Using drawings and deep neural networks to characterize the building blocks of human visual similarity.

Early in life and without special training, human beings discern resemblance between abstract visual stimuli, such as drawings, and the real-world objects they represent. We used this capacity for visual abstraction as a tool for evaluating deep neural networks (DNNs) as models of human visual perception. Contrasting five contemporary DNNs, we evaluated how well each explains human similarity judgments among line drawings of recognizable and novel objects. For object sketches, human judgments were dominated by semantic category information; DNN representations contributed little additional information. In contrast, such features explained significant unique variance perceived similarity of abstract drawings. In both cases, a vision transformer trained to blend representations of images and their natural language descriptions showed the greatest ability to explain human perceptual similarity-an observation consistent with contemporary views of semantic representation and processing in the human mind and brain. Together, the results suggest that the building blocks of visual similarity may arise within systems that learn to use visual information, not for specific classification, but in service of generating semantic representations of objects.

Better than Goodenough? Evaluating new computational techniques for finding diagnostic structure in children's drawings.

In her 1926 book Measurement of Intelligence by Drawings, Florence Goodenough pioneered the quantitative analysis of children's human-figure drawings as a tool for evaluating their cognitive development. This influential work launched a broad enterprise in cognitive evaluation that continues to the present day, with most clinicians and researchers deploying variants of the checklist-based scoring methods that Goodenough invented. Yet recent work leveraging computational innovations in cognitive science suggests that human-figure drawings possess much richer structure than checklist-based approaches can capture. The current study uses these contemporary tools to characterize structure in the images from Goodenough's original work, then assesses whether this structure carries information about demographic and cognitive characteristics of the participants in that early study. The results show that contemporary methods can reliably extract information about participant age, gender, and mental faculties from images produced over 100 years ago, with no expert training and with minimal human effort. Moreover, the new analyses suggest a different relationship between drawing and mental ability than that captured by Goodenough's highly influential approach, with important implications for the use of drawings in cognitive evaluation in the present day.

Frontline and Relapsed Rhabdomyosarcoma (FAR-RMS) Clinical Trial: A Report from the European Paediatric Soft Tissue Sarcoma Study Group (EpSSG).

The Frontline and Relapsed Rhabdomyosarcoma (FaR-RMS) clinical trial is an overarching, multinational study for children and adults with rhabdomyosarcoma (RMS). The trial, developed by the European Soft Tissue Sarcoma Study Group (EpSSG), incorporates multiple different research questions within a multistage design with a focus on (i) novel regimens for poor prognostic subgroups, (ii) optimal duration of maintenance chemotherapy, and (iii) optimal use of radiotherapy for local control and widespread metastatic disease. Additional sub-studies focusing on biological risk stratification, use of imaging modalities, including [18F]FDG PET-CT and diffusion-weighted MRI imaging (DWI) as prognostic markers, and impact of therapy on quality of life are described. This paper forms part of a Special Issue on rhabdomyosarcoma and outlines the study background, rationale for randomisations and sub-studies, design, and plans for utilisation and dissemination of results.

Reappraisal of prognostic factors used in the European Pediatric Soft Tissue Sarcoma Study Group RMS 2005 study for localized rhabdomyosarcoma to optimize risk stratification and generate a prognostic nomogram.

