To compare event-free survival (EFS), overall survival (OS), pattern of relapse, and hearing loss in children with standard-risk medulloblastoma treated by postoperative hyperfractionated or ...conventionally fractionated radiotherapy followed by maintenance chemotherapy.
In all, 340 children age 4 to 21 years from 122 European centers were postoperatively staged and randomly assigned to treatment with hyperfractionated radiotherapy (HFRT) or standard (conventional) fractionated radiotherapy (STRT) followed by a common chemotherapy regimen consisting of eight cycles of cisplatin, lomustine, and vincristine.
After a median follow-up of 4.8 years (range, 0.1 to 8.3 years), survival rates were not significantly different between the two treatment arms: 5-year EFS was 77% ± 4% in the STRT group and 78% ± 4% in the HFRT group; corresponding 5-year OS was 87% ± 3% and 85% ± 3%, respectively. A postoperative residual tumor of more than 1.5 cm(2) was the strongest negative prognostic factor. EFS of children with all reference assessments and no large residual tumor was 82% ± 2% at 5 years. Patients with a delay of more than 7 weeks to the start of RT had a worse prognosis. Severe hearing loss was not significantly different for the two treatment arms at follow-up.
In this large randomized European study, which enrolled patients with standard-risk medulloblastoma from more than 100 centers, excellent survival rates were achieved in patients without a large postoperative residual tumor and without RT treatment delays. EFS and OS for HFRT was not superior to STRT, which therefore remains standard of care in this disease.
This retrospective study aimed at analyzing the impact of metastasectomy on post-metastasis survival (PMS) in bone sarcoma patients with lung metastases. Altogether, 47 bone sarcoma patients (24 ...males, median age at diagnosis of lung metastases: 21.8 (IQR: 15.6-47.3) years) with primary (n = 8) or secondary (n = 39) lung metastases treated at a single university hospital were retrospectively included. Based on a propensity score, inverse probability of treatment weight (IPTW) was calculated to account for selection bias whether patients had undergone metastasectomy or not. The most common underlying histology was osteosarcoma (n = 37; 78.7%). Metastasectomy was performed in 39 patients (83.0%). Younger patients (
= 0.025) with singular (
= 0.043) and unilateral lesions (
= 0.024), as well as those with an interval ≥ 9 months from primary diagnosis to development of lung metastases (
= 0.024) were more likely to undergo metastasectomy. Weighted 1- and 3-year PMS after metastasectomy was 80.8% and 58.3%, compared to 88.5% and 9.1% for patients who did not undergo metastasectomy. Naive Cox-regression analysis demonstrated a significantly prolonged PMS for patients with metastasectomy (HR: 0.142; 95%CI: 0.045-0.450;
= 0.001), which was confirmed after IPTW-weighting (HR: 0.279; 95%CI: 0.118-0.662;
= 0.004), irrespective of age, time to metastasis, and the number of lesions. In conclusion, metastasectomy should be considered in bone sarcoma patients with lung metastases, after carefully considering the individual risks, to possibly improve PMS.
Beckwith–Wiedemann spectrum, Simpson–Golabi–Behmel syndrome, familial adenomatous polyposis and trisomy 18 are the most common congenital conditions associated with an increased incidence of ...hepatoblastoma (HB). In patients with these genetic disorders, screening protocols for HB are proposed that include periodic abdominal ultrasound and measurement of alpha‐fetoprotein levels. Surveillance in these children may contribute to the early detection of HB and possibly improve their chances of overall survival. Therefore, physicians must be aware of the high HB incidence in children with certain predisposing genetic diseases.
