Therapeutic implications of improved molecular diagnostics for rare CNS-embryonal tumor entities: results of an international, retrospective study

BACKGROUND: Only few data are available on treatment-associated behavior of distinct rare CNS-embryonal tumor entities previously treated as "CNS-primitive neuroectodermal tumors" (CNS-PNET). Respective data on specific entities, including CNS neuroblastoma, FOXR2 activated (CNS NB-FOXR2), and embryonal tumor with multi-layered rosettes (ETMR) are needed for development of differentiated treatment strategies. METHODS: Within this retrospective, international study, tumor samples of clinically well-annotated patients with the original diagnosis of CNS-PNET were analyzed using DNA methylation arrays (n=307). Additional cases (n=66) with DNA methylation pattern of CNS NB-FOXR2 were included irrespective of initial histological diagnosis. Pooled clinical data (n=292) were descriptively analyzed. RESULTS: DNA methylation profiling of "CNS-PNET" classified 58(19%) cases as ETMR, 57(19%) as HGG, 36(12%) as CNS NB-FOXR2, and 89(29%) cases were classified into 18 other entities. Sixty-seven (22%) cases did not show DNA methylation patterns similar to established CNS tumor reference classes. Best treatment results were achieved for CNS NB-FOXR2 patients (5-year PFS: 63%±7%, OS: 85%±5%, n=63), with 35/42 progression-free survivors after upfront craniospinal irradiation (CSI) and chemotherapy. The worst outcome was seen for ETMR and HGG patients with 5-year PFS of 18%±6% and 22%±7%, and 5-year OS of 24%±6% and 25%±7%, respectively. CONCLUSION: The historically reported poor outcome of CNS-PNET patients becomes highly variable when tumors are molecularly classified based on DNA methylation profiling. Patients with CNS NB-FOXR2 responded well to current treatments and a standard-risk-CSI based regimen may be prospectively evaluated. The poor outcome of ETMR across applied treatment strategies substantiates the necessity for evaluation of novel treatments

Development of the SIOPE DIPG network, registry and imaging repository : a collaborative effort to optimize research into a rare and lethal disease

Diffuse intrinsic pontine glioma (DIPG) is a rare and deadly childhood malignancy. After 40 years of mostly single-center, often non-randomized trials with variable patient inclusions, there has been no improvement in survival. It is therefore time for international collaboration in DIPG research, to provide new hope for children, parents and medical professionals fighting DIPG. In a first step towards collaboration, in 2011, a network of biologists and clinicians working in the field of DIPG was established within the European Society for Paediatric Oncology (SIOPE) Brain Tumour Group: the SIOPE DIPG Network. By bringing together biomedical professionals and parents as patient representatives, several collaborative DIPG-related projects have been realized. With help from experts in the fields of information technology, and legal advisors, an international, web-based comprehensive database was developed, The SIOPE DIPG Registry and Imaging Repository, to centrally collect data of DIPG patients. As for April 2016, clinical data as well as MR-scans of 694 patients have been entered into the SIOPE DIPG Registry/Imaging Repository. The median progression free survival is 6.0 months (95% Confidence Interval (CI) 5.6-6.4 months) and the median overall survival is 11.0 months (95% CI 10.5-11.5 months). At two and five years post-diagnosis, 10 and 2% of patients are alive, respectively. The establishment of the SIOPE DIPG Network and SIOPE DIPG Registry means a paradigm shift towards collaborative research into DIPG. This is seen as an essential first step towards understanding the disease, improving care and (ultimately) cure for children with DIPG.Peer reviewe

Diagnosis and treatment of thyroid cancer in children in the multicenter analysis in Poland for PPGGL

