Bevacizumab, Irinotecan, or Topotecan Added to Temozolomide for Children With Relapsed and Refractory Neuroblastoma: Results of the ITCC-SIOPEN BEACON-Neuroblastoma Trial.

PURPOSE: Outcomes for children with relapsed and refractory high-risk neuroblastoma (RR-HRNB) remain dismal. The BEACON Neuroblastoma trial (EudraCT 2012-000072-42) evaluated three backbone chemotherapy regimens and the addition of the antiangiogenic agent bevacizumab (B). MATERIALS AND METHODS: Patients age 1-21 years with RR-HRNB with adequate organ function and performance status were randomly assigned in a 3 × 2 factorial design to temozolomide (T), irinotecan-temozolomide (IT), or topotecan-temozolomide (TTo) with or without B. The primary end point was best overall response (complete or partial) rate (ORR) during the first six courses, by RECIST or International Neuroblastoma Response Criteria for patients with measurable or evaluable disease, respectively. Safety, progression-free survival (PFS), and overall survival (OS) time were secondary end points. RESULTS: One hundred sixty patients with RR-HRNB were included. For B random assignment (n = 160), the ORR was 26% (95% CI, 17 to 37) with B and 18% (95% CI, 10 to 28) without B (risk ratio [RR], 1.52 [95% CI, 0.83 to 2.77]; P = .17). Adjusted hazard ratio for PFS and OS were 0.89 (95% CI, 0.63 to 1.27) and 1.01 (95% CI, 0.70 to 1.45), respectively. For irinotecan ([I]; n = 121) and topotecan (n = 60) random assignments, RRs for ORR were 0.94 and 1.22, respectively. A potential interaction between I and B was identified. For patients in the bevacizumab-irinotecan-temozolomide (BIT) arm, the ORR was 23% (95% CI, 10 to 42), and the 1-year PFS estimate was 0.67 (95% CI, 0.47 to 0.80). CONCLUSION: The addition of B met protocol-defined success criteria for ORR and appeared to improve PFS. Within this phase II trial, BIT showed signals of antitumor activity with acceptable tolerability. Future trials will confirm these results in the chemoimmunotherapy era.

Characteristics and outcomes of patients with tricuspid regurgitation and advanced heart failure.

AIMS: To evaluate the role of tricuspid regurgitation in advanced heart failure. METHODS: The multicenter observational HELP-HF registry enrolled consecutive patients with heart failure and at least one 'I NEED HELP' criterion evaluated at four Italian centers between January 2020 and November 2021. Patients with no data on tricuspid regurgitation and/or receiving tricuspid valve intervention during follow-up were excluded. The population was stratified by no/mild tricuspid regurgitation vs. moderate tricuspid regurgitation vs. severe tricuspid regurgitation. Variables independently associated with tricuspid regurgitation, as well as the association between tricuspid regurgitation and clinical outcomes were investigated. The primary outcome was all-cause mortality. RESULTS: Among the 1085 patients included in this study, 508 (46.8%) had no/mild tricuspid regurgitation, 373 (34.4%) had moderate tricuspid regurgitation and 204 (18.8%) had severe tricuspid regurgitation. History of atrial fibrillation, any prior valve surgery, high dose of furosemide, preserved left ventricular ejection fraction, moderate/severe mitral regurgitation and pulmonary hypertension were found to be independently associated with an increased likelihood of severe tricuspid regurgitation. Estimated rates of 1-year all-cause death were of 21.4, 24.5 and 37.1% in no/mild tricuspid regurgitation, moderate tricuspid regurgitation and severe tricuspid regurgitation, respectively (log-rank P  < 0.001). As compared with nonsevere tricuspid regurgitation, severe tricuspid regurgitation was independently associated with a higher risk of all-cause mortality (adjusted hazard ratio 1.38, 95% confidence interval 1.01-1.88, P  = 0.042), whereas moderate tricuspid regurgitation did not. CONCLUSION: In a contemporary, real-world cohort of patients with advanced heart failure, several clinical and echocardiographic characteristics are associated with an increased likelihood of severe tricuspid regurgitation. Patients with severe tricuspid regurgitation have an increased risk of mortality.

Longitudinal Gait Analysis of a Transfemoral Amputee Patient: Single-Case Report from Socket-Type to Osseointegrated Prosthesis.

