Out-of-Hospital Emergencies in Children Under Palliative Home Care.

Introduction: Specialized palliative home care (SPHC) enables children and adolescents with life-limiting illnesses and complex needs to receive care at home. In addition to controlling symptoms and stabilizing the psychosocial situation, crisis anticipation is a component of SPHC. Since the establishment of the reporting SPHC team, parents have called for additional help from emergency medical services (EMS) in emergency situations with unexpected frequency. Children with life limiting diseases could undergo invasive procedures and unhelpful treatments with uncertain consequences. The questions arose as to which factors led to the involvement of the EMS in a palliative situation, what therapy was performed and what outcome could be reached. Methods: Records of the pediatric SPHC patients and EMS call-outs in these children of the reporting SPHC-team in the central region of Hesse, Germany (population: 1.1 million) were retrospectively analyzed from 01.11.2014 to 01.05.2021. The causes of the call-outs, the existence of an emergency agreement, the National Advisory Committee for Aeronautics (NACA) score, EMS therapy and outcome were examined. Patient data included age, palliative-justifying diagnosis, duration and intensity of care, place of death and median overall survival (MOS) and palliative SHPC treatment. Results: In total, 172 patients were analyzed during the study period. There were 27 EMS calls for a total of 20 patients/families (= EMS group). Palliative illness or a complication was the most frequent cause of call-outs. The patients in the EMS group were significantly less likely to have a DNR order, required more home visits and telephone calls and were under SPHC care for longer. There was a significantly higher proportion of crisis interventions at home visits. The children in the EMS group died less often from the underlying disease. Of the remaining 152 patients (= non-EMS group), a significantly higher proportion had a European home country. Conclusions: Despite the introduction of the SPHC, parents still call the EMS. Good cooperation and joint training should be sought to prepare all those involved for future call-outs.

Pediatric neuro-oncology in small centers--quality control of network support: the HIT-GBM experience.

BACKGROUND: The quality of care for children with brain tumors might be higher in large medical centers; however, it may be possible to improve the quality of care received in smaller centers if they join an effective network. AIM: This study used the HIT-GBM® database to compare the quality of care provided to pediatric high-grade glioma and diffuse intrinsic pontine glioma patients among various medical centers of differing sizes. PATIENTS AND METHODS: Overall survival was used as a defining parameter. Indirect measures were the time intervals between the first clinical signs of cancer, initial diagnostic imaging, surgery, or chemotherapy and radiation. RESULTS: From 1995 to 2003, 310 children (137 girls and 173 boys, aged 3 to 18 years old) were registered from 72 medical centers in Europe. Center sizes differed from 1 to 17 registered patients. Center size did not affect survival, nor any of the time intervals studied. CONCLUSION: There was no evidence that the quality of care differed between smaller and larger centers.

Chromatin remodelling at the topoisomerase II-beta promoter is associated with enhanced sensitivity to etoposide in human neuroblastoma cell lines.

Etoposide, an inhibitor of topoisomerase II, promotes DNA damage and apoptosis of cancer cells and is a component of standard therapy for neuroblastoma. Resistance to etoposide has been observed in neural tumour cells expressing lower levels of topoisomerase II. In the present study, we have examined the contribution of epigenetic modulation of gene expression in the potentiation of etoposide-mediated cytotoxicity in neuroblastoma cells. Specifically, we studied the effects of histone deacetylase inhibition with valproic acid on topoisomerase II gene expression and apoptosis in response to etoposide. Using human neuroblastoma cell lines SK-N-AS and SK-N-SH, we show that although the combination of valproic acid and etoposide promoted a reduction in growth compared to either drug alone in both cells, the effect was substantially enhanced in SK-N-AS compared to SK-N-SH cells. An increase in histone H3 acetylation and p21 expression was observed in both cell lines, however, upregulation of topoisomerase II-beta gene expression and an increase in PARP cleavage was observed in SK-N-AS cells only. Furthermore, chromatin immunoprecipitation assays revealed an increase in acetylation of histone H3 at the cognate topoisomerase II-beta gene after treatment with valproic acid in SK-N-AS cells. These results suggest a potential epigenetic mechanism of regulation of the topoisomerase II-beta gene and a possible role for its increased expression in the sensitivity of SK-N-AS neuroblastoma cells to etoposide.