Early diagnosis of primary immunodeficiency disorders (PID) is vital and allows directed treatment, especially in syndromes with severe or profound combined immunodeficiency. In PID patients with ...perinatal CMV or other opportunistic, invasive infections (e.g.,
or
), multi-organ morbidity may already arise within the first months of life, before hematopoietic stem cell transplantation (HSCT) or gene therapy can be undertaken, compromising the definitive treatment and outcome. Deficiency of Wiskott-Aldrich syndrome (WAS) protein-interacting protein (WIP deficiency) causes an autosomal recessive, WAS-like syndrome with early-onset combined immunodeficiency that has been described in three pedigrees to date. While WAS typically includes combined immunodeficiency, microthrombocytopenia, and eczema, the clinical and laboratory phenotypes of WIP-deficient patients-including lymphocyte subsets, platelets, lymphocyte proliferation
, and IgE-varied widely and did not entirely recapitulate WAS, impeding early diagnosis in the reported patients. To elucidate the phenotype of WIP deficiency, we provide a comprehensive synopsis of clinical and laboratory features of all hitherto-described patients (
= 6) and WIP negative mice. Furthermore, we summarize the treatment modalities and outcomes of these patients and review in detail the course of one of them who was successfully treated with serial, unconditioned, maternal, HLA-identical donor lymphocyte infusions (DLI) against life-threatening, invasive CMV infection, followed by a TCRαβ/CD19-depleted, treosulfan/melphalan-conditioned, peripheral blood HSCT and repetitive, secondary-prophylactic, CMV-specific DLI with 1-year post-HSCT follow-up. This strategy could be useful in other patients with substantial premorbidity, considered "
," who have an HLA-identical family donor, to eliminate infections and bridge until definitive treatment.
Glioblastoma (GBM) is an utterly devastating cerebral neoplasm and current therapies only marginally improve patients' overall survival (OS). The PI3K/AKT/mTOR pathway participates in gliomagenesis ...through regulation of cell growth and proliferation. Since it is an upstream regulator of the rate-limiting translation initiation step of protein synthesis, controlled by eukaryotic initiation factors (eIFs), we aimed for a profound basic characterization of 17 eIFs to identify potential novel therapeutic targets for gliomas. Therefore, we retrospectively analyzed expressions of mTOR-related proteins and eIFs in human astrocytoma samples (WHO grades I-IV) and compared them to non-neoplastic cortical control brain tissue (CCBT) using immunoblot analyses and immunohistochemistry. We examined mRNA expression using qRT-PCR and additionally performed in silico analyses to observe the influence of eIFs on patients' survival. Protein and mRNA expressions of eIF3B, eIF3I, eIF4A1, eIF4H, eIF5 and eIF6 were significantly increased in high grade gliomas compared to CCBT and partially in low grade gliomas. However, short OS was only associated with high eIF3I gene expression in low grade gliomas, but not in GBM. In GBM, high eIF4H gene expression significantly correlated with shorter patient survival. In conclusion, we identified eIF3I and eIF4H as the most promising targets for future therapy for glioma patients.
The prognosis for children with central nervous system primitive neuroectodermal tumor (CNS-PNET) or pinealoblastoma is still unsatisfactory. Here we report the results of patients between 4 and 21 ...years of age with nonmetastatic CNS-PNET or pinealoblastoma diagnosed from January 2001 to December 2005 and treated in the prospective GPOH-trial P-HIT 2000-AB4.
After surgery, children received hyperfractionated radiation therapy (36 Gy to the craniospinal axis, 68 Gy to the tumor region, and 72 Gy to any residual tumor, fractionated at 2 × 1 Gy per day 5 days per week) accompanied by weekly intravenous administration of vincristine and followed by 8 cycles of maintenance chemotherapy (lomustine, cisplatin, and vincristine).
Twenty-six patients (15 with CNS-PNET; 11 with pinealoblastoma) were included. Median age at diagnosis was 11.5 years old (range, 4.0-20.7 years). Gross total tumor resection was achieved in 6 and partial resection in 16 patients (indistinct, 4 patients). Median follow-up of the 15 surviving patients was 7.0 years (range, 5.2-10.0 years). The combined response rate to postoperative therapy was 17 of 20 (85%). Eleven of 26 patients (42%; 7 of 15 with CNS-PNET; 4 of 11 with pinealoblastoma) showed tumor progression or relapse at a median time of 1.3 years (range, 0.5-1.9 years). Five-year progression-free and overall survival rates (± standard error SE) were each 58% (± 10%) for the entire cohort: CNS-PNET was 53% (± 13); pinealoblastoma was 64% (± 15%; P=.524 and P=.627, respectively).
