Limb-girdle muscular dystrophies: A scoping review and overview of currently available rehabilitation strategies.

Limb-girdle muscular dystrophies (LGMDs) constitute a diverse group of inherited disorders primarily affecting skeletal muscle. Despite the absence of cures, rehabilitative treatments offer potential for preventing and mitigating loss of muscle strength. However, the role of exercise training in LGMD patients remains contentious. This review aims to provide an overview of the currently available motor rehabilitation strategies for the most common subtypes of LGMD. To identify relevant articles, we performed a systematic search in PubMed, Embase, Cochrane Library, and Web of Science, focusing on muscular and respiratory interventions. The search resulted in 560 potentially relevant articles, of which 16 were included in the review. Eight studies concentrated on neuromuscular functional rehabilitation therapy programs, seven combined both neuromuscular rehabilitation and interventions to maintain or enhance respiratory functionality and one focused on respiratory intervention only. Altogether, the papers examined offered a comprehensive view on the rehabilitative strategies available and provided an indication of the most valuable practices to deal with patients' health and needs. Upon analysis, we conclude that, when tailored to individual needs, muscle training can enhance strength and functional abilities, positively impacting psychological well-being. However, generic protocols may lead to limited benefits, fatigue, pain, and compliance issues. Moreover, early management of respiratory symptoms and personalized respiratory physiotherapy can enhance patients' well-being and their capability to participate in muscle training exercises. Future studies should not only refine rehabilitation approaches but also assess their impact on patients' quality of life, including psychological factors like depression and self-esteem.

Orthotopic patient-derived xenografts of paediatric solid tumours.

Paediatric solid tumours arise from endodermal, ectodermal, or mesodermal lineages. Although the overall survival of children with solid tumours is 75%, that of children with recurrent disease is below 30%. To capture the complexity and diversity of paediatric solid tumours and establish new models of recurrent disease, here we develop a protocol to produce orthotopic patient-derived xenografts at diagnosis, recurrence, and autopsy. Tumour specimens were received from 168 patients, and 67 orthotopic patient-derived xenografts were established for 12 types of cancer. The origins of the patient-derived xenograft tumours were reflected in their gene-expression profiles and epigenomes. Genomic profiling of the tumours, including detailed clonal analysis, was performed to determine whether the clonal population in the xenograft recapitulated the patient's tumour. We identified several drug vulnerabilities and showed that the combination of a WEE1 inhibitor (AZD1775), irinotecan, and vincristine can lead to complete response in multiple rhabdomyosarcoma orthotopic patient-derived xenografts tumours in vivo.

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.

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.

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.

Impact of Neoadjuvant Chemotherapy on Image-Defined Risk Factors in High-Risk Neuroblastoma.

PURPOSE: Image-defined risk factors (IDRFs) are associated with surgical risks in neuroblastoma. We sought to evaluate the impact of neoadjuvant therapy on IDRFs and associated ability to achieve gross total resection (GTR) of locoregional disease in patients with high-risk neuroblastoma. METHODS: We retrospectively reviewed charts of patients treated on four consecutive high-risk neuroblastoma protocols over a 20-year period at a single institution. The number of IDRFs at diagnosis and just prior to surgery, and the percent decrease of tumor volume from just prior to surgery to the end of induction were determined. RESULTS: Eighty-eight patients were included. There were 438 IDRFs (average 5.0 ± 3.1 per patient) at diagnosis and 198 (average 2.3 ± 1.9 per patient) after neoadjuvant chemotherapy (p < 0.01). A reduction in IDRFs was seen in 81.8% of patients with average decrease of 2.9 ± 2.5 per patient. The average percent reduction in tumor volume was 89.8 ± 18.9% and correlated with the number of IDRFs present after chemotherapy (p < 0.01). Three or fewer IDRFs prior to surgery was associated with the highest odds ratio for > 90% GTR at 9.33 [95% confidence interval 3.14-31.5]. CONCLUSION: Neoadjuvant chemotherapy reduced the number of IDRFs in the majority of patients with high-risk neuroblastoma. The number of IDRFs present after neoadjuvant therapy correlated with the extent of resection.

Induction Chemotherapy With an Anti-GD2 Monoclonal Antibody (Dinutuximab) and Cytokines in Children With Newly Diagnosed High-risk Neuroblastoma: A Case Series.