BACKGROUND: The objective of this study was to investigate the role of clinical factors together with FOXO1 fusion status in patients with nonmetastatic rhabdomyosarcoma (RMS) to develop a predictive model for event-free survival and provide a rationale for risk stratification in future trials. METHODS: The authors used data from patients enrolled in the European Pediatric Soft Tissue Sarcoma Study Group (EpSSG) RMS 2005 study (EpSSG RMS 2005; EudraCT number 2005-000217-35). The following baseline variables were considered for the multivariable model: age at diagnosis, sex, histology, primary tumor site, Intergroup Rhabdomyosarcoma Studies group, tumor size, nodal status, and FOXO1 fusion status. Main effects and significant second-order interactions of candidate predictors were included in a multiple Cox proportional hazards regression model. A nomogram was generated for predicting 5-year event-free survival (EFS) probabilities. RESULTS: The EFS and overall survival rates at 5 years were 70.9% (95% confidence interval, 68.6%-73.1%) and 81.0% (95% confidence interval, 78.9%-82.8%), respectively. The multivariable model retained five prognostic factors, including age at diagnosis interacting with tumor size, tumor primary site, Intergroup Rhabdomyosarcoma Studies clinical group, and FOXO1 fusion status. Based on each patient's total score in the nomogram, patients were stratified into four groups. The 5-year EFS rates were 94.1%, 78.4%, 65.2%, and 52.1% in the low-risk, intermediate-risk, high-risk, and very-high-risk groups, respectively, and the corresponding 5-year overall survival rates were 97.2%, 91.5%, 74.3%, and 60.8%, respectively. CONCLUSIONS: The results presented here provide the rationale to modify the EpSSG stratification, with the most significant change represented by the replacement of histology with fusion status. This classification was adopted in the new international trial launched by the EpSSG.

A comparison of three different work to rest periods during intermittent sprint training on maintaining sprint effort performance.

Background/objectives: Team sports are characterised by repeated maximal intensity bursts of activity, requiring significant energy contribution from the phosphagen pathways. The objective of this study was to evaluate the impact of different rest periods on repeated maximal intensity efforts. Methods: The effect of three different recovery periods (60 s, 90 s and 120 s) during a 10 × six-seconds intermittent sprint training protocol performed on a cycle ergometer was investigated. Thirteen part-time female athletes from two sports, Rugby Sevens and Netball competing for their state participated in the study. Peak Power (PPO), Mean Power (MPO), "total work" in the form of calorie expenditure, performance decrement, repetitions over 95% PPO, blood lactate, and RPE were recorded. Results: There was a significant effect of condition on MPO and calorie expenditure (p < 0.050). MPO was significantly lower for 60 s compared to 90 s (710.4 vs 734.4 W, ES = 0.27-0.42) and 120 s (710.4 vs 743.3 W, ES = 0.36-0.47). Calorie expenditure was significantly lower for 60 s compared to 90 s (4.41 vs 4.56 cal, ES = 0.25-0.46) and 120 s (4.41 vs 4.59 cal, ES = 0.40-0.48). There was a significant effect of time (60 s 11.7, 90 s 11.1.120 s 10.9 mmol/L, p < 0.010) but not condition (p = 0.617) for blood lactate accumulation, and a significant difference in session RPE between 60 and both 90 s and 120 s (60 s 15.5, 90 s 14.2. p = 0.034 120 s 13.9, p = 0.039). Conclusion: Shorter recovery durations resulted in decreased mean power and calorie expenditure, but higher RPE when compared to longer recovery periods. All three recovery periods may have fallen between the fast and slow phases of PCr resynthesis of approximately 20 and 180 s resulting in partial but not complete recovery. Total training time should be a consideration when determining what protocol to implement.

Twelve tips for medical school faculty to support students with disabilities.

As medical schools embrace diversity, it is increasingly acknowledged that medical students with disabilities must be welcome and supported in becoming physicians. Students should be able to ask for and receive reasonable accommodations to support their education. However, a practical shared approach to supporting medical students with disabilities is needed. The 12 tips in this article use sense-making theory as a framework to guide medical school faculty in supporting medical students with disabilities. The tips center on perceiving cues, creating interpretations, taking action, and communicating with students. The 12 tips can be utilized by faculty members across universities to take a proactive role in implementing support for medical students with disabilities and, in turn, nurturing an inclusive educational environment.

Pediatric Intensive Care Unit Early Mobility Program: Impact on Patient Functional Status.