The aim of the present case report was to provide a longitudinal functional assessment of a patient with transfemoral amputation from the preoperative status with socket-type prosthesis to one year after the osseointegration surgery. A 44 years-old male patient was scheduled for osseointegration surgery 17 years after transfemoral amputation. Gait analysis was performed through 15 wearable inertial sensors (MTw Awinda, Xsens) before surgery (patient wearing his standard socket-type prosthesis) and at 3-, 6-, and 12-month follow-ups after osseointegration. ANOVA in Statistical Parametric Mapping was used to assess the changes in amputee and sound limb hip and pelvis kinematics. The gait symmetry index progressively improved from the pre-op with socket-type (1.14) to the last follow-up (1.04). Step width after osseointegration surgery was half of the pre-op. Hip flexion-extension range significantly improved at follow-ups while frontal and transverse plane rotations decreased (p < 0.001). Pelvis anteversion, obliquity, and rotation also decreased over time (p < 0.001). Spatiotemporal and gait kinematics improved after osseointegration surgery. One year after surgery, symmetry indices were close to non-pathological gait and gait compensation was sensibly decreased. From a functional point of view, osseointegration surgery could be a valid solution in patients with transfemoral amputation facing issues with traditional socket-type prosthesis.

Spondylolisthesis in young patients: postoperative functional outcomes at 22-year mean follow-up.

INTRODUCTION: Previous short- and intermediate-term clinical and radiographic studies demonstrated good results in patients who underwent spine surgery for spondylolisthesis, long-term outcomes are lacking instead. Young patients are often involved in high-demanding and sport activities, therefore good/excellent functional outcomes are very important for their future quality of life. The aim of this study is to assess the long-term functional results in young patients surgically treated for developmental spondylolisthesis. MATERIALS AND METHODS: Retrospective evaluation of consecutive patients who underwent lumbar surgery for spondylolisthesis. Inclusion criteria were: spondylolisthesis from grade 1 to spondyloptosis, age at surgery < 25 years, follow-up > 15 years. The following outcomes were assessed: VAS back, VAS leg, Oswestry disability index (ODI) score, Short Form 12 (SF-12), rate of revision surgery, postoperative recovery and sport activity. RESULTS: 113 patients were enrolled. Mean age at surgery was 19.8 years and mean follow-up was 22.1 years (16-32). 16 patients (14.2%) needed revision surgery. Functional outcomes at last follow-up were: VAS back = 1.6, VAS leg = 1.4, ODI = 9.2%, SF-12 physical component summary = 50, SF-12 mental component summary = 48.7. Significant differences were assessed in terms of ODI (p = 0.047) and SF-12 PCS (p = 0.015) between group treated with instrumented and non-instrumented techniques. Among the patients who practiced a sport, 87% returned to sport postoperatively (55% at medium-high-intensity level). CONCLUSION: This study shows good long-term functional outcomes in patients surgically treated for developmental spondylolisthesis. After surgery, there is a low incidence of back pain, the residual disability is mild and almost half of patients recover the same level of sport activity. Instrumented surgical techniques developed over the years seem to be related to high revision rate, but this does not affect long-term functional results.

Adolescent Idiopathic Scoliosis Surgery: Postoperative Functional Outcomes at 32 Years Mean Follow-Up.