Although outcomes for patients with high-risk neuroblastoma improved after the addition of a chimeric anti-GD2 monoclonal antibody (dinutuximab) as treatment for minimal residual disease, nearly half of these patients die of disease. Recent studies demonstrated efficacy of the combination of chemotherapy with anti-GD2 mAb in patients with relapsed or newly diagnosed disease. This retrospective case series describes 6 patients treated at St Jude Children's Research Hospital with an induction regimen containing dinutuximab and chemotherapy, followed by consolidation and postconsolidation therapy. The treatment was well tolerated with expected toxicities. All patients completed induction therapy and demonstrated a clinical response. Further studies are warranted.

Clinical impact of post-induction resolution of pulmonary lesions in metastatic Ewing sarcoma.

BACKGROUND: Patients with metastatic Ewing sarcoma experience poor outcomes despite intensive systemic and local therapy. Early chemotherapy response of pulmonary metastases has been associated with prognosis in other pediatric malignancies. We reviewed the outcomes of patients with Ewing sarcoma and pulmonary metastases treated at our institution based on therapy received and early pulmonary response. MATERIALS AND METHODS: We retrospectively reviewed patients with newly diagnosed Ewing sarcoma and pulmonary metastases at St. Jude Children's Research Hospital between 1979 and 2015. Data obtained included demographic and treatment characteristics including chemotherapy, local control measures, whole lung irradiation (WLI) administration, autologous stem cell transplantation, and outcomes. Patients were evaluated for radiographic post-induction pulmonary complete response (CR). We estimated event-free survival (EFS) and overall survival (OS) and used Cox proportional hazards regression to examine the effects of clinical and treatment factors on outcomes. RESULTS: Fifty-four patients (median age, 12.9 years) were evaluated. Post-induction pulmonary CR was observed in 33 (61%) patients. WLI was delivered to 16 patients (4/33 with pulmonary CR and 12/21 with non-CR). At median 3.6 years follow-up, five-year EFS and OS were 30.8% ± 6.4% and 49.6% ± 7.1%, respectively. Post-induction pulmonary CR was associated with prolonged EFS (P < 0.001) but not improved OS (P = 0.065). Post-induction pulmonary CR was associated with a lower incidence of lung failure (P = 0.031). CONCLUSIONS: Post-induction pulmonary CR is associated with improved EFS in patients with Ewing sarcoma who present with pulmonary metastases.

Secondary hemophagocytic syndrome after autologous hematopoietic cell transplant and immune therapy for neuroblastoma.

Secondary hemophagocytic syndrome (HPS) has been described after autologous hematopoietic cell transplant (AutoHCT). We report two cases of secondary HPS after novel consolidation therapy for high-risk neuroblastoma as part of an institutional phase 2 trial incorporating immunotherapy into a "standard" AutoHCT regimen. Both patients developed liver dysfunction beyond expected course of hepatic veno-occlusive disease, coagulopathy, hyperferritinemia, and when evaluated, elevated soluble interleukin-2 receptor and hemophagocytosis. These cases highlight the need for clinicians to have a high index of suspicion for immune-related complications in patients receiving immune therapies.

FDG-PET CT in the evaluation of primary and secondary pancreatic malignancies.

PURPOSE: Primary pancreatic carcinoma and pancreatic metastases are rare in the pediatric population. Pancreatoblastoma is the most common pancreatic malignant tumor in young children and solid-pseudopapillary tumor in teenagers. Pancreatic adenocarcinoma is extremely rare under the age of 40 and is usually associated with underlying genetic abnormalities. Secondary malignancies of the pancreas occur more frequently than primary pancreatic malignancies in children and are most commonly seen with non-Hodgkin lymphomas (NHL) and mesenchymal sarcomas. The purpose of this study was to characterize the metabolism of primary and secondary tumors of the pancreas in pediatric patients. MATERIALS AND METHODS: A retrospective analysis of all primary and secondary pancreatic malignancies imaged with 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) computed tomography (CT) was conducted. RESULTS: Three patients with primary pancreatic cancers were identified, one each with pancreatoblastoma, solid-pseudopapillary tumor, and adenocarcinoma. Each tumor showed elevated uptake of FDG. Metastatic disease in the pancreas was identified in 12 patients-five NHL (including three Burkitt lymphomas), six sarcomas (three osteosarcomas, two rhabdomyosarcomas, and one Ewing sarcoma family tumor), and one malignant rhabdoid tumor. Elevated but variable uptake of FDG was found in each of the tumors of patients with metastatic disease within the pancreas. CONCLUSION: Both primary malignancies and metastatic disease within the pancreas, though very rare in children, adolescents, and young adults, are metabolically active and can be functionally characterized using FDG-PET CT.

