1 using a PARP inhibitor, talazoparib, in combination with cytotoxic chemotherapy and radiation therapy. Allele-specific expression in RNA-seq indicates bi-allelic loss of BARD1 in tumor; however, the HRD score was below the threshold currently used for HRD classification in adult cancers. Our study demonstrates that the use of PARP inhibition in combination with DNA-damaging agents should be considered in children with BARD1-mutated neuroblastoma and cautions against the use of HRD score alone as a biomarker for this pediatric population.

Paediatric Strategy Forum for medicinal product development of DNA damage response pathway inhibitors in children and adolescents with cancer: ACCELERATE in collaboration with the European Medicines Agency with participation of the Food and Drug Administration.

DNA damage response inhibitors have a potentially important therapeutic role in paediatric cancers; however, their optimal use, including patient selection and combination strategy, remains unknown. Moreover, there is an imbalance between the number of drugs with diverse mechanisms of action and the limited number of paediatric patients available to be enrolled in early-phase trials, so prioritisation and a strategy are essential. While PARP inhibitors targeting homologous recombination-deficient tumours have been used primarily in the treatment of adult cancers with BRCA1/2 mutations, BRCA1/2 mutations occur infrequently in childhood tumours, and therefore, a specific response hypothesis is required. Combinations with targeted radiotherapy, ATR inhibitors, or antibody drug conjugates with DNA topoisomerase I inhibitor-related warheads warrant evaluation. Additional monotherapy trials of PARP inhibitors with the same mechanism of action are not recommended. PARP1-specific inhibitors and PARP inhibitors with very good central nervous system penetration also deserve evaluation. ATR, ATM, DNA-PK, CHK1, WEE1, DNA polymerase theta and PKMYT1 inhibitors are early in paediatric development. There should be an overall coordinated strategy for their development. Therefore, an academia/industry consensus of the relevant biomarkers will be established and a focused meeting on ATR inhibitors (as proof of principle) held. CHK1 inhibitors have demonstrated activity in desmoplastic small round cell tumours and have a potential role in the treatment of other paediatric malignancies, such as neuroblastoma and Ewing sarcoma. Access to CHK1 inhibitors for paediatric clinical trials is a high priority. The three key elements in evaluating these inhibitors in children are (1) innovative trial design (design driven by a clear hypothesis with the intent to further investigate responders and non-responders with detailed retrospective molecular analyses to generate a revised or new hypothesis); (2) biomarker selection and (3) rational combination therapy, which is limited by overlapping toxicity. To maximally benefit children with cancer, investigators should work collaboratively to learn the lessons from the past and apply them to future studies. Plans should be based on the relevant biology, with a focus on simultaneous and parallel research in preclinical and clinical settings, and an overall integrated and collaborative strategy.

Venetoclax Penetrates the Blood Brain Barrier: A Pharmacokinetic Analysis in Pediatric Leukemia Patients.

Infiltration of malignant cells into the central nervous system in hematological malignancies correlates with poor clinical outcomes. Investigations into the penetration of venetoclax into the central nervous system have been limited. We report venetoclax pharmacokinetics in plasma and cerebrospinal fluid samples from a Phase 1 study in pediatric patients with relapsed or refractory malignancies that demonstrate venetoclax ability to cross into the central nervous system. Venetoclax was detected in cerebrospinal fluid (CSF) samples, with concentrations ranging from < 0.1 to 26 ng/mL (mean, 3.6 ng/mL) and a plasma:CSF ratio ranging from 44 to 1559 (mean, 385). Plasma:CSF ratios were comparable among patients with AML and ALL and no clear trend was observed in the ratios over the course of treatment. Moreover, improvement in central nervous system (CNS) involvement status was observed in patients who had measurable concentrations of venetoclax in the CSF. CNS resolution was observed for up to six months while on treatment. These findings highlight the potential role of venetoclax and provide the opportunity to further investigate its utility in improving clinical outcomes for patients with CNS complications.

Non-Immersive Virtual Reality Telerehabilitation System Improves Postural Balance in People with Chronic Neurological Diseases.