INTRODUCTION: Recent clinical and radiographic studies conducted over short and medium terms have demonstrated positive results in patients undergoing surgery for adolescent idiopathic scoliosis (AIS). However, the absence of long-term data, crucial for comprehending the impact on future quality of life, especially in young patients actively involved in very intense physical activities, remains a gap. This study aims to evaluate long-term functional outcomes in patients who underwent surgery for Adolescent Idiopathic Scoliosis. MATERIAL AND METHODS: Patients meeting specific criteria (diagnosis of AIS, age at surgery between 12 and 18 years, and follow-up of at least 20 years) were identified from a large spine surgery center database. A questionnaire using "Google Form" assessed various outcomes, including Visual Analog Scale (VAS) back, VAS leg, Short Form 12 score (SF-12), Scoliosis Research Society 22 score (SRS-22), incidence of spine revision surgery, postoperative high demanding activities (work and sport), and possible pregnancies was sent to the enrolled patients. The authors analyzed the results regarding all patients included and, moreover, statistical analysis categorized patients into two groups based on the surgical fusion performed: Group 1 (non-instrumented technique according to Hibbs-Risser) and Group 2 (instrumented tecnique according to Cotrel-Dubousset). RESULTS: A total of 63 patients (mean age 47.5 years) were included, with a mean follow-up of 31.9 years. Patients were, in mean, 47.5 years old. Group 1 comprised 42 patients, and Group 2 had 21 patients. Revision surgery was required in 19% of patients, predominantly for implant issues in Group 2 (11.9% vs. 33%, p < 0.05). Overall outcomes were favorable: VAS back = 3.5, VAS leg = 2.5, SRS-22 = 3.5, SF-12 Physical Component Summary = 41.1, SF-12 Mental Component Summary = 46.7, with no significant differences between the group 1 and group 2. At 5-years FU, the non-reoperation rate was higher in the non-instrumented group (97.6% vs. 71.4%, p < 0.001). By means of SRS-22, overall satisfaction was 3.7 ± 1.2 on a maximum scale of 5. More than half of women have successfully completed one pregnancy. Most patients (87.3%) maintained regular work activity. Among sport practioners, half returned to the similar preoperative level. CONCLUSIONS: This study reveals favorable long-term functional results in adolescent idiopathic scoliosis patients after surgical fusion. Mild to moderate back and leg pain were observed, but overall satisfaction, sport participation, and work activity were high. Surgical technique (non-instrumented vs. instrumented) did not significantly impact long-term results, though the instrumented fusion exhibited a higher revision rate.

Mutations in ALK signaling pathways conferring resistance to ALK inhibitor treatment lead to collateral vulnerabilities in neuroblastoma cells.

BACKGROUND: Development of resistance to targeted therapies has tempered initial optimism that precision oncology would improve poor outcomes for cancer patients. Resistance mechanisms, however, can also confer new resistance-specific vulnerabilities, termed collateral sensitivities. Here we investigated anaplastic lymphoma kinase (ALK) inhibitor resistance in neuroblastoma, a childhood cancer frequently affected by activating ALK alterations. METHODS: Genome-wide forward genetic CRISPR-Cas9 based screens were performed to identify genes associated with ALK inhibitor resistance in neuroblastoma cell lines. Furthermore, the neuroblastoma cell line NBLW-R was rendered resistant by continuous exposure to ALK inhibitors. Genes identified to be associated with ALK inhibitor resistance were further investigated by generating suitable cell line models. In addition, tumor and liquid biopsy samples of four patients with ALK-mutated neuroblastomas before ALK inhibitor treatment and during tumor progression under treatment were genomically profiled. RESULTS: Both genome-wide CRISPR-Cas9-based screens and preclinical spontaneous ALKi resistance models identified NF1 loss and activating NRASQ61K mutations to confer resistance to chemically diverse ALKi. Moreover, human neuroblastomas recurrently developed de novo loss of NF1 and activating RAS mutations after ALKi treatment, leading to therapy resistance. Pathway-specific perturbations confirmed that NF1 loss and activating RAS mutations lead to RAS-MAPK signaling even in the presence of ALKi. Intriguingly, NF1 loss rendered neuroblastoma cells hypersensitive to MEK inhibition. CONCLUSIONS: Our results provide a clinically relevant mechanistic model of ALKi resistance in neuroblastoma and highlight new clinically actionable collateral sensitivities in resistant cells.

Exercise and Oxidative Stress Biomarkers among Adult with Cancer: A Systematic Review.

