Quantitative diffusion-weighted MRI response assessment in rhabdomyosarcoma: an international retrospective study on behalf of the European paediatric Soft tissue sarcoma Study Group Imaging Committee.

Objective: To investigate the feasibility of diffusion-weighted magnetic resonance imaging (DW-MRI) as a predictive imaging marker after neoadjuvant chemotherapy in patients with rhabdomyosarcoma.

Material And Methods: We performed a multicenter retrospective study including pediatric, adolescent and young adult patients with rhabdomyosarcoma, Intergroup Rhabdomyosarcoma Study group III/IV, treated according to the European paediatric Soft tissue sarcoma Study Group (EpSSG) RMS2005 or MTS2008 studies. DW-MRI was performed according to institutional protocols.

Analysis of Cancer Genomic Amplifications Identifies Druggable Collateral Dependencies within the Amplicon.

The identification of novel therapeutic targets for specific cancer molecular subtypes is crucial for the development of precision oncology. In the last few years, CRISPR/Cas9 screens have accelerated the discovery and validation of new targets associated with different tumor types, mutations, and fusions. However, there are still many cancer vulnerabilities associated with specific molecular features that remain to be explored.

Nonmetastatic Rhabdomyosarcoma in Children and Adolescents: Overall Results of the European Pediatric Soft Tissue Sarcoma Study Group RMS2005 Study.

JCO The RMS2005 study included two phase III randomized trials for high-risk (HR) and observational trials for low (LR), standard (SR), and very high-risk (VHR) patients who have been partially reported. Herein, we present a comprehensive report of results achieved for the complete unselected nonmetastatic cohort and analyze the evolution of treatment in comparison with previous European protocols. After a median follow-up of 73.

Targeting the Hedgehog Pathway in Rhabdomyosarcoma.

Aberrant activation of the Hedgehog (Hh) signalling pathway is known to play an oncogenic role in a wide range of cancers; in the particular case of rhabdomyosarcoma, this pathway has been demonstrated to be an important player for both oncogenesis and cancer progression. In this review, after a brief description of the pathway and the characteristics of its molecular components, we describe, in detail, the main activation mechanisms that have been found in cancer, including ligand-dependent, ligand-independent and non-canonical activation. In this context, the most studied inhibitors, i.

Metastatic rhabdomyosarcoma with exclusive distant lymph node involvement: A European Pediatric Soft tissue sarcoma Study Group (EpSSG) report.

Background: The prognosis of patients with metastatic rhabdomyosarcoma (RMS) is not uniformly poor. Tumors with nodal involvement beyond the first lymph node station are currently considered to have distant metastases. The aim of this study is to evaluate the characteristics and outcome of RMS patients with distal nodal involvement as the only site of metastasis.

Integrin alpha9 emerges as a key therapeutic target to reduce metastasis in rhabdomyosarcoma and neuroblastoma.

The majority of current cancer therapies are aimed at reducing tumour growth, but there is lack of viable pharmacological options to reduce the formation of metastasis. This is a paradox, since more than 90% of cancer deaths are attributable to metastatic progression. Integrin alpha9 (ITGA9) has been previously described as playing an essential role in metastasis; however, little is known about the mechanism that links this protein to this process, being one of the less studied integrins.

Structural disruption of BAF chromatin remodeller impairs neuroblastoma metastasis by reverting an invasiveness epigenomic program.

Background: Epigenetic programming during development is essential for determining cell lineages, and alterations in this programming contribute to the initiation of embryonal tumour development. In neuroblastoma, neural crest progenitors block their course of natural differentiation into sympathoadrenergic cells, leading to the development of aggressive and metastatic paediatric cancer. Research of the epigenetic regulators responsible for oncogenic epigenomic networks is crucial for developing new epigenetic-based therapies against these tumours.

Therapy and prognostic significance of regional lymph node involvement in embryonal rhabdomyosarcoma: a report from the European paediatric Soft tissue sarcoma Study Group.