INTRODUCTION: Patients admitted to the pediatric Intensive Care Unit (PICU) are frequently sedated, restrained, and placed on bed rest. These practices have known negative impacts including prolonged hospital stay and diminished functional status after discharge. The authors' objective was to investigate the impact of a PICU early mobility protocol on the frequency of orders for physical, occupational, and speech therapy (PT, OT, ST) and improvement in patient functional status. METHODS: Patients admitted in 2019 prior to the development of the PICU early mobility protocol were compared to those admitted in 2020 who underwent the protocol. Differences in clinical characteristics; PICU length of stay; rates of PT, OT, and ST orders; rates of bedside mobility activities; and functional status scores (FSSs) were assessed in bivariate and multivariate analyses. The protocol included early PT, OT, and ST order placement and frequent in-room mobility activities. RESULTS: Of the 384 patients included in the study, 216 (56%) were preprotocol patients, and 168 (44%) underwent the protocol. Patients in 2020 were more likely to receive a physical therapy order compared to their 2019 counterparts (79% vs 47%, p < 0.001). Patients in 2020 had a higher daily incidence of mobility activities compared to those in 2019 (4.88 activities vs 4.1 activities, p < 0.001). Changes in functional status scores were similar between the 2 groups. CONCLUSION: PICU early mobility was associated with increased physical, occupational, and speech therapy orders and daily mobility activities but was not associated with a reduction in functional morbidity at discharge or 3 months post-discharge.

Complex organic matter degradation by secondary consumers in chemolithoautotrophy-based subsurface geothermal ecosystems.

Microbial communities in terrestrial geothermal systems often contain chemolithoautotrophs with well-characterized distributions and metabolic capabilities. However, the extent to which organic matter produced by these chemolithoautotrophs supports heterotrophs remains largely unknown. Here we compared the abundance and activity of peptidases and carbohydrate active enzymes (CAZymes) that are predicted to be extracellular identified in metagenomic assemblies from 63 springs in the Central American and the Andean convergent margin (Argentinian backarc of the Central Volcanic Zone), as well as the plume-influenced spreading center in Iceland. All assemblies contain two orders of magnitude more peptidases than CAZymes, suggesting that the microorganisms more often use proteins for their carbon and/or nitrogen acquisition instead of complex sugars. The CAZy families in highest abundance are GH23 and CBM50, and the most abundant peptidase families are M23 and C26, all four of which degrade peptidoglycan found in bacterial cells. This implies that the heterotrophic community relies on autochthonous dead cell biomass, rather than allochthonous plant matter, for organic material. Enzymes involved in the degradation of cyanobacterial- and algal-derived compounds are in lower abundance at every site, with volcanic sites having more enzymes degrading cyanobacterial compounds and non-volcanic sites having more enzymes degrading algal compounds. Activity assays showed that many of these enzyme classes are active in these samples. High temperature sites (> 80°C) had similar extracellular carbon-degrading enzymes regardless of their province, suggesting a less well-developed population of secondary consumers at these sites, possibly connected with the limited extent of the subsurface biosphere in these high temperature sites. We conclude that in < 80°C springs, chemolithoautotrophic production supports heterotrophs capable of degrading a wide range of organic compounds that do not vary by geological province, even though the taxonomic and respiratory repertoire of chemolithoautotrophs and heterotrophs differ greatly across these regions.

Outcome of patients with undifferentiated embryonal sarcoma of the liver treated according to European soft tissue sarcoma protocols.

BACKGROUND: To assess the outcomes of pediatric patients with undifferentiated embryonal sarcoma of the liver (UESL) and treatment including at least surgery and systemic chemotherapy. METHODS: This study included patients aged up to 21 years with a pathological diagnosis of UESL prospectively enrolled from 1995 to 2016 in three European trials focusing on the effects of surgical margins, preoperative chemotherapy, use of radiotherapy (RT), and chemotherapy. RESULTS: Out of 65 patients with a median age at diagnosis of 8.7 years (0.6-20.8), 15 had T2 tumors, and one had lymph node spread, 14 were Intergroup Rhabdomyosarcoma Study (IRS) I, nine IRS II, 38 IRS III, and four IRS IV. Twenty-eight upfront surgeries resulted in five operative spillages and 11 infiltrated surgical margins, whereas 37 delayed surgeries resulted in no spillages (p = .0119) and three infiltrated margins (p = .0238). All patients received chemotherapy, including anthracyclines in 47. RT was administered in 15 patients. With a median follow-up of 78.6 months, 5-year overall and event-free survivals (EFS) were 90.1% (95% confidence interval [CI]: 79.2-95.5) and 89.1% (95% CI: 78.4-94.6), respectively. Two out four local relapses had previous infiltrated margins and two out of three patients with metastatic relapses received reduced doses of alkylating agents. Infiltrated margins (p = .1607), T2 stage (p = .3870), use of RT (p = .8731), and anthracycline-based chemotherapy (p = .1181) were not correlated with EFS. CONCLUSIONS: Multimodal therapy improved the outcome of UESL. Neoadjuvant chemotherapy for pediatric patients increases the probability of complete surgical resection. The role of anthracyclines and RT for localized disease remains unclear.