Evidence shows that exercise can have a favourable effect in cancer patients. The exercise's clinical benefits are likely to concern multiple interrelated biological pathways, among which oxidative stress plays a key role. Regular training can induce an adaptive response that strengthens the antioxidative status of the body. To formulate public health recommendations regarding the optimal exercise prescription for cancer patients, a detailed understanding is needed regarding the effect of exercise on variables linked to oxidative stress and antioxidant status of patients. The goal of this systematic review, based on PRISMA, was to explore and critically analyse the evidence regarding the efficacy of exercise on oxidative stress biomarkers among people with cancer. Study search was conducted in the following databases: PubMed, Cochrane, CINAHL, Embase, PEDro, and SPORTDiscus. The studies' quality was assessed with the Cochrane risk-of-bias tool and STROBE scale. After identification and screening steps, 10 articles were included. The findings provide an encouraging picture of exercise, including resistance training and aerobic activities, in people with cancer. The exercise improved the indicators of the total antioxidant capacity, increased the antioxidant enzymes' activity, or reduced the biomarkers of oxidative damage in various forms of cancer such as breast, lung, head, and neck. Regarding oxidative DNA damage, the role of exercise intervention has been difficult to assess. The heterogeneity of study design and the plethora of biomarkers measured hampered the comparison of the articles. This limited the possibility of establishing a comprehensive conclusion on the sensitivity of biomarkers to estimate the exercise's benefits. Further high-quality studies are required to provide data regarding oxidative stress biomarkers responding to exercise. This information will be useful to assess the efficacy of exercise in people with cancer and support the appropriate prescription of exercise in anticancer strategy.

Managing Adverse Events Associated with Dinutuximab Beta Treatment in Patients with High-Risk Neuroblastoma: Practical Guidance.

Neuroblastoma is the most common extracranial solid tumour in children, accounting for 15% of all paediatric cancer deaths. High-risk neuroblastoma is a particularly challenging-to-treat form of disease that requires multimodality treatment, consisting of chemotherapy, surgery, high-dose chemotherapy with autologous haematopoietic stem cell rescue, radiotherapy and differentiation therapy. However, despite intense multimodal treatment regimens, the prognosis for this patient population remains poor. In recent years, immunotherapy with anti-disialoganglioside 2 (anti-GD2) antibodies was found to improve survival rates for patients with high-risk neuroblastoma. Based on studies led by the SIOPEN (International Society of Paediatric Oncology European Neuroblastoma) group, the anti-GD2 antibody dinutuximab beta was approved for use in high-risk neuroblastoma by the European Medicines Agency and has been implemented into the standard of care in many countries across Europe. However, immunotherapy with dinutuximab beta is associated with a number of adverse events that may be challenging for clinicians, such as pain, fever, hypersensitivity reactions and capillary leak syndrome. While these adverse events are considered manageable, there are currently no formal guidelines to support clinicians with their management. The aim of this article is to discuss the management of the most common adverse events encountered in clinical practice and to provide practical guidance to assist clinicians in minimising toxicity associated with dinutuximab beta.

Evaluation of the Efficacy and Safety of an Exercise Program for Persons with Total Hip or Total Knee Replacement: Study Protocol for a Randomized Controlled Trial.

Total hip replacement (THR) and total knee replacement (TKR) are among the most common elective surgical procedures. There is a large consensus on the importance of physical activity promotion for an active lifestyle in persons who underwent THR or TKR to prevent or mitigate disability and improve the quality of life (QoL) in the long term. However, there is no best practice in exercise and physical activity specifically designed for these persons. The present protocol aims to evaluate the efficacy and safety of an exercise program (6 month duration) designed for improving quality of life in people who had undergone THR or TKR. This paper describes a randomized controlled trial protocol that involves persons with THR or TKR. The participant will be randomly assigned to an intervention group or a control group. The intervention group will perform post-rehabilitation supervised training; the control group will be requested to follow the usual care. The primary outcome is QoL, measured with the Short-Form Health Survey (SF-36); Secondary outcomes are clinical, functional and lifestyle measures that may influence QoL. The results of this study could provide evidence for clinicians, exercise trainers, and policymakers toward a strategy that ensures safe and effective exercise physical activity after surgery.

Causes of stiffness after total knee arthroplasty: a systematic review.

BACKGROUND: Knee stiffness after total knee arthroplasty (TKA) often leads to pain and discomfort, failing to meet patients' expectations on the surgical procedure. Despite the growing debate on the topic, a comprehensive literature analysis of stiffness causes has never been conducted. Thus, the purpose of the present study was to systematically review the literature regarding the main causes of stiffness after TKA. METHODS: Pubmed Central, Scopus, and EMBASE databases were systematically reviewed according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines for studies on stiffness and pain or discomfort after TKA through November 2020. Overall, 25 articles matched the selection criteria and were included in the study. Clinical relevance and strength of evidence of the included studies were graded using the risk of bias and the methodological index for non-randomized studies quality assessment tools. RESULTS: The main causes of pain and discomfort due to stiffness were surgery-related issues, i.e., component malpositioning and over-voluming, implant loosening, psychological distress, and obesity, which could be considered "modifiable" factors, and expression of profibrotic markers, high material hypersensitivity-related cytokines level, male gender, previous contralateral TKA, and high pre-operative pain, which could be considered "non-modifiable" factors. CONCLUSION: The use of alternative technologies such as surgical robots, anatomy-based devices, and more inert and less stiff component materials could help in reducing stiffness caused by both modifiable and even some non-modifiable factors. Furthermore, early diagnostic detection of stiffness onset could consistently support surgeons in patient-specific decision-making.