Measuring performance status in pediatric patients with brain tumors--experience of the HIT-GBM-C protocol.

BACKGROUND: Measuring the quality of life or performance status in pediatric neurooncology has proven a challenge. Here, we report in a treatment protocol for pediatric patients with high-grade glioma and diffuse intrinsic pontine glioma. PROCEDURE: The Fertigkeitenskala Münster-Heidelberg (FMH) is a 56-item quantitative measure of health status. The number of yes answers is transformed to age-dependent percentiles. Physicians were also asked the patients' health status by their own judgment on a 1-5 scale: normal, mild handicap, age-normal activity severely reduced but patient not in bed, in bed, and in ICU. RESULTS: Assessments were available from 50 of 97 eligible patients. For 22 patients both questionnaire and the physicians score obtained. At the beginning of the treatment, only 5 patients scored over 40 FMH%, and 4 of these survived. Of 16 patients who initially scored less than 40 FMH%, 15 died. During later assessments, most FMH measures became gradually worse. FMH scores improved in three patients. The physician's judgment was documented at diagnosis and during treatment (n = 50). Per physician, 22% of the patients were normal before chemotherapy, decreasing to 16% in the middle of the protocol. At diagnosis only 16% of patients had severely reduced activity, which increased to 30.6% in the middle of the protocol. The FMH% correlated well with the physicians' judgments (P < 0.005). CONCLUSION: The FMH scale is easily obtained and provides a valid assessment of health status. Patients with poor performance at diagnosis had a poorer prognosis.

Vincristine in high-grade glioma.

AIM: Numerous chemotherapeutics are used in the treatment of high-grade glioma (HGG). The purpose of this study was to evaluate the therapeutic value of vincristine (VCR) in the treatment of HGGs. MATERIALS AND METHODS: A meta-analysis of HGG studies was performed to evaluate and compare the efficacy of chemotherapy drugs using observed and predicted median overall survival and survival gain as previously described. RESULTS: Patient cohorts treated with VCR-containing-regimens had a significant survival gain advantage over cohorts treated with other chemotherapy drugs (p<0.0001). VCR was most effective in treating newly diagnosed adult (p<0.0001) and elderly (p=0.0001) patients. When VCR was combined with nimustine, carmustine, cytarabine or etoposide, the effect was antagonistic, but when VCR was combined with lomustine, procarbazine, cyclophosphamide, dacarbazine, hydroxyurea, or cisplatin it was synergistic. CONCLUSION: Results from this study suggest that VCR should be included in chemotherapy regimens for patients being treated for newly diagnosed or recurrent HGG.

99mTc-sestamibi scan differentiates tumor from other contrast enhancing tissue in choroid plexus tumors.

Choroid plexus tumors are rare brain tumors which account for 0.4% to 0.6% among brain tumors. Tumor resection is known to be of large prognostic impact, and re-resection of residual tumors is a part of standard care. However, after multiple resections it can become difficult to differentiate tumor from reactive tissue. 99mTC-sestamibi scans may assist in differentiating neoplastic (99mTC-sestamibi positive) from non-neoplastic tissue (99mTC-sestamibi negative). Previous literature showed sestamibi to be helpful in detecting residual choroid plexus tumors resulting in further resection. Here, we report the first case to show that sestamibi scans can also help with the opposite decision.

Intensive chemotherapy improves survival in pediatric high-grade glioma after gross total resection: results of the HIT-GBM-C protocol.