Introduction: Differentiated thyroid carcinoma (DTC) in children presents different biological behavior in comparison to adults. Authors presents preliminary results of multicenter analysis concerning incidence, diagnostics and treatment of DTC in children. Material and methods: The study is a retrospective analysis of 107 pediatric patients from 14 academic centers based on the data from 2000 to 2005 obtained by questionnaire in hospitals involved in the treatment of DTC in children. Results: Papillary thyroid cancer was diagnosed in 83 children, follicular thyroid cancer in 10 children and medullary thyroid cancer in 14 children. Incidence of DTC in children was estimated between 18 and 23 cases per year. The biggest group of patients consisted of children between 11 and 15 years of age, with girls to boys ratio 3.3 : 1. Clinically DTC in children presented most often as solitary thyroid nodule. Cervical lymphadenopathy was observed in 42% of patients. Intraoperative verification indicated metastatic nodes in 50% of children. Low stage DTC predominated (T1 in 36% and T2 in 26% of children). One step surgery was performed in 65% of children with DTC, two step surgery in 25% of patients. I131 therapy was undertaken in 80% of children. Lung metastases were indicated in post therapeutic studies in 14% of children with DTC. Prophylactic thyroidectomies were performed in 79% of children in the group of patients with MTC and RET gene mutations. Conclusions: The necessity of introduction of unified therapeutic standard in children with DTC in Poland is underlined.Wstęp: Zróżnicowane raki tarczycy (DTC, differentiated thyroid carcinoma) występują u dzieci rzadko. Większość przypadków wykrywanych jest w wieku 11-17 lat. W odróżnieniu od dorosłych DTC u dzieci prezentują odmienne zachowanie biologiczne. Mała liczba przypadków DTC w poszczególnych ośrodkach oraz względnie łagodny ich przebieg utrudniają ocenę występowania i leczenia DTC u dzieci w Polsce, uzależniając ją od wysiłków włożonych w uzyskanie rzetelnych danych. Autorzy przedstawiają wstępne wyniki analizy wieloośrodkowej dotyczące występowania, diagnostyki i leczenia DTC u dzieci. Materiał i metody: Podjęte badania są retrospektywną analizą obejmującą lata 2000-2005, opartą na danych z historii chorób uzyskanych z ankiet rozesłanych do ośrodków dla dzieci i dorosłych podejmujących leczenie DTC. Do analizy zgłoszono 107 pacjentów z 14 ośrodków akademickich w Polsce. Analizie poddano wiek i płeć dzieci z DTC, wielkość i lokalizację zmian w tarczycy, sposoby rozpoznawania DTC, rodzaje i zakres wykonywanych zabiegów operacyjnych oraz leczenie uzupełniające izotopem J131. Wyniki: Raka brodawkowatego stwierdzono u 83 dzieci, pęcherzykowego u 10 dzieci, a rdzeniastego u 14 dzieci. Częstość występowania DTC u dzieci w Polsce wahała się między 18 a 23 przypadkami rocznie. W województwach: mazowieckim i połączonych wielkopolskim i lubuskim wykazano w okresie 2000-2005 wyższą (24 i 25) częstość występowania DTC, w pozostałych województwach wykazywano od 2 do 10 przypadków DTC. Największą grupę pacjentów stanowiły dzieci w wieku 11-15 lat, a stosunek dziewcząt do chłopców wynosił 3,3 : 1. Klinicznie DTC prezentowały się najczęściej jako pojedyncze guzki tarczycy. Limfadenopatię szyjną w badaniu klinicznym stwierdzono u 42% pacjentów, a śródoperacyjnie u 50% dzieci. U większości pacjentów dominowały niższe stopnie zaawansowania DTC (T1 u 36% i T2 u 26% dzieci). Operacje jednoetapowe wykonano u 65% dzieci, operacje dwuetapowe u 25% dzieci, a profilaktyczne tyreoidektomie u 79% dzieci z grupy pacjentów z rakiem rdzeniastym tarczycy (MTC, medullary thyroid cancinoma) i mutacją genu Ret. Leczenie izotopowe J131 podjęto u 80% dzieci. Przerzuty do płuc w scyntygrafii poterapeutycznej wykazano u 14% dzieci z DTC. Wnioski: We wnioskach podkreśla się konieczność wdrożenia na terenie całego kraju ujednoliconego i ocenianego na podstawie obiektywnych przesłanek sposobu postępowania z dziećmi z DTC

TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma

Telomerase reverse transcriptase (TERT) promoter mutations were recently shown to drive telomerase activity in various cancer types, including medulloblastoma. However, the clinical and biological implications of TERT mutations in medulloblastoma have not been described. Hence, we sought to describe these mutations and their impact in a subgroup-specific manner. We analyzed the TERT promoter by direct sequencing and genotyping in 466 medulloblastomas. The mutational distributions were determined according to subgroup affiliation, demographics, and clinical, prognostic, and molecular features. Integrated genomics approaches were used to identify specific somatic copy number alterations in TERT promoter-mutated and wild-type tumors. Overall, TERT promoter mutations were identified in 21 % of medulloblastomas. Strikingly, the highest frequencies of TERT mutations were observed in SHH (83 %; 55/66) and WNT (31 %; 4/13) medulloblastomas derived from adult patients. Group 3 and Group 4 harbored this alteration in <5 % of cases and showed no association wit

