Autologous haematopoietic stem cell transplantation in childhood solid tumours

The data were presented partially at the Conference “Haematopoietic Stem Cell Transplantation in Children: Current Status, Controversies and Perspectives” held in Poznan, 16–17, Dec. 1999

High-dose chemotherapy followed by autologous haematopoietic cell transplantation for children, adolescents, and young adults with first recurrence of Ewing sarcoma

BACKGROUND Ewing sarcoma is a solid tumour, which is the second most common primary bone malignancy in children, often occurring in the long bones and pelvis. An incidence rate of 4.5 per million a year is reported, with a peak incidence of 11 per million at the age of 12 years. Despite more intensive chemotherapy, 30% to 40% of young people with Ewing sarcoma will have recurrence of the disease. Less than 30% of young people with a recurrence of Ewing sarcoma are alive at 24 months, and less than 10% are alive at 48 months. High-dose chemotherapy (HDC), followed by autologous haematopoietic cell transplantation (AHCT), is used in a variety of paediatric groups with diverse solid tumours. The hypothesis is that HDC regimens may overcome resistance to standard polychemotherapy, and this way may eradicate minimal residual disease, leading to improved survival after a first recurrence of disease. OBJECTIVES To assess the efficacy of HDC with AHCT versus conventional chemotherapy in improving event-free survival, overall survival, quality-adjusted survival, and progression-free survival in children, adolescents, and young adults with first recurrence of Ewing sarcoma, and to determine the toxicity of the treatment. SEARCH METHODS We searched CENTRAL, MEDLINE, Embase, conference proceedings from the SIOP, ASPHO, CTOS, ASBMT, EBMT, and EMSOS, and two trial registries in January 2020. We also searched reference lists of relevant articles and review articles. SELECTION CRITERIA We planned to include randomised controlled trials (RCTs) or (historical) controlled clinical trials (CCTs) comparing the effectiveness of HDC plus AHCT with conventional chemotherapy for children, adolescents, and young adults (up to 30 years old at the date of diagnostic biopsy) with a first recurrence of Ewing sarcoma. DATA COLLECTION AND ANALYSIS We used standard methodological procedures expected by Cochrane. MAIN RESULTS We did not identify any eligible studies. AUTHORS' CONCLUSIONS Since we did not identify any eligible studies, we are unable to draw any conclusions about the efficacy and toxicity of HDC with AHCT versus conventional chemotherapy in children, adolescents, and young adults with a first recurrence of Ewing sarcoma. Further high-quality research is urgently needed

High-Dose Chemotherapy Followed by Peripheral and/or Bone Marrow Stem Cell Transplant in Patients With Advanced Sarcoma: Experience of a Canadian Centre

Purpose: Few reports have been published on the evaluation of stem cell auto transplantation for chemosensitive sarcomas. Some suggest benefit, others do not. We present results of 24 patients with sarcoma undergoing autotransplantation at a Canadian institution