Human perception and machine vision reveal rich latent structure in human figure drawings.

For over a hundred years, children's drawings have been used to assess children's intellectual, emotional, and physical development, characterizing children on the basis of intuitively derived checklists to identify the presence or absence of features within children's drawings. The current study investigates whether contemporary data science tools, including deep neural network models of vision and crowd-based similarity ratings, can reveal latent structure in human figure drawings beyond that captured by checklists, and whether such structure can aid in understanding aspects of the child's cognitive, perceptual, and motor competencies. We introduce three new metrics derived from innovations in machine vision and crowd-sourcing of human judgments and show that they capture a wealth of information about the participant beyond that expressed by standard measures, including age, gender, motor abilities, personal/social behaviors, and communicative skills. Machine-and human-derived metrics captured somewhat different aspects of structure across drawings, and each were independently useful for predicting some participant characteristics. For example, machine embeddings seemed sensitive to the magnitude of the drawing on the page and stroke density, while human-derived embeddings appeared sensitive to the overall shape and parts of a drawing. Both metrics, however, independently explained variation on some outcome measures. Machine embeddings explained more variation than human embeddings on all subscales of the Ages and Stages Questionnaire (a parent report of developmental milestones) and on measures of grip and pinch strength, while each metric accounted for unique variance in models predicting the participant's gender. This research thus suggests that children's drawings may provide a richer basis for characterizing aspects of cognitive, behavioral, and motor development than previously thought.

Decoding semantic representations in mind and brain.

A key goal for cognitive neuroscience is to understand the neurocognitive systems that support semantic memory. Recent multivariate analyses of neuroimaging data have contributed greatly to this effort, but the rapid development of these novel approaches has made it difficult to track the diversity of findings and to understand how and why they sometimes lead to contradictory conclusions. We address this challenge by reviewing cognitive theories of semantic representation and their neural instantiation. We then consider contemporary approaches to neural decoding and assess which types of representation each can possibly detect. The analysis suggests why the results are heterogeneous and identifies crucial links between cognitive theory, data collection, and analysis that can help to better connect neuroimaging to mechanistic theories of semantic cognition.

Neonatologists and vitamin K hesitancy.

Hemorrhagic disease of the newborn, more aptly termed "Vitamin K Deficiency Bleeding (VKDB)," has long been recognized as a cause of significant morbidity and mortality in early infancy. A single intramuscular dose of vitamin K administered at birth has virtually eliminated VKDB, and this prophylactic regimen has been recommended by the American Academy of Pediatrics since 1961. Although most newborns in the United States receive vitamin K at birth, a growing number of parents are hesitant about this intervention, citing concerns about harm from the injection, preservatives contained in the medication, and clashes with personal belief systems. Ultimately, there is distrust in the medical establishment as many of these parents also opt out of newborn ophthalmic prophylaxis and importantly, childhood vaccinations, establishing a dangerous public health precedent that will lead to resurgence of vaccine-preventable diseases. Various shared decision making models and educational efforts can assist newborn health care professionals in addressing these parental concerns so that VKDB can be effectively prevented in all newborns.

Developments in the Surgical Approach to Staging and Resection of Rhabdomyosarcoma.

Although survival after rhabdosarcoma treatment has improved over the years, one third of patients still develop locoregional relapse. This review aims to highlight developments pertaining to staging and local treatment of specific RMS tumor sites, including head and neck, chest/trunk, bladder-prostate, female genito-urinary, perianal, and extremity sites.