Postoperative hyperfractionated radiation therapy with local dose escalation followed by maintenance chemotherapy was feasible without major acute toxicity. Survival rates are comparable to those of a few other recent studies but superior to those of most other series, including the previous trial, HIT 1991.
Background
Management of pediatric post‐transplantation lymphoproliferative disorder (PTLD) after hematopoietic stem cell (HSCT) and solid organ transplantation (SOT) is challenging.
Aim
This study ...of 34 PTLD patients up to 19‐years old diagnosed in Austria from 2000 to 2018 aimed at assessing initial characteristics, therapy, response, and outcome as well as prognostic markers of this rare pediatric disease.
Methods and results
A retrospective data analysis was performed. Types of allografts were kidney (n = 12), liver (n = 7), heart (n = 5), hematopoietic stem cells (n = 4), lungs (n = 2), multi‐visceral (n = 2), small intestine (n = 1), and vessels (n = 1). Eighteen/34 were classified as monomorphic PTLD, with DLBCL accounting for 15 cases. Polymorphic disease occurred in nine, and non‐destructive lesions in six cases. One patient had a non‐classifiable PTLD. Thirteen/34 patients are surviving event‐free in first remission (non‐destructive, n = 4/6; polymorphic, n = 4/9; monomorphic, n = 6/18). Fourteen/34 patients lacked complete response to first‐line therapy, of whom seven died. Four/34 patients relapsed, of whom two died. In 3/34 patients, death occurred as a first event. The 5‐year overall and event‐free survival rates were 64% ± 9% and 35% ± 9% for the whole cohort. Among all parameters analyzed, only malignant disease as the indication for transplantation had a significantly poor influence on survival.
Conclusions
This study shows PTLD still to be a major cause of mortality following SOT or HSCT in children. A continued understanding of the molecular biology of the disease shall allow to decrease treatment intensity for lower risk patients and to identify patients who may benefit from newer therapy approaches to improve outcome and decrease morbidity.
Background
Treatment stratification and response assessment in pediatric sarcomas has relied on imaging studies and surgical/histopathological evidence of vital tumor cells. Such studies and evidence ...collection processes often involve radiation and/or general anesthesia in children. Cell-free circulating tumor DNA (ctDNA) detection in blood plasma is one available method of so-called liquid biopsies that has been shown to correlate qualitatively and quantitatively with the existence of vital tumor cells in the body. Our clinical observational study focused on the utility and feasibility of ctDNA detection in pediatric Ewing sarcoma (EWS) as a marker of minimal residual disease (MRD).
Patients and methods
We performed whole genome sequencing (WGS) to identify the exact breakpoints in tumors known to carry the
EWS-FLI1
fusion gene. Patient-specific fusion breakpoints were tracked in peripheral blood plasma using digital droplet PCR (ddPCR) before, during, and after therapy in six children and young adults with EWS. Presence and levels of fusion breakpoints were correlated with clinical disease courses.
Results
We show that the detection of ctDNA in the peripheral blood of EWS patients (i) is feasible in the clinical routine and (ii) allows for the longitudinal real-time monitoring of MRD activity in children and young adults. Although changing ctDNA levels correlated well with clinical outcome within patients, between patients, a high variability was observed (inter-individually).
Conclusion
ctDNA detection by ddPCR is a highly sensitive, specific, feasible, and highly accurate method that can be applied in EWS for follow-up assessments as an additional surrogate parameter for clinical MRD monitoring and, potentially, also for treatment stratification in the near future.
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