Development of a new ultrasound device for determining maturity based on bone age assessment

1 Summary 1.1 Abstract 1.1.1 Aim The aim of this project was to develop and test an acceptable portable system to assess maturity, without the use of radiation, for use at international borders to detect underage victims of human trafficking. This study covers testing of the developed ultrasound device on young women, assessing the accuracy of the maturity categorisation given by the device, as well as assessing the usability and functionality of the device. 1.1.2 Materials and methods The ultrasound device was used to measure the left ulna and radius epiphyseal plates in 148 young female participants, aged between 9-23 years (41% minors <18 years (n= 61), 59% adults ≥18 years (n=87)). The device consists of two ultrasound array transducers which travel along the forearm collecting reflection and transmission measurements from multiple pathways through the growth plates. The measurements were taken, and then assessed using a variety of machine learning methods, to categorise the individuals into minors or adults. Statistical analysis of each machine learning method was carried out and the most effective method was tested further for accuracy. 1.1.3 Results Classical signal processing analysis of the ultrasound waves showed a difference between underage and adult epiphyseal plates. Using machine learning methods, correct age categorisation of the participants (minors <18 years, adults ≥18 years) was achieved with an F1 score of approximately 87%. 1.1.4 Conclusion The novel use of ultrasound combined with machine learning techniques demonstrated in this study, provides a solid foundation for further progress in bone age assessment, including its use as a safe and quick screening tool to counter human trafficking.1.2 Zusammenfassung auf Deutsch: 1.2.1 Ziel Das Ziel unseres Projektes beinhaltet die Entwicklung und klinische Evaluation eines mobilen Systems, welches ohne Strahlenbelastung minderjährige Personen identifiziert. Endzweck ist die Prävention und Intervention bei Menschenhandel zum Zwecke sexueller Ausbeutung. Diese Studie stellt die Prüfung des entwickelten Ultraschallgerätes an junge Frauen dar, es werden Genauigkeit der Minder/Voll-jährigkeits Klassifikation und die Handhabung des Gerätes überprüft. 1.2.2 Methoden Die Wachstumsfugen der Elle und Speiche von 148 jungen Frauen im Alter von 9 bis 23 Jahren (41% unter 18 (n=61), 59% über 18 Jahre (n=87)) wurden mit dem Ultraschallgerät gemessen. Das Gerät ermittelt sowohl Reflektions- als auch Transmissionsdaten in zahlreichen Bereichen über dem Unterarm, während die zwei Ultraschallelemente mechanisch entlang des Armes bewegt werden. Diese Messdaten werden durch Maschinelle Lernmethoden auf eine Weise analysiert, dass die Probandinnen in Minderjährig und Volljährig unterschieden werden können. Statistische Analysen der Ergebnisse jeder Maschinellen Lernmethode wurden durchgeführt und die Effektivste Methode weiter auf Genauigkeit untersucht. 1.2.3 Wesentliche Ergebnisse Klassische Signalverarbeitungsmethoden zeigten eine Differenz zwischen den Messungen der minderjährigen und der erwachsenen Epiphysen. Mithilfe Maschineller Lernmethoden konnte dadurch mit einer Genauigkeit (F1-Score) von ca. 87% die korrekte Altersklasse ermittelt werden (Minderjährig <18 Jahre, volljährig ≥18 Jahre). 1.2.4 Schlussfolgerung Die Nutzung von Ultraschall kombiniert mit maschinellen Lernmethoden zur Feststellung des Knochenalters stellt eine sichere und schnelle Screening-Methode dar. Diese Studie erweist sich als gute Grundlage für weitere Forschung in diesem Bereich, welcher auch im Kampf gegen Menschenhandel eine wichtige Rolle spielt

Classification of Distal Growth Plate Ossification States of the Radius Bone Using a Dedicated Ultrasound Device and Machine Learning Techniques for Bone Age Assessments