Surgical management of extremity rhabdomyosarcoma: A consensus opinion from the Children's Oncology Group, the European Pediatric Soft-Tissue Sarcoma Study Group, and the Cooperative Weichteilsarkom Studiengruppe.

The treatment of extremity rhabdomyosarcoma remains a challenge due to several adverse prognostic factors frequently associated with this tumor site. The International Soft-Tissue Sarcoma Database Consortium (INSTRuCT) is a collaboration of the Children's Oncology Group Soft-Tissue Sarcoma Committee, the European Pediatric Soft-Tissue Sarcoma Study Group, and the Cooperative Weichteilsarkom Studiengruppe. The INSTRuCT surgical committee developed an internationally applicable consensus opinion document for the surgical treatment of extremity rhabdomyosarcoma. This document addresses surgical management, including biopsy, nodal staging, timing of therapy, resection and reexcision, reconstruction, and surgical approach at relapse.

Chemolithoautotroph distributions across the subsurface of a convergent margin.

Subducting oceanic crusts release fluids rich in biologically relevant compounds into the overriding plate, fueling subsurface chemolithoautotrophic ecosystems. To understand the impact of subsurface geochemistry on microbial communities, we collected fluid and sediments from 14 natural springs across a ~200 km transect across the Costa Rican convergent margin and performed shotgun metagenomics. The resulting 404 metagenome-assembled genomes (MAGs) cluster into geologically distinct regions based on MAG abundance patterns: outer forearc-only (25% of total relative abundance), forearc/arc-only (38% of total relative abundance), and delocalized (37% of total relative abundance) clusters. In the outer forearc, Thermodesulfovibrionia, Candidatus Bipolaricaulia, and Firmicutes have hydrogenotrophic sulfate reduction and Wood-Ljungdahl (WL) carbon fixation pathways. In the forearc/arc, Anaerolineae, Ca. Bipolaricaulia, and Thermodesulfovibrionia have sulfur oxidation, nitrogen cycling, microaerophilic respiration, and WL, while Aquificae have aerobic sulfur oxidation and reverse tricarboxylic acid carbon fixation pathway. Transformation-based canonical correspondence analysis shows that MAG distribution corresponds to concentrations of aluminum, iron, nickel, dissolved inorganic carbon, and phosphate. While delocalized MAGs appear surface-derived, the subsurface chemolithoautotrophic, metabolic, and taxonomic landscape varies by the availability of minerals/metals and volcanically derived inorganic carbon. However, the WL pathway persists across all samples, suggesting that this versatile, energy-efficient carbon fixation pathway helps shape convergent margin subsurface ecosystems.

Shedding a Light on the Challenges of Adolescents and Young Adults with Rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is a typical tumour of childhood but can occur at any age. Several studies have reported that adolescent and young adult (AYA) patients with RMS have poorer survival than do younger patients. This review discusses the specific challenges in AYA patients with pediatric-type RMS, exploring possible underlying factors which may influence different outcomes. Reasons for AYA survival gap are likely multifactorial, and might be related to differences in tumor biology and intrinsic aggressiveness, or differences in clinical management (that could include patient referral patterns, time to diagnosis, enrolment into clinical trials, the adequacy and intensity of treatment), as well as patient factors (including physiology and comorbidity that may influence treatment tolerability, drug pharmacokinetics and efficacy). However, improved survival has been reported in the most recent studies for AYA patients treated on pediatric RMS protocols. Different strategies may help to further improve outcome, such as supporting trans-age academic societies and national/international collaborations; developing specific clinical trials without upper age limit; defining integrated and comprehensive approach to AYA patients, including the genomic aspects; establishing multidisciplinary tumor boards with involvement of both pediatric and adult oncologists to discuss all pediatric-type RMS patients; developing dedicated projects with specific treatment recommendations and registry/database.

Patients with completely resected nongenitourinary low-risk embryonal rhabdomyosarcoma are candidates for reduced duration low-intensity chemotherapy.