Ewing sarcoma : treatment, prognosis and late effects

Ewing sarcoma (ES) is a rare and aggressive childhood/adolescent malignancy which relies on a multidisciplinary treatment approach for cure. The overall survival rate for this young patient group has hardly improved over the last 30 years despite large multinational treatment trials. Thus, there are important research questions to be answered with regards to systemic treatment. However, this thesis is about local treatment. Local treatment is indisputably important for overall survival, yet we have not reached a consensus for which local treatment regime is best for the individual patient. Therefore, local treatment is always a matter of debate on multidisciplinary meetings in sarcoma centers around the world. In the national multidisciplinary sarcoma conferences hosted at the Karolinska University Hospital every fortnight, every ES case in the country is brought up for discussion and there is an unproportioned amount of time spent on each case compared to other sarcomas. Due to the rare nature of this disease, randomized trials on local treatment are unlikely to occur and local treatment relies on case series and studies hampered by low number of patients. This thesis aims to shed light on the following questions: (1) which is the optimal local treatment strategy for pelvic ES; (2) how are ES of the spine treated in Scandinavia and what is the neurologic and oncologic outcome; (3) what is the true risk for subsequent primary neoplasms (SPNs) among ES survivors and (4) what is the effect of local treatment on local failure, long term mortality and morbidity? Study 1 evaluates different local treatment options in treatment of pelvic ES and whether local control of sacral ES can be achieved with radiotherapy alone. Innominate bone ES were in most cases treated surgically and sacral bone tumors were largely treated with radiotherapy (RT) alone. We found that sacral site was an independently favorable site as regards disease- free survival compared with the innominate bones. Furthermore, good local control could be obtained with RT alone for tumors located in the sacrum. Study 2 investigated if the same good outcome found among ES of the sacrum could be seen among patients with ES of the mobile spine. Additionally, the neurologic deficits at time of diagnosis and at end of follow-up for ES of the mobile spine were examined in relation to local treatment. Only 24 patients with sufficient data were found eligible for the analysis. Neurologic deficits at presentation were common which often led to emergency decompression before having a histopathologic diagnosis. Emergency decompression was associated with a higher rate of local failure. Most patients recovered neurologically regardless of local treatment, perhaps because of prompt initiation of systemic treatment leading to tumor shrinkage and less pressure on the spinal cord. Disease-free survival was relatively favorable, but perhaps not as good as that of sacral ES. As was the case with sacral ES, the majority of patient were treated with RT exclusively which reflects the difficulties in performing “en bloc” surgery in this site. Local control was excellent for the few patients with tumors manageable by surgery. Study 3 investigated the risk for secondary malignancies among Ewing- and osteosarcoma (OS) survivors in a population-based nationwide cohort. ES survivors had double the risk of OS survivors, and a four times higher risk than the general population of acquiring an SPN. The excess risk was largely driven by breast cancer and female genital malignancies for ES as well as OS survivors, and not as much by secondary sarcoma as anticipated. Due to the high background breast cancer incidence in the general population, the excess breast cancer risk among ES survivors translates to 127 extra breast cancers per 10 000 person years. The excess cancer risk remained elevated with increasing follow-up and over calendar time. Study 4 evaluated the role of surgery and RT in relation to surgical margin and local control. Secondarily, the effect of local treatment on long-term mortality, occurrence of SPN and hospitalization was studied. Local treatment had a significant effect not only on local failure, but also on overall survival. Surgical treatment gave superior local control compared with definitive RT. The lowest local failure rate was achieved if surgery was performed with a wide surgical margin. Nonetheless, RT also played a significant role with regards to local control since marginally resected tumors treated with adjuvant RT achieved an equal local control rate to that of a wide margin. This is a key finding because accomplishing a wide surgical margin is rarely possible for tumors located in the pelvis or spine, sites which comprise a third of all ES. In conclusion, tumor site is an important prognostic factor in ES. Pelvic and spinal sites pose a specific challenge since surgery of the primary tumor is less often performed due to the morbidity associated with surgery in these sites. Hence, more patients will receive definitive RT. Definitive RT seems to achieve good local control for tumors of the sacrum. Nevertheless, the long-term results of definitive RT are unknown. For tumors located in sites other than the sacrum, surgery is superior to definitive RT in achieving local control and improving survival. Moreover, best local control is achieved when surgery is carried out with wide margins, in which case RT does not improve outcome. Importantly, radiotherapy improves local control for marginally resected tumors. The long-term excess risks for SPNs are mainly driven by breast cancer among females. Unfortunately, the risks remain high in recent treatment periods. Moreover, the excess risk persists with extended follow-up, indicating the need for lifelong surveillance and tailored follow-up. However, the outcome after local recurrence is dismal. The benefit of administering RT when indicated must therefore not be overshadowed by the risk for treatment related cancer

Treatment of Ewing Sarcoma, Paediatric Bone Sarcomas and Severe Paediatric Spinal Deformities in Finland