BACKGROUND: People with chronic neurological diseases, such as Parkinson's Disease (PD) and Multiple Sclerosis (MS), often present postural disorders and a high risk of falling. When difficulties in achieving outpatient rehabilitation services occur, a solution to guarantee the continuity of care may be telerehabilitation. This study intends to expand the scope of our previously published research on the impact of telerehabilitation on quality of life in an MS sample, testing the impact of this type of intervention in a larger sample of neurological patients also including PD individuals on postural balance. METHODS: We included 60 participants with MS and 72 with PD. All enrolled subjects were randomized into two groups: 65 in the intervention group and 67 in the control group. Both treatments lasted 30-40 sessions (5 days/week, 6-8 weeks). Motor, cognitive, and participation outcomes were registered before and after the treatments. RESULTS: All participants improved the outcomes at the end of the treatments. The study's primary outcome (Mini-BESTest) registered a greater significant improvement in the telerehabilitation group than in the control group. CONCLUSIONS: Our results demonstrated that non-immersive virtual reality telerehabilitation is well tolerated and positively affects static and dynamic balance and gait in people with PD and MS.

The use of respiratory muscle training in patients with pulmonary dysfunction, internal diseases or central nervous system disorders: a systematic review with meta-analysis.

OBJECTIVE: The aim of this systematic review with meta-analysis was to evaluate the effectiveness of RMT in internal and central nervous system disorders, on pulmonary function, exercise capacity and quality of life. METHODS: The inclusion criteria were (1) publications designed as Randomized Controlled Trial (RCT), with (2) participants being adults with pulmonary dysfunction caused by an internal disease or central nervous system disorder, (3) an intervention defined as RMT (either IMT or EMT) and (4) with the assessment of exercise capacity, respiratory function and quality of life. For the methodological quality assessment of risk of bias, likewise statistical analysis and meta-analysis the RevMan version 5.3 software and the Cochrane Risk of Bias Tool were used. Two authors independently analysed the following databases for relevant research articles: PubMed, Scopus, Cochrane Library, Web of Science, and Embase. RESULTS: From a total of 2200 records, the systematic review includes 29 RCT with an overall sample size of 1155 patients. Results suggest that patients with internal and central nervous system disorders who underwent RMT had better quality of life and improved significantly their performance in exercise capacity and in respiratory function assessed with FVC and MIP when compared to control conditions (i.e. no intervention, sham training, placebo or conventional treatments). CONCLUSION: Respiratory muscle training seems to be more effective than control conditions (i.e. no intervention, sham training, placebo or conventional treatment), in patients with pulmonary dysfunction due to internal and central nervous system disorders, for quality of life, exercise capacity and respiratory function assessed with MIP and FVC, but not with FEV1.

Progression-Free Survival and Patterns of Response in Patients With Relapsed High-Risk Neuroblastoma Treated With Irinotecan/Temozolomide/Dinutuximab/Granulocyte-Macrophage Colony-Stimulating Factor.

PURPOSE: Although chemoimmunotherapy is widely used for treatment of children with relapsed high-risk neuroblastoma (HRNB), little is known about timing, duration, and evolution of response after irinotecan/temozolomide/dinutuximab/granulocyte-macrophage colony-stimulating factor (I/T/DIN/GM-CSF) therapy. PATIENTS AND METHODS: Patients eligible for this retrospective study were age < 30 years at diagnosis of HRNB and received ≥ 1 cycle of I/T/DIN/GM-CSF for relapsed or progressive disease. Patients with primary refractory disease who progressed through induction were excluded. Responses were evaluated using the International Neuroblastoma Response Criteria. RESULTS: One hundred forty-six patients were included. Tumors were MYCN-amplified in 50 of 134 (37%). Seventy-one patients (49%) had an objective response to I/T/DIN/GM-CSF (objective response; 29% complete response, 14% partial response [PR], 5% minor response [MR], 21% stable disease [SD], and 30% progressive disease). Of patients with SD or better at first post-I/T/DIN/GM-CSF disease evaluation, 22% had an improved response per International Neuroblastoma Response Criteria on subsequent evaluation (13% of patients with initial SD, 33% with MR, and 41% with PR). Patients received a median of 4.5 (range, 1-31) cycles. The median progression-free survival (PFS) was 13.1 months, and the 1-year PFS and 2-year PFS were 50% and 28%, respectively. The median duration of response was 15.9 months; the median PFS off all anticancer therapy was 10.4 months after discontinuation of I/T/DIN/GM-CSF. CONCLUSION: Approximately half of patients receiving I/T/DIN/GM-CSF for relapsed HRNB had objective responses. Patients with initial SD were unlikely to have an objective response, but > 1 of 3 patients with MR/PR on first evaluation ultimately had complete response. I/T/DIN/GM-CSF was associated with extended PFS in responders both during and after discontinuation of treatment. This study establishes a new comparator for response and survival in patients with relapsed HRNB.