Purpose: Regional lymph node disease (N1) is a component of the risk-based treatment stratification in rhabdomyosarcoma (RMS). The purpose of this study was to determine the contribution of nodal disease to the prognosis of patients with non-metastatic embryonal RMS (ERMS) and analyse their outcome by treatment received.

Patients And Methods: Between 2005 and 2016, 1294 children with ERMS were enrolled in the European paediatric Soft tissue sarcoma Study Group (EpSSG) RMS 2005 protocol, 143 patients with N1.

Metastatic Rhabdomyosarcoma: Results of the European Soft Tissue Sarcoma Study Group MTS 2008 Study and Pooled Analysis With the Concurrent BERNIE Study.

Purpose: Outcome for patients with metastatic rhabdomyosarcoma (RMS) is poor. This study presents the results of the MTS 2008 study with a pooled analysis including patients from the concurrent BERNIE study.

Patients And Methods: In MTS 2008, patients with metastatic RMS received four cycles of ifosfamide, vincristine, and actinomycin D (IVA) plus doxorubicin, five cycles of IVA, and 12 cycles of maintenance chemotherapy (low-dose cyclophosphamide and vinorelbine).

MET Inhibition Sensitizes Rhabdomyosarcoma Cells to NOTCH Signaling Suppression.

Rhabdomyosarcoma (RMS) is a pediatric myogenic soft tissue sarcoma. The Fusion-Positive (FP) subtype expresses the chimeric protein PAX3-FOXO1 (P3F) while the Fusion-Negative (FN) is devoid of any gene translocation. FP-RMS and metastatic FN-RMS are often unresponsive to conventional therapy.

MEK and MCL-1 sequential inhibition synergize to enhance rhabdomyosarcoma treatment.

Targeted agents have emerged as promising molecules for cancer treatment, but most of them fail to achieve complete tumor regression or attain durable remissions due to tumor adaptations. We used dynamic BH3 profiling to identify targeted agents effectiveness and anti-apoptotic adaptations upon targeted treatment in rhabdomyosarcoma. We focused on studying the use of BH3 mimetics to specifically inhibit pro-survival BCL-2 family proteins, overwhelm resistance to therapy and prevent relapse.

Dickkopf-1 Inhibition Reactivates Wnt/β-Catenin Signaling in Rhabdomyosarcoma, Induces Myogenic Markers In Vitro and Impairs Tumor Cell Survival In Vivo.

The Wnt/β-catenin signaling pathway plays a pivotal role during embryogenesis and its deregulation is a key mechanism in the origin and progression of several tumors. Wnt antagonists have been described as key modulators of Wnt/β-catenin signaling in cancer, with Dickkopf-1 (DKK-1) being the most studied member of the DKK family. Although the therapeutic potential of DKK-1 inhibition has been evaluated in several diseases and malignancies, little is known in pediatric tumors.

Localised rhabdomyosarcoma in infants (<12 months) and young children (12-36 months of age) treated on the EpSSG RMS 2005 study.

Background: Infants (<12 months) with rhabdomyosarcoma have historically had poorer outcome than the older age groups. We present outcomes for infants and young children aged 12-36 months with localised rhabdomyosarcoma with a particular emphasis on infants.

Patients And Methods: All children less than 36 months of age enrolled on the EpSSG RMS 2005 study for localised disease are included.

Methodological advances in the discovery of novel neuroblastoma therapeutics.

Introduction: Neuroblastoma is a cancer of the sympathetic nervous system that causes up to 15% of cancer-related deaths among children. Among the ~1,000 newly diagnosed cases per year in Europe, more than half are classified as high-risk, with a 5-year survival rate <50%. Current multimodal treatments have improved survival among these patients, but relapsed and refractory tumors remain a major therapeutic challenge.

Engineering pH-Sensitive Stable Nanovesicles for Delivery of MicroRNA Therapeutics.