BACKGROUND: The survival of patients with localized embryonal rhabdomyosarcoma (RMS) completely resected at diagnosis is greater than 90%. Most patients have paratesticular, uterine, or vaginal RMS, limiting specific analyses of RMS localized in other anatomic regions. This international study was conducted to define the outcome for completely resected embryonal RMS at sites other than paratesticular, uterine, or vaginal primary sites. METHODS: A total of 113 patients aged 0-18 years were identified who were enrolled from January 1995 to December 2016 in Children's Oncology Group (COG) (64 patients) and European protocols (49). Genitourinary nonbladder and prostate RMS were excluded. The recommended chemotherapy was vincristine and actinomycin-D (VA) for 24 weeks or ifosfamide plus VA in the European protocols and VA for 48 weeks or VA plus cyclophosphamide in the COG protocols. RESULTS: The most common primary sites were nonparameningeal head and neck (40.7%), other (23.9%), and extremities (20.4%). In the COG studies, 42% of patients received VA and 58% VA plus cyclophosphamide. In Europe, 53% received VA and 47% ifosfamide plus VA. With a median follow-up of 97.5 months, the 5-year progression-free and overall survival was 80.0% (71.2%-86.4%) and 92.5% (85.6%-96.2%), respectively, without significant differences between chemotherapy regimens. Tumor size (< or >5 cm) significantly influenced overall survival: 96.2% (88.6%-98.8%) vs. 80.6% (59.5%-91.4%), respectively (p = .01). CONCLUSIONS: Survival of patients with nonalveolar RMS completely resected at diagnosis is excellent among tumors arising from nonparatesticular, uterine, and vaginal sites, and patients may be treated successfully with low-intensity chemotherapy. To reduce the burden of treatment, VA for 24 weeks may be considered in children with tumors <5 cm.

Automated stress detection using mobile application and wearable sensors improves symptoms of mental health disorders in military personnel.

Leading causes in global health-related burden include stress, depression, anger, fatigue, insomnia, substance abuse, and increased suicidality. While all individuals are at risk, certain career fields such as military service are at an elevated risk. Cognitive behavioral therapy (CBT) is highly effective at treating mental health disorders but suffers from low compliance and high dropout rates in military environments. The current study conducted a randomized controlled trial with military personnel to assess outcomes for an asymptomatic group (n = 10) not receiving mental health treatment, a symptomatic group (n = 10) using a mHealth application capable of monitoring physiological stress via a commercial wearable alerting users to the presence of stress, guiding them through stress reduction techniques, and communicating information to providers, and a symptomatic control group (n = 10) of military personnel undergoing CBT. Fifty percent of symptomatic controls dropped out of CBT early and the group maintained baseline symptoms. In contrast, those who used the mHealth application completed therapy and showed a significant reduction in symptoms of depression, anxiety, stress, and anger. The results from this study demonstrate the feasibility of pairing data-driven mobile applications with CBT in vulnerable populations, leading to an improvement in therapy compliance and a reduction in symptoms compared to CBT treatment alone. Future work is focused on the inclusion of passive sensing modalities and the integration of additional data sources to provide better insights and inform clinical decisions to improve personalized support.

Adolescents and young adults with rhabdomyosarcoma treated in the European paediatric Soft tissue sarcoma Study Group (EpSSG) protocols: a cohort study.