Effects of Immersive Virtual Reality on Upper-Extremity Stroke Rehabilitation: A Systematic Review with Meta-Analysis.

Virtual reality (VR) is an innovative rehabilitation tool increasingly used in stroke rehabilitation. Fully immersive VR is a type of VR that closely simulates real-life scenarios, providing a high level of immersion, and has shown promising results in improving rehabilitation functions. This study aimed to assess the effect of immersive VR-based therapy for stroke patients on the upper extremities, activities of daily living (ADLs), and pain reduction and its acceptability and side effects. For this review, we gathered all suitable randomized controlled trials from PubMed, EMBASE, Cochrane Library, Scopus, and Web of Science. Out of 1532, 10 articles were included, with 324 participants. The results show that immersive VR offers greater benefits in comparison with conventional rehabilitation, with significant improvements observed in ADLs (SMD 0.58, 95% CI 0.25 to 0.91, I2 = 0%, p = 0.0005), overall function as measured by the Fugl-Meyer Assessment (MD 6.33, 95% CI 4.15 to 8.50, I2 = 25%, p = 0.00001), and subscales for the shoulder (MD 4.96, 95% CI-1.90-8.03, I2 = 25%, p = 0.002), wrist (MD 2.41, 95% CI-0.56-4.26, I2 = 0%, p = 0.01), and hand (MD 2.60, 95% CI-0.70-4.5°, I2 = 0%, p = 0.007). These findings highlight the potential of immersive VR as a valuable therapeutic option for stroke survivors, enhancing their ADL performance and upper-limb function. The immersive nature of VR provides an engaging and immersive environment for rehabilitation.

Bevacizumab, With Sorafenib and Cyclophosphamide Provides Clinical Benefit for Recurrent or Refractory Osseous Sarcomas in Children and Young Adults.

Objective: Children and adolescents with recurrent and metastatic solid tumors have a poor outcome. A previous phase 1 study (ANGIO1) targeting angiogenesis with bevacizumab, sorafenib, and cyclophosphamide, demonstrated a signal of activity in a subset of patients. Here we report the results of a cohort of pediatric and young adult patients treated at the recommended phase 2 doses. Methods: Electronic medical records of patients with refractory or recurrent solid tumors who received ANGIO1 therapy were reviewed. Treatment cycles lasted 21 days and included bevacizumab, sorafenib, and cyclophosphamide. Toxicities were assessed using Common Terminology Criteria for Adverse Events, v5.0. Responses were evaluated using Response Evaluation Criteria in Solid Tumors (RECIST1.1). Results: Thirty-nine patients (22 male, 17 female; median age 15 years; range 1-22 years) received the treatment regimen. The most common diagnoses included bone sarcomas (n=21; 14 Ewing sarcoma, 7 osteosarcoma) and soft tissue sarcomas (n=9; 2 rhabdomyosarcoma, 3 synovial sarcoma, 2 desmoplastic small round cell tumors, and 2 high-grade sarcoma). The most common Grade 3 non-hematologic toxicities included hypertension (2, 5.4%) and hematuria (2, 5.4%). Five patients (13.5%) had a pneumothorax (3 at progressive disease, 1 post lung biopsy, and 1 spontaneous). Common Grade 3/4 hematologic toxicities were lymphopenia (19, 51%) and leukopenia (13, 35%). Sixteen patients (43.2%) developed palmar-plantar erythrodysesthesia Grade 2 or less. A total of 297 cycles were administered. Twenty-three patients required a dose reduction of cyclophosphamide, sorafenib or bevacizumab during therapy, all of whom continued to have clinical benefit following dose modification. One patient (Ewing sarcoma) achieved a complete response after 11 cycles; 2 patients (Ewing sarcoma, high grade sarcoma) achieved a partial response following cycles 2 and 4, respectively and 20 patients had stable disease as a best response. Conclusions: Intravenous bevacizumab combined with oral sorafenib and metronomic cyclophosphamide was tolerated and required minimal supportive care or additional clinic visits. Disease stabilization for prolonged time periods was observed in greater than half of the treated patients. Patients with bone sarcoma demonstrated a signal of activity suggesting possible benefit from incorporation of the therapy as a maintenance regimen in upfront setting, or as a palliative regimen.