Cytogenetic Prognostication Within Medulloblastoma Subgroups

PURPOSE: Medulloblastoma comprises four distinct molecular subgroups: WNT, SHH, Group 3, and Group 4. Current medulloblastoma protocols stratify patients based on clinical features: patient age, metastatic stage, extent of resection, and histologic variant. Stark prognostic and genetic differences among the four subgroups suggest that subgroup-specific molecular biomarkers could improve patient prognostication. PATIENTS AND METHODS: Molecular biomarkers were identified from a discovery set of 673 medulloblastomas from 43 cities around the world. Combined risk stratification models were designed based on clinical and cytogenetic biomarkers identified by multivariable Cox proportional hazards analyses. Identified biomarkers were tested using fluorescent in situ hybridization (FISH) on a nonoverlapping medulloblastoma tissue microarray (n = 453), with subsequent validation of the risk stratification models. RESULTS: Subgroup information improves the predictive accuracy of a multivariable survival model compared with clinical biomarkers alone. Most previously published cytogenetic biomarkers are only prognostic within a single medulloblastoma subgroup. Profiling six FISH biomarkers (GLI2, MYC, chromosome 11 [chr11], chr14, 17p, and 17q) on formalin-fixed paraffin-embedded tissues, we can reliably and reproducibly identify very low-risk and very high-risk patients within SHH, Group 3, and Group 4 medulloblastomas. CONCLUSION: Combining subgroup and cytogenetic biomarkers with established clinical biomarkers substantially improves patient prognostication, even in the context of heterogeneous clinical therapies. The prognostic significance of most molecular biomarkers is restricted to a specific subgroup. We have identified a small panel of cytogenetic biomarkers that reliably identifies very high-risk and very low-risk groups of patients, making it an excellent tool for selecting patients for therapy intensification and therapy de-escalation in future clinical trials

An innovative power supply and control system for mining roadheading machine

Spągoładowarki są powszechnie stosowanymi maszynami w polskim górnictwie węglowym. Zazwyczaj maszyny te stosowane są do prac związanych z odpowiednim utrzymaniem spągu w chodnikach. Są to maszyny samobieżne zbudowane na podwoziu gąsiennicowym o napędzie elektrohydraulicznym, w którym wszystkie funkcje sterownicze realizowane są na drodze hydraulicznej. Pompa hydrauliczna napędzana jest silnikiem elektrycznym, zasilanym z rozwijanego kabla podłączonego do kopalnianej sieci elektroenergetycznej. Wadą takiego rozwiązania jest ograniczona mobilność oraz to, że w trakcie przemieszczania się spągoładowarki, rozwijany kabel narażony jest na uszkodzenia mechaniczne. W związku z powyższym, zasadnym było podjęcie prac nad układem napędowym zasilanym z własnego źródła zasilania w postaci baterii ogniw. Prace nad innowacyjnym rozwiązaniem zespołu zasilającego górniczych maszyn małej mechanizacji zostały już rozpoczęte w Instytucie Techniki Górniczej KOMAG przy współpracy z producentem maszyn górniczych firmą HYDROTECH S.A. W pracy omówiono aktualny stan wiedzy w zakresie układów zasilania górniczych spągoładowarek. Przedstawiono wyniki badań zapotrzebowania na energię przedmiotowej maszyny górniczej, na podstawie których opracowano założenia techniczno-technologiczne dla nowego rozwiązania. W podsumowaniu sformułowano wnioski końcowe, nakreślono przebieg dalszych prac przywidzianych do realizacji w ramach opracowania nowego układu zasilającego oraz wskazano kierunki rozwoju napędów górniczych maszyn małej mechanizacji z perspektywy nadchodzących lat.Roadheading machines are widely used machines in Polish coal mining. Typically, these machines are used for works related to proper maintenance of the floor in the sidewalks. These are self-propelled machines built on a tracked electro-hydraulic chassis, in which all control functions are carried out on the hydraulic path. The hydraulic pump is driven by an electric motor, powered from a drop-down cable connected to the mine power network. The disadvantage of this solution is limited mobility and the fact that during the displacement of the stranger, the cable being unwound is exposed to mechanical damage. In connection with the above, it was reasonable to start work on the drive system supplied from its own power source in the form of battery cells. Work on an innovative solution for the power supply team for mining machinery of small mechanization has already been started at the KOMAG Institute of Mining Technology in cooperation with the mining machine manufacturer HYDROTECH S.A. The work discusses the current state of knowledge in the field of feeding systems for mining machines. There are presented the results of research on the energydemand of the mining machine, on the basis of which technical and technological assumptions for the new solution were developed. The conclusions formulate final conclusions, outlines the course of further work to be implemented as part of the development of a new power supply system and indicate the directions of development of mining drives for small mechanization machines from the perspective of the coming years

Postural sway in children and young adults, survivors of CNS tumours

ABSTRACT Purpose: Brain tumours are the most common solid tumours in children and adolescents. The increasing survival rate of these patients makes their follow-up and quality of life assessment an important task. The evaluation of the negative influence of anti-cancer treatment on their balance is the aim of this study. Material and Methods: The balance assessment was performed on patients who completed the treatment of CNS tumours and were disease-free at the time of the study. Eighty-eight patients aged 5 to 24 years participated in the study. Postural sway was recorded using Kistler force plate. Balance test parameters from two conditions: eyes open and eyes closed were calculated and compared with reference data. The severity of the balance disorders was scored for both conditions. Results: The balance disorders were generally not dependent on the localisation of the tumour. Only patients treated for posterior fossa tumours had a higher score (indicating pronounced balance deficit) in eyes closed condition comparing to others. The patients treated for spinal cord tumours seemed to have increased total sway path in comparison to others. The severity of the balance deficits tended to diminish in time. Conclusions: These results suggest that the repair mechanisms of the CNS could overcome the problems inflicted by the illness and therapy