Background: Ewing sarcomas are rare highly malignant tumours. There are not many population-based studies including both bone and soft tissue tumours. Previous reports have suggested that the incidence of Ewing sarcoma in the paediatric population may be lower in Northern Europe compared to other parts of Europe. Ewing sarcomas frequently arise in the pelvis and other axial sites and rarely in the spine. Surgical techniques of vertebral column resection to treat spinal tumours or severe spinal deformities have evolved with techniques using only a posterior approach. Aims: Our aim was to find out how the treatment of Ewing sarcoma is carried out in Finland and what are the five-year survival rates and to reveal the surgical treatment and its complications. We also aimed at establishing the incidence rates of bone sarcomas in the paediatric and adolescent population in Finland and to establish the ten-year survival rates. Additionally, we aimed to report the results of a population-based material on paediatric vertebral column resection. Material and methods: We identified all Finnish patients with Ewing sarcoma diagnosed during 1990-2009, all paediatric bone sarcoma patients diagnosed during 1991-2005 and all paediatric patients who underwent vertebral column resection during 2005-2009. The medical records were reviewed for detailed information and these data were analysed. The study is retrospective, nationwide and population-based. Results: Seventy-six Ewing sarcoma patients were included in the final analyses. The five-year sarcoma-specific survival rates were 70% for those with localized and 33% for those with metastatic disease (p=0.001). Fifty-seven patients underwent surgical treatment of the primary tumour. The annual incidence rates of osteosarcoma, Ewing sarcoma and chondrosarcoma per million 0-18-year-old people in Finland during 1991-2005 were 3.6, 1.2 and 0.3, respectively. The ten-year overall survival was 74% for osteosarcoma, 76% for Ewing sarcoma and 80% for chondrosarcoma. Fourteen paediatric patients underwent vertebral column resection during 2005-2009. There were no differences between those operated via posterior-only approach (n=7) compared to those operated via antero-posterior approach (n=7) in the mean final radiological corrections or the quality-of-life results. Conclusions: We conclude that the outcomes of treatment of Ewing sarcoma and paediatric bone sarcomas in Finland are comparable to previously reported outcomes. The incidence of Ewing sarcoma in Finland seems to be a bit lower than reported elsewhere in Europe. Posterior-only approach in paediatric vertebral column resections carry comparable results to anteroposterior approach.Tausta: Ewingin sarkooma on harvinainen pahanlaatuinen kasvain. Sekä luun että pehmytkudoksen kasvaimia käsitteleviä, väestöön pohjautuvia tutkimuksia on julkaistu vain vähän. Aiemmat tutkimukset ovat viitanneet siihen, että Ewingin sarkooma olisi Pohjois-Euroopassa harvinaisempi kuin muissa osissa Eurooppaa. Ewingin sarkooma voi harvoin sijaita myös selkärangassa. Kirurgiset tekniikat rangan kasvainten ja vaikeiden epämuodostumien hoidossa ovat kehittyneet ja nykyisin leikkauksia voidaan tehdä yhtä selän puoleista avausta käyttäen. Tavoitteet: Tavoitteemme oli selvittää miten Ewingin sarkooman hoito, erityisesti kirurginen hoito, on Suomessa on toteutunut ja mitkä ovat potilaiden viiden vuoden elossaololuvut. Halusimme myös selvittää lasten ja nuorten luusarkoomien ilmaantuvuusluvut ja 10 vuoden elossaololuvut. Lisäksi tavoitteenamme selvittää lasten nikamanpoistojen tulokset Suomessa. Aineisto ja menetelmät: Tunnistimme kaikki potilaat, joilla oli diagnosoitu Suomessa vuosina Ewingin sarkooma 1990-2009 ja kaikki alle 18-vuotiaat, joilla oli diagnosoitu luusarkooma vuosina 1991-2005 ja kaikki alle 18-vuotiaat, joille oli 2005-2009 tehty nikamanpoistoleikkaus. Sairaskertomukset käytiin läpi yksityiskohtaisten tietojen saamiseksi ja kerätyt aineistot analysoitiin. Tutkimus on malliltaan takautuva, valtakunnallinen ja väestöön pohjautuva. Tulokset: Lopullisiin analyyseihin otettiin mukaan 76 Ewingin sarkooma sairastanutta potilasta. Viiden vuoden elossaololuvut olivat 70% paikallista tautia sairastaneilla ja 33% levinnyttä tautia sairastaneilla (p=0.001). Potilaista 57:llä primaarikasvain hoidettiin kirurgisesti. Osteosarkooman, Ewingin sarkooman ja kondrosarkooman vuosittaiset ilmaantuvuusluvut miljoonaa alle 18-vuotiasta kohden olivat 3.6, 1.2 ja 0.3. 10 vuoden elossaololuvut olivat vastaavasti 74%, 76% ja 80%. Suomessa tehtiin 2005-2009 nikamanpoistoleikkaus 14:lle alle 18-vuotiaalle potilaalle. Verrattaessa sekä selän- että etupuolelta suoritettuja toimenpiteitä (n=7) niihin, jotka suoritettiin pelkästä selän puoleisesta viillosta (n=7), eroja ei ollut radiologisen virheasennon korjautumisen tai elämänlaatua mittaavien kyselytulosten suhteen. Yhteenveto: Tutkimuksen perusteella voidaan todeta, että Ewingin sarkooman ja lasten luusarkoomien hoito Suomessa on tuloksiltaan hyvää kansainvälistä tasoa. Ewingin sarkooman ilmaantuvuus Suomessa alle 18-vuotiailla näyttäisi hieman pienemmältä kuin mitä muualla Euroopassa on raportoitu. Pelkästä selän puoleisesta viillosta suoritettujen nikamanpoistojen tulokset ovat hyvät, eivätkä eroa sekä selän- että etupuolelta tehtyjen toimenpiteiden tuloksista