BACKGROUND: The authors hypothesized that intensified chemotherapy in protocol HIT-GBM-C would increase survival of pediatric patients with high-grade glioma (HGG) and diffuse intrinsic pontine glioma (DIPG). METHODS: Pediatric patients with newly diagnosed HGG and DIPG were treated with standard fractionated radiation and simultaneous chemotherapy (cisplatin 20 mg/m2 x 5 days, etoposide 100 mg/m2 x 3 days, and vincristine, and 1 cycle of cisplatin + etoposide + ifosfamide 1.5 g/m x 5 days [PEI] during the last week of radiation). Subsequent maintenance chemotherapy included further cycles of PEI in Weeks 10, 14, 18, 22, 26, and 30, followed by oral valproic acid. RESULTS: Ninety-seven (pons, 37; nonpons, 60) patients (median age, 10 years; grade IV histology, 35) were treated. Resection was complete in 21 patients, partial in 29, biopsy only in 26, and not performed in 21. Overall survival rates were 91% (standard error of the mean [SE] +/- 3%), 56%, and 19% at 6, 12, and 60 months after diagnosis, respectively. When compared with previous protocols, there was no significant benefit for patients with residual tumor, but the 5-year overall survival rate for patients with complete resection treated on HIT-GBM-C was 63% +/- 12% SE, compared with 17% +/- 10% SE for the historical control group (P = .003, log-rank test). CONCLUSIONS: HIT-GBM-C chemotherapy after complete tumor resection was superior to previous protocols.

Clinical and epidemiological characteristics of pediatric gliosarcomas.

Gliosarcoma (GS) is a glioblastoma with a sarcomatous component that is presumed to be a metaplastic differentiation of glioma cells. We studied the clinical relevance of this histological glioblastoma subentity within the pediatric population. We obtained patient data from the German HIT-GBM database, which contains clinical data for more than 600 pediatric patients with centrally reviewed high-grade gliomas. By applying defined inclusion criteria (diagnosis of GS proven by central neuropathological review; patient age 0 to 21 years), four patients were identified. In addition, after a review of the English medical scientific literature, 19 additional cases were found. The relative frequency of GS in the German HIT-GBM database was only 1.9%. In the whole series of 23 pediatric GS patients, including previously reported cases, the male-to-female-ratio was 1.2:1. GS was found in all pediatric age groups with a median age of 11 years, but there was an unexpectedly high accumulation in infants (6 of 23 <3 years of age, 26%). GS showed a strong predilection of the cerebral hemispheres (22 out of 23 cases). Increased intracranial pressure was the leading symptom of a short clinical history with a median duration of 0.7 month. Interestingly, six patients (26%) were reported with a history of cranial radiotherapy prior to GS diagnosis. In 60% of the GS patients in our series, gross total resection was achieved. Median overall (OS) and event-free survivals (EFS) of the total cohort were 12.1 and 9.8 months, respectively. In conclusion, GS is a very rare tumor entity in children. Literature review suggests a relatively higher incidence in infants and in patients with a previous history of radiotherapy.

Adjuvant dendritic cell-based tumour vaccination for children with malignant brain tumours.

BACKGROUND: A large experience with dendritic cell (DC)-based vaccination for malignant brain tumours has been gained in adults. Here we focus on the results obtained in children with relapsed malignant brain tumours. PROCEDURE: In total 45 children were vaccinated: 33 high grade glioma (HGG), 5 medulloblastoma (MB)/primitive neuro-ectodermal tumour (PNET), 4 ependymoma and 3 atypical teratoid-rhabdoid tumour (ATRT). Autologous, monocyte-derived DC were generated and loaded with tumour lysate, which was used as source of tumour-associated antigens. RESULTS: In 38 patients peripheral blood mononuclear cells (PBMC) were obtained from leukapheresis and in 7 patients from fresh blood samples. 7 HGG patients are still alive with median follow-up (FU) of 35.7 months (range: 12.1-85.6). Median overall survival (OS) was 13.5 months (range: 1.4-85.6). All patients with MB/PNET died (median OS 5.7 months; range 4.3-51.2). One patient with ependymoma is still alive at 22.3 months FU. The other three patients died at, respectively, 7.7, 30.1 and 31.5 months. Two patients with ATRT are still alive at, respectively, 34.1 and 52.6 months FU. The third patient died at 50.5 months. No severe adverse events were noticed. CONCLUSIONS: In this exploratory study, HGG and ATRT seem to respond more favourably to vaccination than MB/PNET and ependymoma. Although preliminary, our results are promising and support further testing of DC-based immunotherapy in new treatment protocols for HGG and ATRT.

MGMT as a potential stratification marker in relapsed high-grade glioma of children: the HIT-GBM experience.