MicroRNAs (miRNAs) are small non-coding endogenous RNAs, which are attracting a growing interest as therapeutic molecules due to their central role in major diseases. However, the transformation of these biomolecules into drugs is limited due to their unstability in the bloodstream, caused by nucleases abundantly present in the blood, and poor capacity to enter cells. The conjugation of miRNAs to nanoparticles (NPs) could be an effective strategy for their clinical delivery.

Neuronal Differentiation-Related Epigenetic Regulator Has Independent Prognostic Value in Neuroblastoma but Is Functionally Dispensable In Vitro.

Neuroblastoma is a pediatric tumor of the peripheral nervous system that accounts for up to ~15% of all cancer-related deaths in children. Recently, it has become evident that epigenetic deregulation is a relevant event in pediatric tumors such as high-risk neuroblastomas, and a determinant for processes, such as cell differentiation blockade and sustained proliferation, which promote tumor progression and resistance to current therapies. Thus, a better understanding of epigenetic factors implicated in the aggressive behavior of neuroblastoma cells is crucial for the development of better treatments.

Congenital rhabdomyosarcoma: A report from the European paediatric Soft tissue sarcoma Study Group.

Procedure: Congenital rhabdomyosarcoma (RMS) represents a challenging disease due to its characteristics and the difficulties in delivering treatment in this immature population.

Methods: We analyzed treatment and outcome of patients with congenital RMS, defined as tumor diagnosed in the first 2 months of life, enrolled in the European paediatric Soft tissue sarcoma Study Group protocols.

Results: Twenty-four patients with congenital RMS were registered.

Dickkopf Proteins and Their Role in Cancer: A Family of Wnt Antagonists with a Dual Role.

The Wnt signaling pathway regulates crucial aspects such as cell fate determination, cell polarity and organogenesis during embryonic development. Wnt pathway deregulation is a hallmark of several cancers such as lung, gastric and liver cancer, and has been reported to be altered in others. Despite the general agreement reached by the scientific community on the oncogenic potential of the central components of the pathway, the role of the antagonist proteins remains less clear.

Role of F-FDG-PET/CT in the staging of metastatic rhabdomyosarcoma: a report from the European paediatric Soft tissue sarcoma Study Group.

Background: Initial staging of rhabdomyosarcoma is crucial for prognosis and to tailor the treatment. The standard radiology workup (SRW) includes magnetic resonance imaging, chest computed tomography (CT) and bone scintigraphy, but 18 Fluorine-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) (F-FDG-PET/CT (PET-CT)) use is increasing. The aim of this study was to evaluate the impact of PET-CT in the initial staging of patients with metastatic rhabdomyosarcoma enrolled in the European protocol MTS2008.

Embryonal rhabdomyosarcoma completely resected at diagnosis: The European paediatric Soft tissue sarcoma Study Group RMS2005 experience.

Background: Rhabdomyosarcoma (RMS) is the most common form of soft tissue sarcoma in children. We report the results of the European paediatric Soft tissue sarcoma Study Group (EpSSG) RMS 2005 study, which prospectively evaluated the reduction of chemotherapy in patients with embryonal RMS (ERMS) after initial surgery.

Methods: Between October 2005 and December 2016, all patients with localised ERMS with an initial microscopically complete resection (IRS group I) with lymph node-negative (N0) were prospectively enrolled in the low-risk (n = 70, subgroup A; age < 10 years and tumour size ≤ 5 cm) or standard-risk group (n = 108, subgroup B; age ≥ 10 years or tumour size > 5 cm.

Alveolar rhabdomyosarcoma with regional nodal involvement: Results of a combined analysis from two cooperative groups.

Background: Treatment of children and adolescents with alveolar rhabdomyosarcoma (ARMS) and regional nodal involvement (N1) have been approached differently by North American and European cooperative groups. In order to define a better therapeutic strategy, we analyzed two studies conducted between 2005 and 2016 by the European paediatric Soft tissue sarcoma Study Group (EpSSG) and Children's Oncology Group (COG).

Methods: We retrospectively identified patients with ARMS N1 enrolled in either EpSSG RMS2005 or in COG ARST0531.