Mechanical Complications in Adult Spine Deformity Surgery: Retrospective Evaluation of Incidence, Clinical Impact and Risk Factors in a Single-Center Large Series.

The advancement of deformity-specific implants and surgical techniques has improved the surgical treatment of Adult Spine Deformity (ASD), allowing surgeons to treat more complex deformities. Simultaneously, high rates of medical and surgical complications have been reported. The aim of this study is to describe the risk factors, the rate and the clinical impact of mechanical complications in ASD surgery. A retrospective review of a large, single-center database of consecutive ASD patients was conducted. Inclusion criteria were as follows: Cobb coronal curve > 20° or alteration of at least one of sagittal vertical axis (SVA > 40 mm), thoracic kyphosis (TK > 60°), pelvic tilt (PT > 20°) and pelvic incidence minus lumbar lordosis mismatch (PI-LL > 10°), at least four levels of posterior instrumented fusion and 2-year follow-up. At the baseline and at each follow-up end point, the authors collected clinical and radiographic outcomes and recorded any mechanical complications that occurred. One hundred and two patients were enrolled. Clinical outcomes significantly were improved at the last follow-up (mean 40.9 months). Postoperative mechanical complications occurred in 15 patients (14.7%); proximal junctional disease was the most common complication (60%) and the revision rate was 53.3%. Patients who experienced mechanical complications were older (61.2 vs. 54.8 years, p = 0.04); they had also a higher rate of pelvic fusion and posterior-only approach, a lower LL (-37.9 vs. -46.2, p = 0.02) and a higher PT (26.3 vs. 19.8, p = 0.009), TK (41.8 vs. 35.7, p = 0.05), PI-LL (12.9 vs. 5.4, p = 0.03) and Global Alignment and Proportion score (6.9 vs. 4.3, p = 0.01). This study showed a significant improvement in pain and disability after ASD surgery. Regarding the risk of developing a mechanical complication, not only postoperative radiographic parameters affected the risk but also patient age and surgical features.

Tumor to normal single-cell mRNA comparisons reveal a pan-neuroblastoma cancer cell.

Neuroblastoma is a childhood cancer that resembles developmental stages of the neural crest. It is not established what developmental processes neuroblastoma cancer cells represent. Here, we sought to reveal the phenotype of neuroblastoma cancer cells by comparing cancer (n = 19,723) with normal fetal adrenal single-cell transcriptomes (n = 57,972). Our principal finding was that the neuroblastoma cancer cell resembled fetal sympathoblasts, but no other fetal adrenal cell type. The sympathoblastic state was a universal feature of neuroblastoma cells, transcending cell cluster diversity, individual patients, and clinical phenotypes. We substantiated our findings in 650 neuroblastoma bulk transcriptomes and by integrating canonical features of the neuroblastoma genome with transcriptional signals. Overall, our observations indicate that a pan-neuroblastoma cancer cell state exists, which may be attractive for novel immunotherapeutic and targeted avenues.

Comparison Between Diffusion-Weighted MRI and 123 I-mIBG Uptake in Primary High-Risk Neuroblastoma.