The Childhood Solid Tumor Network: A new resource for the developmental biology and oncology research communities.

Significant advances have been made over the past 25 years in our understanding of the most common adult solid tumors such as breast, colon, lung and prostate cancer. Much less is known about childhood solid tumors because they are rare and because they originate in developing organs during fetal development, childhood and adolescence. It can be very difficult to study the cellular origins of pediatric solid tumors in developing organs characterized by rapid proliferative expansion, growth factor signaling, developmental angiogenesis, programmed cell death, tissue reorganization and cell migration. Not only has the etiology of pediatric cancer remained elusive because of their developmental origins, but it also makes it more difficult to treat. Molecular targeted therapeutics that alter developmental pathway signaling may have devastating effects on normal organ development. Therefore, basic research focused on the mechanisms of development provides an essential foundation for pediatric solid tumor translational research. In this article, we describe new resources available for the developmental biology and oncology research communities. In a companion paper, we present the detailed characterization of an orthotopic xenograft of a pediatric solid tumor derived from sympathoadrenal lineage during development.

Consolidation Therapy for Newly Diagnosed Pediatric Patients with High-Risk Neuroblastoma Using Busulfan/Melphalan, Autologous Hematopoietic Cell Transplantation, Anti-GD2 Antibody, Granulocyte-Macrophage Colony-Stimulating Factor, Interleukin-2, and Haploidentical Natural Killer Cells.

The treatment of pediatric high-risk neuroblastoma is intensive and multimodal. Despite the introduction of immunotherapy for minimal residual disease, survival rates remain suboptimal and new therapies are needed. As part of a phase 2 trial, we are using a consolidation therapy regimen that combines a busulfan/melphalan conditioning schema, autologous hematopoietic cell transplantation (AHCT), and experimental immunotherapy with hu14.18K322A (a humanized anti-GD2 monoclonal antibody), granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-2, with or without the adoptive transfer of haploidentical natural killer cells (NKs). Here we report on 30 patients who have undergone AHCT with this experimental immunotherapy regimen, 21 of whom received haploidentical NKs. The median time to neutrophil engraftment was 13 days (range, 10 to 28 days) and to platelet engraftment of at least 20 × 103/mm3 was 36.5 days (range, 0 to 102 days); no clinical difference was seen in those who did or did not receive NKs. Eight patients developed veno-occlusive disease, with 3 having multiorgan dysfunction. Toxicities were similar for patients who did or did not receive NKs. We conclude that this consolidation regimen is feasible and has an acceptable acute toxicity profile.

Development and characterization of a human orthotopic neuroblastoma xenograft.

Neuroblastoma is a pediatric cancer of the developing sympathoadrenal lineage. The tumors are known to develop from the adrenal gland or paraspinal ganglia and have molecular and cellular features of sympathetic neurons such as dense core vesicles and catecholamine production. Here we present the detailed molecular, cellular, genetic and epigenetic characterization of an orthotopic xenograft derived from a high-risk stage 4 neuroblastoma patient. Overall, the xenografted tumor retained the high risk features of the primary tumor and showed aggressive growth and metastasis in the mouse. Also, the genome was preserved with no additional copy number variations, structural variations or aneuploidy. There were 13 missense mutations identified in the xenograft that were not present in the patient's primary tumor and there were no new nonsense mutations. None of the missense mutations acquired in the xenograft were in known cancer genes. We also demonstrate the feasibility of using the orthotopic neuroblastoma xenograft to test standard of care chemotherapy and molecular targeted therapeutics. Finally, we optimized a new approach to produce primary cultures of the neuroblastoma xenografts for high-throughput drug screening which can be used to test new combinations of therapeutic agents for neuroblastoma.

Orbital Metastasis Is Associated With Decreased Survival in Stage M Neuroblastoma.