X-ray imaging, based on ionizing radiation, can be used to determine bone age by examining distal growth plate fusion in the ulna and radius bones. Legal age determination approaches based on ultrasound signals exist but are unsuitable to reliably determine bone age. We present a low-cost, mobile system that uses one-dimensional ultrasound radio frequency signals to obtain a robust binary classifier enabling the determination of bone age from data of girls and women aged 9 to 24 years. These data were acquired as part of a clinical study conducted with 148 subjects. Our system detects the presence or absence of the epiphyseal plate by moving ultrasound array transducers along the forearm, measuring reflection and transmission signals. Even though classical digital signal processing methods did not achieve a robust classifier, we achieved an F1 score of approximately 87% for binary classification of completed bone growth with machine learning approaches, such as the gradient boosting machine method CatBoost. We demonstrate that our ultrasound system can classify the fusion of the distal growth plate of the radius bone and the completion of bone growth with high accuracy. We propose a non-ionizing alternative to established X-ray imaging methods for this purpose

The First European Interdisciplinary Ewing Sarcoma Research Summit

The European Network for Cancer Research in Children and Adolescents (ENCCA) provides an interaction platform for stakeholders in research and care of children with cancer. Among ENCCA objectives is the establishment of biology-based prioritization mechanisms for the selection of innovative targets, drugs, and prognostic markers for validation in clinical trials. Specifically for sarcomas, there is a burning need for novel treatment options, since current chemotherapeutic treatment protocols have met their limits. This is most obvious for metastatic Ewing sarcoma (ES), where long term survival rates are still below 20%. Despite significant progress in our understanding of ES biology, clinical translation of promising laboratory results has not yet taken place due to fragmentation of research and lack of an institutionalized discussion forum. To fill this gap, ENCCA assembled 30 European expert scientists and five North American opinion leaders in December 2011 to exchange thoughts and discuss the state of the art in ES research and latest results from the bench, and to propose biological studies and novel promising therapeutics for the upcoming European EWING2008 and EWING2012 clinical trials

TThe ENCCA-WP7/EuroSarc/EEC/PROVABES/EURAMOS 3rd European Bone Sarcoma Networking Meeting/Joint Workshop of EU Bone Sarcoma Translational Research Networks; Vienna, Austria, September 24–25, 2015. Workshop Report

This report summarizes the results of the 3rd Joint ENCCA-WP7, EuroSarc, EEC, PROVABES, and EURAMOS European Bone Sarcoma Network Meeting, which was held at the Children's Cancer Research Institute in Vienna, Austria on September 24-25, 2015. The joint bone sarcoma network meetings bring together European bone sarcoma researchers to present and discuss current knowledge on bone sarcoma biology, genetics, immunology, as well as results from preclinical investigations and clinical trials, to generate novel hypotheses for collaborative biological and clinical investigations. The ultimate goal is to further improve therapy and outcome in patients with bone sarcomas

Outcome of Children and Adolescents With Relapsed/Refractory/Progressive Malignancies Treated With Molecularly Informed Targeted Drugs in the Pediatric Precision Oncology Registry INFORM

PURPOSE: INFORM is an international pediatric precision oncology registry, prospectively collecting molecular and clinical data of children with recurrent, progressive, or very high-risk malignancies. We have previously identified a subgroup of patients with improved outcomes on the basis of molecular profiling. The present analysis systematically investigates progression-free survival (PFS) and overall survival (OS) of patients receiving matching targeted treatment (MTT) with the most frequently applied drug classes and its correlation with underlying molecular alterations. METHODS: A cohort of 519 patients with relapsed or refractory high-risk malignancies who had completed a follow-up of at least 2 years or shorter in the case of death or loss to follow-up was analyzed. Survival times were compared using the log-rank test. RESULTS: MTT with anaplastic lymphoma kinase (ALK), neurotrophic tyrosine receptor kinase (NTRK), and B-RAF kinase (BRAF) inhibitors showed significantly improved PFS (P = .012) and OS (P = .036) in comparison with conventional treatment or no treatment. However, analysis of the four most commonly applied MTT groups, mitogen-activated protein kinase (MEK- n = 19), cyclin-dependent kinase (CDK- n = 23), other kinase (n = 62), and mammalian-target of rapamycin (mTOR- n = 20) inhibitors, did not reveal differences in PFS or OS compared with conventional treatment or no treatment in patients with similar molecular pathway alterations. We did not observe differences in the type of pathway alterations (eg, copy number alterations, single-nucleotide variants, InDels, gene fusions) addressed by MTT. CONCLUSION: Patients with respective molecular alterations benefit from treatment with ALK, NTRK, and BRAF inhibitors as previously described. No survival benefit was observed with MTT for mutations in the MEK, CDK, other kinase, or mTOR signaling pathways. The noninterventional character of a registry has to be taken into account when interpreting these data and underlines the need for innovative interventional biomarker-driven clinical trials in pediatric oncology