Lapsuusiän kantasolusiirrot HUS:ssa vuosina 1993-2006

Tutkielma kuvaa lapsuusiän kantasolusiirtojen merkittävimmät tulokset ja komplikaatiot keskeisissä tautiryhmissä modernin hoidon aikakaudella HUS:ssä. Aineistona on HUS:n Lasten ja nuorten sairaalan veri- ja syöpätautien sekä kantasolusiirtoyksikön potilaista kerätty, vuonna 1993 perustetun ProLapsi-rekisterin sisältämä kliininen kantasolusiirtoaineisto vuosilta 1993-2006. Aineisto sisältää runsaat 90% Suomessa tehdyistä lasten allogeenisista kantasolusiirroista (n=233) sekä kaikki HUS:in autologiset siirrot (n=117) ko. aikajaksolla. Tutkielma on toteutettu kvantitatiivisia tutkimusmenetelmiä käyttäen. Suurin allogeenisen kantasolusiirron saaneiden potilaiden diagnoosiryhmä oli akuutti lymfoblastileukemia, ja suurin autologisen kantasolusiirron saaneiden ryhmä neuroblastoomapotilaat. Allogeenisista kantasolusiirroista 38% tehtiin HLA-identtiseltä sukulaisluovuttajalta ja 53% rekisteriluovuttajan soluilla. Kumulatiivinen kokonaisselviytyminen oli merkitsevästi parempaa sukulaisluovuttajan soluilla tehdyissä siirroissa kuin rekisteriluovuttajan (p=0,003). Allogeenisen kantasolusiirron saaneista potilaista 71% sai jonkin asteisen akuutin ja 42% kroonisen käänteishyljinnän (GVHD). Sekä akuutin että kroonisen GVHD:n vaikeus puolestaan korreloi kuolleisuuteen. Allogeenisen kantasolusiirron pitkäaikaisvaikutusta arvioitiin seurantatietojen perusteella. 58%:lla elämänlaatu arvioitiin normaaliksi, 35%:lla hieman rajoittuneeksi ja 7%:lla heikoksi

Inhibition of the Hedgehog pathway in combination with cytostatics as potential therapeutic option in Ewing Sarcoma