BACKGROUND: High-risk neuroblastoma (HR-NB) has a variable response to preoperative chemotherapy. It is not possible to differentiate viable vs. nonviable residual tumor before surgery. PURPOSE: To explore the association between apparent diffusion coefficient (ADC) values from diffusion-weighted magnetic resonance imaging (DW-MRI), 123 I-meta-iodobenzyl-guanidine (123 I-mIBG) uptake, and histology before and after chemotherapy. STUDY TYPE: Retrospective. SUBJECTS: Forty patients with HR-NB. FIELD STRENGTH/SEQUENCE: 1.5T axial DW-MRI (b = 0,1000 s/mm2 ) and T2 -weighted sequences. 123 I-mIBG scintigraphy planar imaging (all patients), with additional 123 I-mIBG single-photon emission computed tomography / computerized tomography (SPECT/CT) imaging (15 patients). ASSESSMENT: ADC maps and 123 I-mIBG SPECT/CT images were coregistered to the T2 -weighted images. 123 I-mIBG uptake was normalized with a tumor-to-liver count ratio (TLCR). Regions of interest (ROIs) for primary tumor volume and different intratumor subregions were drawn. The lower quartile ADC value (ADC25prc ) was used over the entire tumor volume and the overall level of 123 I-mIBG uptake was graded into avidity groups. STATISTICAL TESTS: Analysis of variance (ANOVA) and linear regression were used to compare ADC and MIBG values before and after treatment. Threshold values to classify tumors as viable/necrotic were obtained using ROC analysis of ADC and TLCR values. RESULTS: No significant difference in whole-tumor ADC25prc values were found between different 123 I-mIBG avidity groups pre- (P = 0.31) or postchemotherapy (P = 0.35). In the "intratumor" analysis, 5/15 patients (prechemotherapy) and 0/14 patients (postchemotherapy) showed a significant correlation between ADC and TLCR values (P < 0.05). Increased tumor shrinkage was associated with lower pretreatment tumor ADC25prc values (P < 0.001); no association was found with pretreatment 123 I-mIBG avidity (P = 0.17). Completely nonviable tumors had significantly lower postchemotherapy ADC25prc values than tumors with >10% viable tumor (P < 0.05). Both pre- and posttreatment TLCR values were significantly higher in patients with >50% viable tumor than those with 10-50% viable tumor (P < 0.05). DATA CONCLUSION: 123 I-mIBG avidity and ADC values are complementary noninvasive biomarkers of therapeutic response in HR-NB. LEVEL OF EVIDENCE: 4. TECHNICAL EFFICACY STAGE: 3.

Importance of Magnetic Resonance Imaging With Diffusion-weighted Imaging in Guiding Biopsy of Nodular Ganglioneuroblastoma: A Case Report.

BACKGROUND: Nodular ganglioneuroblastoma is a rare peripheral neuroblastic tumor of variable prognosis. Accurate diagnosis, staging, and risk categorization can be particularly challenging in patients with nodular ganglioneuroblastoma due to the inherent heterogeneity of these lesions. CASE PRESENTATION: We illustrate the use of diffusion-weighted magnetic resonance imaging to identify tumor nodules and guide tumor biopsy in an almost 5-year-old boy with a large abdominal tumor. CONCLUSIONS: Diffusion-weighted magnetic resonance imaging was successful in detecting and guiding biopsy of a poorly differentiated neuroblastoma nodule within the context of a well-differentiated ganglioneuroma, allowing the diagnosis and characterization of a ganglioneuroblastoma nodular, thus influencing the child's prognosis and treatment.

Flow cytometry of bone marrow aspirates from neuroblastoma patients is a highly sensitive technique for quantification of low-level neuroblastoma.

Background: Bone marrow involvement is an important aspect of determining staging of disease and treatment for childhood neuroblastoma. Current standard of care relies on microscopic examination of bone marrow trephine biopsies and aspirates respectively, to define involvement. Flow cytometric analysis of disaggregated tumour cells, when using a panel of neuroblastoma specific markers, allows for potentially less subjective determination of the presence of tumour cells. Methods: A retrospective review of sequential bone marrow trephine biopsies and aspirates, performed at Great Ormond Street Hospital, London, between the years 2015 and 2018, was performed to assess whether the addition of flow cytometric analysis to these standard of care methods provided concordant or additional information. Results: There was good concurrence between all three methods for negative results 216/302 (72%). Positive results had a concordance of 52/86 (61%), comparing samples positive by flow cytometry and positive by either or both cytology and histology.  Of the remaining samples, 20/86 (23%) were positive by either or both cytology and histology, but negative by flow cytometry. Whereas 14/86 (16%) of samples were positive only by flow cytometry. Conclusions: Our review highlights the ongoing importance of expert cytological and histological assessment of bone marrow results. Flow cytometry is an objective, quantitative method to assess the level of bone marrow disease in aspirates.  In this study, flow cytometry identified low-level residual disease that was not detected by cytology or histology. The clinical significance of this low-level disease warrants further investigation.