Classification of Distal Growth Plate Ossification States of the Radius Bone Using a Dedicated Ultrasound Device and Machine Learning Techniques for Bone Age Assessments

X-ray imaging, based on ionizing radiation, can be used to determine bone age by examining distal growth plate fusion in the ulna and radius bones. Legal age determination approaches based on ultrasound signals exist but are unsuitable to reliably determine bone age. We present a low-cost, mobile system that uses one-dimensional ultrasound radio frequency signals to obtain a robust binary classifier enabling the determination of bone age from data of girls and women aged 9 to 24 years. These data were acquired as part of a clinical study conducted with 148 subjects. Our system detects the presence or absence of the epiphyseal plate by moving ultrasound array transducers along the forearm, measuring reflection and transmission signals. Even though classical digital signal processing methods did not achieve a robust classifier, we achieved an F1 score of approximately 87% for binary classification of completed bone growth with machine learning approaches, such as the gradient boosting machine method CatBoost. We demonstrate that our ultrasound system can classify the fusion of the distal growth plate of the radius bone and the completion of bone growth with high accuracy. We propose a non-ionizing alternative to established X-ray imaging methods for this purpose

Quality of Survivorship in a Rare Disease: Clinicofunctional Outcome and Physical Activity in an Observational Cohort Study of 618 Long-Term Survivors of Ewing Sarcoma

PurposeSignificantly improved survival rates in patients with Ewing sarcoma have raised interest in accessing the quality of long-term survivorship. In this study, subjective and objective measurement tools, preclassified as physical or mental scores, were used to assess clinicofunctional outcome and physical activity after intensive bone tumor treatment.MethodsLong-term outcome of 618 survivors from consecutive Ewing sarcoma trials was assessed by the Toronto Extremity Salvage Score, Short-Form Health Survey (SF-36), Brief Symptom Inventory (BSI), and Rosenberg Self-Esteem Scale questionnaires and by the accelerometric StepWatch 3 Activity Monitor. Prospective measurements were correlated retrospectively with standardized primary trial data. Results were compared with 316 nonrandom healthy peers by using effect sizes (d). Median observation time was 12.9 years from primary diagnosis (range, 3.7 to 31.2 years).ResultsAbsolute subjective scores were moderate to good for survivors. Compared with control subjects, unfavorable outcome was shown on physical Toronto Extremity Salvage Score, SF-36 Physical Component Summary, and BSI-Somatization scales (|d| 0.50; P <.01), in contrast to SF-36 Mental Component Summary, BSI-Anxiety, BSI-Depression, and Rosenberg Self-Esteem Scale mental scales (|d| 0.31). Survivors were less active than control subjects, as demonstrated by a step count difference of 1,742 steps per day (d = -0.43; P <.01); however, on average, the recommended level for an active lifestyle was achieved ( 10,000 steps). Location of pelvic tumor was the major inferior disease-specific prognostic factor in physical scores (P <.01), whereas nondisease-specific inferior factors in questionnaires were older age and female sex (P <.01).ConclusionSurvivors of Ewing sarcoma apparently returned to a normal life with minor limitations. Observed reductions in physical scores should be a focus in future research to optimize treatment strategies to reduce a negative impact on the quality of survivorshi