Ewing Sarkome (EWS) zählen zu den mesenchymalen Tumoren und treten gehäuft bei Kindern und Jugendlichen auf. Patienten mit nicht-metastasiertem EWS, die sich einer radikalen chirurgischen Intervention, Radiotherapie und/oder Chemotherapie unterziehen, zeigen eine durchschnittliche 5-Jahres Überlebensrate von über 70 %, wohingegen metastasierte und rezidivierte EWS deutlich schwerer zu behandeln sind. Einer der vielen Gründe dafür ist die zunehmende Resistenz von rezidivierten EWS gegen Chemotherapeutika. Diese beruht unter anderem darauf, dass ABC Transporter wie PGP oder MRP1, welche die Chemotherapeutika wieder aus der Tumorzelle in den Extrazellularraum befördern, von diesen exprimiert werden. Darüber hinaus wird vom EWS das für den Tumor charakteristische Fusionsprotein EWS-FLI1 exprimiert, welches auch die GLI Proteine im Hedgehog (Hh) Signalweg moduliert. Veränderungen im Hh Signalweg wurden bereits in verschiedenen Tumoren beobachtet und korrelieren mit einer erhöhten Tumorbildung und Progression. Da der Hh Signalweg direkt die Expression von ABC Transportern beeinflusst, wurde in dieser Arbeit die Inhibition der GLI Proteine als mögliche zusätzliche Therapieoption zur Unterdrückung der Chemoresistenz getestet. Dafür wurden drei EWS Zelllinien mit den GLI Inhibitoren GANT61 und ATO, sowie den bereits etablierten Chemotherapeutika Etoposid und Doxorubicin behandelt und ihre Viabilität, Koloniebildungsfähigkeit, Wachstum in 3D Kulturen und Induktion von Zelltod mittels MTS Assay, Koloniebildungs-Assay, 3D Spheroid Assay, Durchflusszytometrie und Western Blot getestet. ATO, Etoposid und Doxorubicin reduzierten die Viabilität signifikant und selektiv in allen drei EWS Zelllinien im Vergleich zu mesenchymalen Stammzellen (MSC). Dahingegen war GANT61 weniger effizient in zwei der drei EWS Zelllinien und vor allem nicht selektiv gegenüber MSC. Zelltod konnte durch ATO, Etoposid und Doxorubicin in allen EWS Zelllinien, nicht aber in MSC induziert werden. Dieser Effekt wurde mit der Kombination von ATO und Etoposid noch einmal potenziert. Die Kombination von ATO und Doxorubicin reduzierte die Viabilität ebenfalls signifikant, verglichen mit der Einzelgabe. Eine dreifache Kombination aus ATO, Etoposid und Doxorubicin zeigte jedoch keinen zusätzlichen Nutzen im Vergleich zu den Zweifach-Kombinationen. Die bisherigen Ergebnisse deuten darauf hin, dass ATO zur Erhöhung der Überlebensraten von EWS Patienten und zur Reduzierung von Resistenzen gegen Chemotherapeutika in aggressiven EWS beitragen kann. Durch die reduzierte Dosis der kombinierten Substanzen können Nebenwirkungen der Chemotherapeutika vermindert werden. Vor einem potenziellen klinischen Einsatz werden allerdings weitere Informationen über die detaillierten Wirkmechanismen in EWS benötigt.Ewing sarcoma (EWS) are mesenchymal tumours usually occurring in children and adolescents. Currently, patients with non-metastatic EWS show 5-year survival rates above 70 % when treated radically with surgery, chemotherapy and radiotherapy, whereas relapsed or metastasised EWS are more difficult to treat. One of many reasons is the increasing drug resistance in relapsed EWS including the expression of ABC transporters such as PGP or MRP1 which transport cytostatic drugs back through the cell membrane into the extracellular matrix. Furthermore, EWS express the characteristic EWS-FLI1 fusion protein which also modulates the GLI proteins in the Hedgehog (Hh) pathway. Aberrant Hh-signalling has been observed in several malignancies including EWS and correlates with cancer formation and progression. As the Hh pathway directly targets expression of ABC transporter proteins, GLI inhibition as additional therapeutic option to overcome multi drug resistance was investigated. In the present study viability, colony formation, growth of 3D cultures and induction of cell death was analysed in three EWS cell lines treated with the GLI inhibitors GANT61 and ATO as well as the established cytostatics etoposide and doxorubicin using MTS assay, clonogenic assay, 3D spheroid assay, flow cytometry and western blot. ATO, etoposide and doxorubicin reduced viability significantly and selectively in all three EWS cell lines in comparison to mesenchymal stem cells (MSC). On the other hand, GANT61 was less efficient in two of three EWS cell lines and particularly not selective compared to MSC. Cell death was induced by ATO, etoposide and doxorubicin in all three EWS cell lines, but not MSC. The combination of ATO and etoposide potentiated this effect. The combined application of ATO and doxorubicin also significantly compromised viability compared to individual treatment. However, a triple combination of ATO with both cytostatics did not compromise cells more than the double combinations. The present results indicate that ATO is effective in EWS. Therefore, ATO may contribute to increased survival rates of patients with EWS and especially reduce resistance of aggressive EWS against chemotherapeutics. Furthermore, as doses for drugs can be reduced in combined treatment, adverse effects of chemotherapy may be diminished. However, further evaluation of the detailed inhibitory mechanisms in EWS is needed before transferring this approach to the clinic