Antitumor activity without on-target off-tumor toxicity of GD2-chimeric antigen receptor T cells in patients with neuroblastoma.

The reprogramming of a patient's immune system through genetic modification of the T cell compartment with chimeric antigen receptors (CARs) has led to durable remissions in chemotherapy-refractory B cell cancers. Targeting of solid cancers by CAR-T cells is dependent on their infiltration and expansion within the tumor microenvironment, and thus far, fewer clinical responses have been reported. Here, we report a phase 1 study (NCT02761915) in which we treated 12 children with relapsed/refractory neuroblastoma with escalating doses of second-generation GD2-directed CAR-T cells and increasing intensity of preparative lymphodepletion. Overall, no patients had objective clinical response at the evaluation point +28 days after CAR-T cell infusion using standard radiological response criteria. However, of the six patients receiving ≥108/meter2 CAR-T cells after fludarabine/cyclophosphamide conditioning, two experienced grade 2 to 3 cytokine release syndrome, and three demonstrated regression of soft tissue and bone marrow disease. This clinical activity was achieved without on-target off-tumor toxicity. Targeting neuroblastoma with GD2 CAR-T cells appears to be a valid and safe strategy but requires further modification to promote CAR-T cell longevity.

Orally bioavailable CDK9/2 inhibitor shows mechanism-based therapeutic potential in MYCN-driven neuroblastoma.

The undruggable nature of oncogenic Myc transcription factors poses a therapeutic challenge in neuroblastoma, a pediatric cancer in which MYCN amplification is strongly associated with unfavorable outcome. Here, we show that CYC065 (fadraciclib), a clinical inhibitor of CDK9 and CDK2, selectively targeted MYCN-amplified neuroblastoma via multiple mechanisms. CDK9 - a component of the transcription elongation complex P-TEFb - bound to the MYCN-amplicon superenhancer, and its inhibition resulted in selective loss of nascent MYCN transcription. MYCN loss led to growth arrest, sensitizing cells for apoptosis following CDK2 inhibition. In MYCN-amplified neuroblastoma, MYCN invaded active enhancers, driving a transcriptionally encoded adrenergic gene expression program that was selectively reversed by CYC065. MYCN overexpression in mesenchymal neuroblastoma was sufficient to induce adrenergic identity and sensitize cells to CYC065. CYC065, used together with temozolomide, a reference therapy for relapsed neuroblastoma, caused long-term suppression of neuroblastoma growth in vivo, highlighting the clinical potential of CDK9/2 inhibition in the treatment of MYCN-amplified neuroblastoma.

Accelerating drug development for neuroblastoma: Summary of the Second Neuroblastoma Drug Development Strategy forum from Innovative Therapies for Children with Cancer and International Society of Paediatric Oncology Europe Neuroblastoma.

Only one class of targeted agents (anti-GD2 antibodies) has been incorporated into front-line therapy for neuroblastoma since the 1980s. The Neuroblastoma New Drug Development Strategy (NDDS) initiative commenced in 2012 to accelerate the development of new drugs for neuroblastoma. Advances have occurred, with eight of nine high-priority targets being evaluated in paediatric trials including anaplastic lymphoma kinase inhibitors being investigated in front-line, but significant challenges remain. This article reports the conclusions of the second NDDS forum, which expanded across the Atlantic to further develop the initiative. Pre-clinical and clinical data for 40 genetic targets and mechanisms of action were prioritised and drugs were identified for early-phase trials. Strategies to develop drugs targeting TERT, telomere maintenance, ATRX, alternative lengthening of telomeres (ALT), BRIP1 and RRM2 as well as direct targeting of MYCN are high priority and should be championed for drug discovery. Promising pre-clinical data suggest that targeting of ALT by ATM or PARP inhibition may be potential strategies. Drugs targeting CDK2/9, CDK7, ATR and telomere maintenance should enter paediatric clinical development rapidly. Optimising the response to anti-GD2 by combinations with chemotherapy, targeted agents and other immunological targets are crucial. Delivering this strategy in the face of small patient cohorts, genomically defined subpopulations and a large number of permutations of combination trials, demands even greater international collaboration. In conclusion, the NDDS provides an internationally agreed, biologically driven selection of prioritised genetic targets and drugs. Improvements in the strategy for conducting trials in neuroblastoma will accelerate bringing these new drugs more rapidly to front-line therapy.

