Metastatic adult-type non-rhabdomyosarcoma soft tissue sarcomas in children and adolescents: A cohort study from the European paediatric Soft tissue sarcoma Study Group

Background

Limited data exist on the clinical behavior of pediatric non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) with distant metastases at onset, and a clear standard of care has not yet been defined.

Methods

This cohort study reports on pediatric adult-type metastatic NRSTS enrolled in two concurrent prospective European studies, i.e., the randomized BERNIE study and the single-arm MTS 2008 study developed by the European paediatric Soft tissue sarcoma Study Group. Treatment programs were originally designed for patients with metastatic rhabdomyosarcoma, i.e., nine courses of multidrug chemotherapy (with or without bevacizumab in the BERNIE study), followed by 12 cycles of maintenance therapy, whereas radiotherapy and/or surgery (on primary tumor and/or metastases) were delayed until after seven courses of chemotherapy had been administered.

Results

The study included 61 patients <21 years old treated from July 2008 to December 2016. The lung was the site of metastases in 75% of the cases. All patients received multi-agent chemotherapy, 44% had local therapy to primary tumor, and 18% had treatment of metastases. Median time to progression/relapse was 6 months. A high rate of tumor progression was observed during the initial part of the chemotherapy program. With a median follow-up of 41.5 months (range, 2–111 months), 3-year event-free survival and overall survival were 15.4% (95% confidence interval [CI], 7.6–25.7) and 34.9% (95% CI, 22.7–47.5), respectively. There were no statistically significant differences in outcome depending on the type of treatment administered.

Conclusions

The study confirmed the overall poor outcome for patients with metastatic NRSTS, whose treatment remains a challenge.

Plain Language Summary

• Pediatric non-rhabdomyosarcoma soft tissue sarcomas form a heterogeneous group of rare tumors.
• Although recent international studies have defined the standard of care for patients with localized disease, limited data are available on the clinical behavior of patients with distant metastases.
• This study on 61 metastatic cases treated on two prospective European protocols confirms that the chances of survival of such patients are often dismal and a standard treatment is still lacking.

     

Automatizing a nonscripting TPS for optimizing clinical workflow and reoptimizing IMRT/VMAT plans

The purpose of this study was to design a toolkit that interacts with the Monaco (Elekta AB, Stockholm, Sweden) treatment planning system (TPS) for optimization of intensity-modulated radiation therapy and volumetric-modulated arc therapy without the need for a dedicated application programming interface. Successful inverse planning of radiotherapeutic treatment depends on the tweaking of many parameters; a tool was thus needed to explore these parameters more exhaustively without significantly increasing planning time. The software that we used was based on an open-source library that mimics human interaction with Microsoft Windows applications. We developed a simple Autoflow software routine that analyzes and optimizes calculated plans by considering the relative impact of different cost functions and modifying constraints accordingly. It was also designed to change segmentation parameters to fit more complex treatments. The toolkit is publicly available for download at https://bitbucket.org/hgugmradiofisica/pymonaco/src/master/. A study of prostate cancer cases was conducted to compare automatically created plans with previously treated cases. The toolkit fully automated the radiotherapy planning procedure, allowing the TPS to calculate or optimize plans during nonworking hours. In the prostate study, the use of this tool reduced the dose to organs at risk with a negligible decrease in target coverage. This tool enables the efficient use of the TPS, allowing research and clinical applications to coexist without conflict. It provides consistency and efficiency throughout the treatment planning process, which may be of great value to clinics with few resources. The impact of this tool on clinical workflow is important, as it not only provides better efficiency, but also increases treatment quality.     

Mutations in PLS1, encoding fimbrin,cause autosomal dominant nonsyndromic hearing loss

Nonsyndromic hearing loss (NSHL), a common sensory disorder, is characterized by high clinical and genetic heterogeneity (i.e., approximately 115 genes and 170 loci so far identified). Nevertheless, almost half of patients submitted for genetic testing fail to receive a conclusive molecular diagnosis. We used next‐generation sequencing to identify causal variants in PLS1 (c.805G>A, p.[E269K]; c.713G>T, p.[L238R], and c.383T>C, p.[F128S]) in three unrelated families of European ancestry with autosomal dominant NSHL. PLS1 encodes Plastin 1 (also called fimbrin), one of the most abundant actin‐bundling proteins of the stereocilia. In silico protein modeling suggests that all variants destabilize the structure of the actin‐binding domain 1, likely reducing the protein's ability to bind F actin. The role of PLS1 gene in hearing function is further supported by the recent demonstration that Pls1^?/? mice show a hearing loss phenotype similar to that of our patients. In summary, we report PLS1 as a novel gene for autosomal dominant NSHL, suggesting that this gene is required for normal hearing in humans and mice.     