Management and Outcome of Ewing Sarcoma of the Head and Neck

Ewing sarcoma (EWS) of the head and neck is rare. Multimodal treatment consists of chemotherapy and local treatment; however, local treatment for EWS of the head and neck is challenging. The first objective was to describe local treatment administered to the patients with localized EWS of the head and neck according to the EURO-E.W.I.N.G.99-trial, and to assess the impact on survival. The second objective was to systematically review the scientific literature available for this topic. Fifty-one patients were included. Local control consisted of surgery and/or radiotherapy (RT). Event-free survival (EFS) and overall survival (OS) were determined. Outcome was analyzed by comparing local treatment approaches. A Medline search was performed for EWS of the head and neck. Eighty-six percent of patients had localized disease. Most common primary sites included the skull (45%), maxilla (14%), and mandible (12%). Three-year EFS was 74% and 3-year OS was 87% for patients with localized disease. EFS was 40% for patients >15 years compared to 81% for patients <15 years. Local control consisted of surgery (S; 33%), RT (18%), or S + RT (45%). Related 3-year EFS was 81% (S), 80% (RT), and 72% (S + RT); 3-year OS was 80%, 76%, and 81%, respectively. In patients with EWS of the head and neck, age, and stage are important prognostic factors. Although not statistically significant, large tumor volume seems to be a negative prognostic factor. No difference in EFS and OS could be found when comparing patients treated with surgery, RT, or combined surgery and R

Primary Disseminated Multifocal Ewing Sarcoma: Results of the Euro-EWING 99 Trial

Purpose To improve the poor prognosis of patients with primary disseminated multifocal Ewing sarcomas (PDMES) with a dose-intense treatment concept. Patients and Methods From 1999 to 2005, 281 patients with PDMES were enrolled onto the Euro-EWING 99 R3 study. Median age was 16.2 years (range, 0.4 to 49 years). Recommended treatment consisted of six cycles of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE), one cycle of vincristine, dactinomycin, and ifosfamide (VAI), local treatment (surgery and/or radiotherapy), and high-dose busulfan-melphalan followed by autologous stem-cell transplantation (HDT/SCT). Results After a median follow-up of 3.8 years, event-free survival (EFS) and overall survival (OS) at 3 years for all 281 patients were 27% +/- 3% and 34% +/- 4% respectively. Six VIDE cycles were completed by 250 patients (89%); 169 patients (60%) received HDT/SCT. The estimated 3-year EFS from the start of HDT/SCT was 45% for 46 children younger than 14 years. Cox regression analyses demonstrated increased risk at diagnosis for patients older than 14 years (hazard ratio [HR] = 1.6), a primary tumor volume more than 200 mL (HR = 1.8), more than one bone metastatic site (HR = 2.0), bone marrow metastases (HR = 1.6), and additional lung metastases (HR = 1.5). An up-front risk score based on these HR factors identified three groups with EFS rates of 50% for score = 5 (70 patients; P <.0001). Conclusion PDMES patients may survive with intensive multimodal therapy. Age, tumor volume, and extent of metastatic spread are relevant risk factors. A score based on these factors may facilitate risk-adapted treatment approache

Ewing Sarcoma as Secondary Malignant Neoplasm—Epidemiological and Clinical Analysis of an International Trial Registry

Ewing sarcoma (EwS) is the second most common bone and soft tissue tumor, affecting primarily adolescents and young adults. Patients with secondary EwS are excluded from risk stratification in several studies and therefore do not benefit from new therapies. More knowledge about patients with EwS as secondary malignant neoplasms (SMN) is needed to identify at-risk patients and adapt follow-up strategies. Epidemiology, clinical characteristics, and survival analyses of EwS as SMN were analyzed in 3844 patients treated in the last three consecutive international EwS trials, EICESS 92, Euro-E.W.I.N.G. 99, and EWING 2008. Forty-two cases of EwS as SMN (approximately 1.1% of all patients) were reported, preceded by a heterogeneous group of malignancies, mainly acute lymphoblastic leukemias (n = 7) and lymphomas (n = 7). Three cases of EwS as SMN occurred in the presumed radiation field of the primary tumor. The median age at diagnosis of EwS as SMN was 19.4 years (range, 5.9–72) compared with 10.8 years (range, 0.9–51.2) for primary EwS. The median interval between first malignancy and EwS diagnosis was 7.4 years. The 3-year overall survival (OS)/event-free survival (EFS) was 0.69 (SE = 0.09)/0.53 (SE = 0.10) for localized patients and 0.36 (SE = 0.13)/0.29 (SE = 0.12) for metastatic patients (OS: p = 0.02; EFS: p = 0.03). Survival in patients with EwS as SMN did not differ between hematologic or solid primary malignancies. EwS as SMN is rare; however, survival is similar to that of primary EwS, and its risk-adjusted treatment should be curative, especially in localized patients