Noninvasive MRI Native T1 Mapping Detects Response to MYCN-targeted Therapies in the Th-MYCN Model of Neuroblastoma.

Noninvasive early indicators of treatment response are crucial to the successful delivery of precision medicine in children with cancer. Neuroblastoma is a common solid tumor of young children that arises from anomalies in neural crest development. Therapeutic approaches aiming to destabilize MYCN protein, such as small-molecule inhibitors of Aurora A and mTOR, are currently being evaluated in early phase clinical trials in children with high-risk MYCN-driven disease, with limited ability to evaluate conventional pharmacodynamic biomarkers of response. T1 mapping is an MRI scan that measures the proton spin-lattice relaxation time T1. Using a multiparametric MRI-pathologic cross-correlative approach and computational pathology methodologies including a machine learning-based algorithm for the automatic detection and classification of neuroblasts, we show here that T1 mapping is sensitive to the rich histopathologic heterogeneity of neuroblastoma in the Th-MYCN transgenic model. Regions with high native T1 corresponded to regions dense in proliferative undifferentiated neuroblasts, whereas regions characterized by low T1 were rich in apoptotic or differentiating neuroblasts. Reductions in tumor-native T1 represented a sensitive biomarker of response to treatment-induced apoptosis with two MYCN-targeted small-molecule inhibitors, Aurora A kinase inhibitor alisertib (MLN8237) and mTOR inhibitor vistusertib (AZD2014). Overall, we demonstrate the potential of T1 mapping, a scan readily available on most clinical MRI scanners, to assess response to therapy and guide clinical trials for children with neuroblastoma. The study reinforces the potential role of MRI-based functional imaging in delivering precision medicine to children with neuroblastoma. SIGNIFICANCE: This study shows that MRI-based functional imaging can detect apoptotic responses to MYCN-targeted small-molecule inhibitors in a genetically engineered murine model of MYCN-driven neuroblastoma.

Evaluation of proprioception and postural control at a minimum 1 year follow-up after ankle capsuloligamentous lateralplasty with Brostrom technique: A cohort study.

Recovery of postural control and proprioception in patients affected by chronic ankle instability (CAI) and operated on capsulo-ligaments reconstructive surgery lacks of objective assessment. The aim of this study was to evaluate long-term post-surgical postural and proprioceptive control through the DPPS device in a cohort of patients operated on ligaments reconstruction through the modified Brostrom procedure at a minimum follow up of 12 months.Eleven patients with post-traumatic lateral CAI, operated of external capsulo-ligamentous complex repair according to Brostrom technique at a minimum follow-up of 1 year were enrolled. Physical examination and American Orthopaedics Foot and Ankle Society (AOFAS) ankle-hindfoot score. Proprioceptive and postural stability was assessed by DPPS - Delos Postural Proprioceptive System, linked to a computer with a specific software and including a flat table, an electronic unstable proprioceptive board, a Delos Vertical Controller, a monitor and a horizontal bar fitted with an infra-red sensor for hand support.Patients were 5 males and 6 females, mean age of 38.4 ±â€Š12 years. Mean BMI of the patients was 26.8 ±â€Š4.4. Mean follow up was 13.4 ±â€Š2.1. The mean value of (AOFAS) clinical score was 90.3/100. Mean Static Stability Index (SSI) with open eyes was 87.7% (±7.6) in the operated leg and 90.4% (±6.1) in the contra-lateral. SSI with closed eyes was 64.5% (±11.2) in the operated leg and 61.6% (±16.8) in the contra-lateral. Mean Dynamic Stability Index (DSI) without restrictions was 56.2% (±14.6) in the operated leg and 56.8% (±10.6) in the contra-lateral. DSI with restricted upper limbs, had a mean value of 56.3% (±11.4) in the operated leg and 58.1% (±11.9) in the contra-lateral.Re-tensioning capsular-ligamentous surgery of the external compartment for CAI allow to recovery proprioceptive and postural control on the operated side, comparable with data from the contralateral limb and from the healthy population of the same age and sex.