Mis-splicing in breast cancer: identification of pathogenic BRCA2 variants by systematic minigene assays

This commentary addresses the issue of the classification of sarcomas in the article written by Watson and colleagues published recently in this journal. The article delves into the molecular characterization and distinct phenotypes of some recently described entities (e.g. BCOR-rearranged sarcomas, CIC-fused sarcomas) and describes new groups with common characteristics. This commentary focuses on several questions raised in the article, such as what makes a group of sarcomas become a clinical entity, which should be the main driver of sarcoma classification, how the classification of small round cell sarcomas is expected to evolve and how high-throughput techniques could be applied to sarcoma diagnosis in the short term. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Effect of olive cultivar on bioaccessibility and antioxidant activity of phenolic fraction of virgin olive oil

Aim

This study aims to characterize the phenolic profile and antioxidant capacity of seven monovarietal virgin olive oils (VOOs) and evaluate their in vitro gastrointestinal stability.

Methods

‘Picual’, ‘Blanqueta’, ‘Sevillana’, ‘Habichuelero’, and ‘Chetoui’ olive cultivars were selected for VOO extraction. The oils were subjected to in vitro digestion. The recovery index (RI) of phenolic compounds after each digestion step and the bioaccessibility index (BI) were evaluated. In addition, the antioxidant activity of the bioaccessible fraction (BF) of VOOs was determined by DPPH, ABTS, and ORAC assays, as well as by studying the intracellular reactive oxygen species in Caco-2 cells.

Results

Differences were found in the composition of phenolic compounds in VOOs depending on cultivars. During the digestive process, important losses of phenolic compounds were observed between the buccal and duodenal steps, unlike HTy and Ty, which presented increased recovery due to the hydrolysis of secoiridoid derivatives. Differences in the bioaccessibility of phenolic compounds were found between varieties of VOOs. ‘Sevillana’ VOO had the highest total bioaccessibility (36%), followed by the ‘Picual’ (19%), ‘Chetoui’ (17%), ‘Habichuelero’ (10%), and ‘Blanqueta’ (8%) varieties. The BF of all the varieties of VOO showed similar radical ABTS scavenging capacity, ‘Chetoui’, and ‘Blanqueta’-BF having the highest radical DPPH scavenging capacity, and ‘Habichuelero’ and ‘Picual’-BF showing protective effects against the peroxyl radical measured by ORAC_FL assay. All VOO-BFs presented decreases in ROS levels in Caco-2 cells.

Conclusions

Our results suggest differences in the bioaccessibility of phenolics from diverse VOO varieties, which could lead to different biological properties. Therefore, this study represents a first step toward the development of novel dietary strategies focusing on the phenolic supplementation of different VOOs to preserve human health.

     

Adherence to transition guidelines in European paediatric nephrology units

Background

There is increasing focus on the problems involved in the transition and transfer of young adult patients from paediatric to adult renal units. This situation was addressed by the 2011 International Pediatric Nephrology Association/International Society of Nephrology (IPNA/ISN) Consensus Statement on transition.

Methods

We performed a survey of transition practices of 15 paediatric nephrology units across Europe 2 years after publication of the consensus statement.

Results

Two thirds of units were aware of the guidelines, and one third had integrated them into their transition practice. Forty-seven per cent of units transfer five or fewer patients with chronic kidney disease (CKD) stage 5 per year to a median of five adult centres, with higher numbers of CKD stages 2–4 patients. Seventy-three per cent of units were required by the hospital or government to transfer patients by a certain age. Eighty per cent of units commenced transition planning after the patient turned 15 years of age and usually within 1–2 years of the compulsory transfer age. Forty-seven per cent of units used a transition or transfer clinic. Prominent barriers to effective transition were patient and parent attachment to the paediatric unit and difficulty in allowing the young person to perform self-care.

Conclusions

Whereas awareness of the consensus statement is suboptimal, it has had some impact on practice. Adult nephrologists receive transferred patients infrequently, and the process of transition is introduced too late by paediatricians. Government- and hospital-driven age-based transfer policies distract focus from the achievement of competencies in self care. Variable use of transition clinics, written patient information and support groups is probably due to economic and human-resource limitations. The consensus statement provides a standard for evolving and evaluating transition policies jointly agreed upon by paediatric and adult units.     

Constitutional mosaicism in RASA1-related capillary malformation-arteriovenous malformation

Capillary malformation-arteriovenous malformation (CM-AVM) is caused by germline RASA1 and EPHB4 alterations. RASA1 intralesional second hits have also been reported. Here we report RASA1 constitutional mosaicism, defined here as the presence of a mosaic variant in all cell types of an individual, in two patients with CM-AVM. High-throughput sequencing was used to search for RASA1 pathogenic variants in blood samples from two unrelated patients with CM-AVM. An affected tissue sample from one of the patients was also analyzed. Both patients showed different nonsense RASA1 variants in mosaic, ranging from 7% to 21.5%, in blood samples and in the corresponding affected tissue sample from one of the patients. In conclusion, we report for the first time the presence of RASA1 constitutional mosaicism in CM-AVM. Constitutional mosaicism has implications for accurate molecular diagnosis and recurrence risk and helps to explain the great phenotypic variability in CM-AVM.