BACKGROUND: Adolescent and young adult patients with rhabdomyosarcoma often have poorer outcomes than do children. We aimed to compare the findings of adolescent and young adult patients with children enrolled in two prospective clinical protocols. METHODS: This retrospective observational analysis was based on data from the European paediatric Soft tissue sarcoma Study Group (EpSSG) rhabdomyosarcoma 2005 trial (phase 3 randomised trial for localised rhabdomyosarcoma, open from April, 2006, to December, 2016) and the EpSSG MTS 2008 protocol (prospective, observational, single-arm study for metastatic rhabdomyosarcoma, open from June, 2010, to December, 2016), which involved 108 centres from 14 different countries in total. For this analysis, patients were categorised according to their age into children (age 0-14 years) and adolescents and young adults (age 15-21 years). For the analysis of adherence to treatment and toxicity, only patients with high-risk localised rhabdomyosarcoma included in the randomised part of the rhabdomyosarcoma 2005 study were considered. The primary outcome of event-free survival (assessed in all participants) was defined as the time from diagnosis to the first event (eg, tumour progression, relapse) or to the latest follow-up. Secondary outcomes were overall survival, response to chemotherapy, and toxicity. FINDINGS: Our analysis included 1977 patients, 1720 children (median age 4·7 years; IQR 2·6-8·4) and 257 adolescents and young adults (16·6 years; 15·8-18·0). 1719 patients were from the EpSSG rhabdomyosarcoma 2005 study (1523 aged <15 years and 196 aged 15-21 years) and 258 patients were from the EPSSG MTS 2008 study (197 aged <15 years and 61 aged 15-21 years). Adolescent and young adult patients were more likely than were children to have metastatic tumours (61 [23·7%] of 257 vs 197 [11·5%] of 1720; p<0·0001), unfavourable histological subtypes (119 [46·3%] vs 451 [26·2%]; p<0·0001), tumours larger than 5 cm (177 [68·9%] vs 891 [51·8%]; p<0·0001), and regional lymph node involvement (109 [42·4%] vs 339 [19·7%]; p<0·0001). Adolescent and young adult patients had lower 5-year event-free survival (52·6% [95% CI 46·3-58·6] vs 67·8% [65·5-70·0]; p<0·0001) and lower 5-year overall survival (57·1% [50·4-63·1] vs 77·9% [75·8-79·8]; p<0·0001) than did children. The multivariable analysis confirmed the inferior prognosis of patients aged 15-21 years (hazard ratios 1·48 [95% CI 1·20-1·83; p=0·0002] for poorer event-free survival and 1·73 [1·37-2·19; p<0·0001] for poorer overall survival). Modifications of administered chemotherapy occurred in 13 (15·3%) of 85 adolescents and young adults, and in 161 (21·4%) of 754 children. Grade 3-4 haematological toxicity and infection were observed more frequently in children than in adolescent and young adult patients. INTERPRETATION: This study found better outcomes for adolescent and young adult patients than those reported in epidemiological studies (eg, the EUROCARE-5 study reported 5-year overall survival of 39·6% for patients aged 15-19 years in the 2000-07 study period), suggesting that adolescent and young adult patients, at least up to age 21 years, can be treated with intensive paediatric therapies with no major tolerability issues and should be included in paediatric rhabdomyosarcoma trials. However, the inferior outcomes in adolescent and young adult patients compared with those in children, despite receiving similar therapy, suggest that a tailored and intensive treatment strategy might be warranted for these patients. FUNDING: Fondazione Città della Speranza.

Metastatic Rhabdomyosarcoma: Results of the European Paediatric 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). The BERNIE study randomly assigned patients to the addition or not of bevacizumab to the same chemotherapy. Local therapy (surgery/radiotherapy) was given to the primary tumor and all metastatic sites when feasible. RESULTS: MTS 2008 included 270 patients (median age, 9.6 years; range, 0.07-20.8 years). With a median follow-up of 50.3 months, 3-year event-free survival (EFS) and overall survival (OS) were 34.9% (95% CI, 29.1 to 40.8) and 47.9% (95% CI, 41.6 to 53.9), respectively. In pooled analyses on 372 patients with a median follow-up of 55.2 months, 3-year EFS and OS were 35.5% (95% CI, 30.4 to 40.6) and 49.3% (95% CI, 43.9 to 54.5), respectively. Patients with ≤ 2 Oberlin risk factors (ORFs) had better outcome than those with ≥ 3 ORFs: 3-year EFS was 46.1% versus 12.5% (P < .0001) and 3-year OS 60.0% versus 26.0% (P < .0001). Induction chemotherapy and maintenance appeared tolerable; however, about two third of patients needed dose adjustments during maintenance. CONCLUSION: Outcome remains poor for patients with metastatic RMS and multiple ORFs. Because of the design of the studies, it was not possible to determine whether the intensive induction regimen and/or the addition of maintenance treatment resulted in apparent improvement of outcome compared with historical cohorts. Further studies, with novel treatment approaches are urgently needed, to improve outcome for the group of patients with adverse prognostic factors.