BACKGROUND: Approximately 30% of patients with metastatic (stage M) neuroblastoma present with periorbital ecchymosis from orbital osseous disease. Though locoregional disease is staged by imaging, the prognostic significance of metastatic site in stage M disease is unknown. We hypothesize that, compared to nonorbital metastasis, orbital metastasis is associated with decreased survival in patients with stage M neuroblastoma, and that periorbital ecchymosis reflects location and extent of orbital disease. PROCEDURE: Medical records and imaging from 222 patients with stage M neuroblastoma seen at St. Jude Children's Research Hospital between January 1995 and May 2009 were reviewed. Thirty-seven patients were <18 months of age at diagnosis and 185 were ≥18 months of age. Overall survival (OS) and 5-year survival (5YS) were compared for patients with and without orbital, calvarial and nonorbital osseous metastasis, and with and without periorbital ecchymosis (log-rank test). Associations of periorbital ecchymosis with orbital metastasis location/extent were explored (Fisher's exact test, t-test). RESULTS: In patients ≥18 months of age, only orbital metastasis was associated with decreased 5YS (P = 0.0323) and OS (P = 0.0288). In patients <18 months of age, neither orbital, calvarial, or nonorbital bone metastasis was associated with OS or 5YS. Periorbital ecchymosis was associated with higher number of involved orbital bones (P = 0.0135), but not location or survival. CONCLUSIONS: In patients ≥ 18 months of age with stage M neuroblastoma, orbital metastatic disease is associated with decreased 5YS and OS. In future clinical trials, orbital disease may be useful as an imaging-based risk factor for substratification of stage M neuroblastoma.

Visual Diagnosis: New Lung Nodules in a 3-year-old Girl with Wilms Tumor.

The most significant oncologic concern with finding new pulmonary nodules on imaging in a pediatric patient who has anaplastic Wilms tumor is progressive disease with new pulmonary metastases. This case emphasizes the importance of employing a creative clinical differential diagnosis, even for patients with known underlying oncologic disease.

The role of chest computed tomography (CT) as a surveillance tool in children with high-risk neuroblastoma.

BACKGROUND: Standardization of imaging obtained in children with neuroblastoma is not well established. This study examines chest CT in pediatric patients with high-risk neuroblastoma. PROCEDURE: Medical records and imaging from 88 patients with high-risk neuroblastoma, diagnosed at St. Jude Children's Research Hospital between January, 2002 and December, 2009, were reviewed. Surveillance imaging was conducted through 2013. Ten patients with thoracic disease at diagnosis were excluded. Event free survival (EFS) and overall survival (OS) were estimated. Size specific dose estimates for CT scans of the chest, abdomen, and pelvis were used to estimate absolute organ doses to 23 organs. Organ dosimetry was used to calculate cohort effective dose. RESULTS: The 5 year OS and EFS were 51.9% ± 6.5% and 42.6% ± 6.5%, respectively. Forty-six (58.9%) patients progressed/recurred and 41 (52.6%) died of disease. Eleven patients (14%) developed thoracic disease progression/recurrence identified by chest CT (1 paraspinal mass, 1 pulmonary nodules, and 9 nodal). MIBG (metaiodobenzylguanidine) scans identified thoracic disease in six patients. Five of the 11 had normal chest MIBG scans; three were symptomatic and two were asymptomatic with normal chest MIBG scans but avid bone disease. The estimated radiation dose savings from surveillance without CT chest imaging was 42%, 34% when accounting for modern CT acquisition (2011-2013). CONCLUSIONS: Neuroblastoma progression/recurrence in the chest is rare and often presents with symptoms or is identified using standard non-CT imaging modalities. For patients with non-thoracic high-risk neuroblastoma at diagnosis, omission of surveillance chest CT imaging can save 35-42% of the radiation burden without compromising disease detection.

Subsequent malignant neoplasms in pediatric patients initially diagnosed with neuroblastoma.

BACKGROUND: Most prior studies evaluating subsequent malignant neoplasms (SMNs) in patients with neuroblastoma are restricted to long-term survivors and/or their treatment exposures. This study investigates SMNs in patients diagnosed with neuroblastoma at our institution. METHODS: Records of 646 patients treated for neuroblastoma at St Jude Children's Research Hospital between 1961 and 2005 were reviewed. Data from patients with SMNs were analyzed and the 20- and 30-year cumulative incidence of SMNs and standardized incidence ratio were calculated. RESULTS: Twenty-one patients had a SMN. The 20- and 30-year cumulative incidences of a SMN were 2.6%±0.7% and 4.6%±1.1%, respectively. The standardized incidence ratio was 8.3 (95% confidence interval, 5.0-13.0). Five patients developed a SMN within 5 years from diagnosis. The median latency for the development of acute myeloid leukemia/myelodysplastic syndrome (n=4), sarcomas (n=7), and carcinomas (n=5) were 3.6, 9, and 24.2 years, respectively. Nine patients died from their SMN, including all with acute myeloid leukemia/myelodysplastic syndrome. CONCLUSIONS: Patients with neuroblastoma have an increased risk of secondary neoplasia. Modification of risk-adapted therapies will likely alter the affected patient population and the incidence of SMNs. Future studies are necessary to link SMNs to treatment exposures and to evaluate the risk of SMNs beyond 30 years from diagnosis.