Risk factors associated with metastatic site failure in patients with high-risk neuroblastoma.

Purpose: This retrospective study sought to identify predictors of metastatic site failure (MSF) at new and/or original (present at diagnosis) sites in high-risk neuroblastoma patients. Methods and materials: Seventy-six high-risk neuroblastoma patients treated on four institutional prospective trials from 1997 to 2014 with induction chemotherapy, surgery, myeloablative chemotherapy, stem-cell rescue, and were eligible for consolidative primary and metastatic site (MS) radiotherapy were eligible for study inclusion. Computed-tomography and I-123 MIBG scans were used to assess disease response and Curie scores at diagnosis, post-induction, post-transplant, and treatment failure. Outcomes were described using the Kaplan-Meier estimator. Cox proportional hazards frailty (cphfR) and CPH regression (CPHr) were used to identify covariates predictive of MSF at a site identified either at diagnosis or later. Results: MSF occurred in 42 patients (55%). Consolidative MS RT was applied to 30 MSs in 10 patients. Original-MSF occurred in 146 of 383 (38%) non-irradiated and 18 of 30 (60%) irradiated MSs (p = 0.018). Original- MSF occurred in post-induction MIBG-avid MSs in 68 of 81 (84%) non-irradiated and 12 of 14 (85%) radiated MSs (p = 0.867). The median overall and progression-free survival rates were 61 months (95% CI 42.6-Not Reached) and 24.1 months (95% CI 16.5-38.7), respectively. Multivariate CPHr identified inability to undergo transplant (HR 32.4 95%CI 9.3-96.8, p < 0.001) and/or maintenance chemotherapy (HR 5.2, 95%CI 1.7-16.2, p = 0.005), and the presence of lung metastases at diagnosis (HR 4.4 95%CI 1.7-11.1, p = 0.002) as predictors of new MSF. The new MSF-free survival rate at 3 years was 25% and 87% in patients with and without high-risk factors. Conclusions: Incremental improvements in systemic therapy influence the patterns and type of metastatic site failure in neuroblastoma. Persistence of MIBG-avidity following induction chemotherapy and transplant at MSs increased the hazard for MSF.

Antigen cross-presentation in young tumor-bearing hosts promotes CD8+ T cell terminal differentiation.

The immune system undergoes a progressive functional remodeling with age. Understanding how age bias shapes antitumor immunity is essential in designing effective immunotherapies, especially for pediatric patients. Here, we explore antitumor CD8+ T cell responses generated in young (prepubescent) and adult (presenescent) mice. Using an MHCI-deficient tumor model, we observed that tumor-reactive CD8+ T cells expanded in young tumor-bearing (TB) mice acquired a terminally differentiated phenotype characterized by overexpression of inhibitory receptors and the transcription factor Tox1. Furthermore, tumor-infiltrating CD8+ T cells from young tumors yielded a poor cytokine response compared with CD8+ T cells infiltrating adult tumors. Young migratory dendritic cells (migDCs) from the draining lymph nodes (dLNs), and mononuclear phagocytic cells (MPCs) infiltrating young tumors, were more competent in capturing and cross-presenting tumor antigen, leading to enhanced priming of CD8+ T cells in dLNs and their subsequent terminal differentiation in the tumors. Single-cell transcriptional profiling of tumor-infiltrating MPCs demonstrated that young MPCs are polarized toward an inflammatory, effector phenotype. Consistent with our observations in young versus adult TB mice, analysis of immune infiltrates from pediatric solid tumors showed a correlation between tumor-infiltrating CD8+ T cells with an exhaustion phenotype and the frequency of PD-L1-expressing monocytes/macrophages. Collectively, these data indicate that a young tissue microenvironment contributes to the generation of an immune response skewed toward a less pliable terminal effector state, thus narrowing the window for immunotherapeutic interventions.