BACKGROUND: Studies in adults with malignant glioma suggest MGMT methylation as a stratification marker. Similar data for children are sparse. We investigated the impact of MGMT methylation and expression on survival of children with high-grade glioma (HGG) registered into the German HIT-GBM database receiving temozolomide (TMZ) as part of their treatment (n = 21 relapsed, n = 4 primary). PROCEDURE: Twenty-four patients were included retrospectively. Methylation specific PCR (MSP), calibrated combined bisulfite restriction analysis (COBRA), and immunohistochemistry (IHC) were applied. Survival analyses were performed by Kaplan-Meier and Cox proportional-hazards models. RESULTS: MSP demonstrated DNA methylation in 77%. Patients with a methylated MGMT promoter had a sixfold longer median EFS (P = 0.015; 5.5 months vs. 0.9 months). Considering the results of calibrated COBRA, MGMT methylation was again associated with an elevated EFS (P = 0.05; 10.2 months vs. 2.6 months) and OS (P = 0.06; 18.7 months vs. 7.2 months) only if methylation was >14%. No difference in EFS and OS at all was noted between unmethylated and tumors methylated at low level (n = 9). Twenty-two tumors were positive by IHC, 10 showed low MGMT expression (IHC score 0-4). We did not detect any difference in EFS and OS between moderate/high-expressing tumors (IHC score 6-12) and those with low or no expression (IHC score 0-4). CONCLUSION: DNA methylation, but not protein expression of MGMT was associated with an increased median EFS and OS of children with relapsed HGG. MGMT methylation status warrants prospective evaluation as a stratification marker for children with HGG.

Platelet-derived growth factor receptor expression and activation in choroid plexus tumors.

Choroid plexus tumors are intraventricular neoplasms predominantly affecting young children. In contrast to choroid plexus papillomas, choroid plexus carcinomas progress frequently, necessitating the development of adjuvant treatment concepts. Platelet derived growth factor (PDGF) signaling has been shown to support growth in a variety of tumors. The finding of PDGF receptor expression in choroid plexus tumors prompted us to elucidate PDGF receptor activation state using a novel method, in situ proximity ligation assay, on formalin-fixed, paraffin-embedded, archival samples of 19 choroid plexus tumors. As assessed by in situ proximity ligation assay, the proportion of phosphorylated PDGF receptor alpha was low in choroid plexus papillomas and choroid plexus carcinomas, whereas phosphorylated PDGF receptor beta was found to be significantly higher in choroid plexus carcinomas. In the immortalized choroid plexus epithelial cell line Z310 expressing PDGF receptor beta, PDGF-BB exhibited a time- and dose-dependent proliferative response, which was significantly attenuated by imatinib (gleevec). In conclusion, our findings suggest that PDGF receptor beta is functionally involved in the biology of choroid plexus tumors and may represent a molecular target for therapy. In addition, this study demonstrates the feasibility and usefulness of in situ proximity ligation assay for monitoring receptor tyrosine kinase activation in formalin-fixed, paraffin-embedded, archival tissues.

Bilateral gonadoblastoma with dysgerminoma and pilocytic astrocytoma with WT1 GT-IVS9 mutation: A 46 XY phenotypic female with Frasier syndrome.

Frasier syndrome is characterized by a 46 XY disorder of sex development, nephropathy, and increased risk for gonadoblastoma due to Wilms tumor 1(WT1) mutation in the donor splice site of intron-9, resulting in the splice form +KTS. Germ cell tumors and gonadoblastomas have been reported previously in Frasier syndrome. We present the clinical, radiological, and genetic (WT1 mutation analysis) of a 46 XY phenotypic female with Frasier syndrome with bilateral gonadoblastoma with dysgerminoma who developed pilocytic astrocytoma.

Atypical choroid plexus papilloma: clinical experience in the CPT-SIOP-2000 study.

Atypical choroid plexus papilloma (APP) represents a novel intermediate-grade subtype of choroid plexus tumor (CPT), the clinical outcome of which has not been described yet. We present the first analysis of a group of APP patients enrolled in the ongoing CPT-SIOP-2000 study of CPTs. A worldwide registration and a randomized trial for those patients who require chemotherapy started in 2000. For APP, maximal surgical resection was recommended. After surgery, patients who had undergone complete resection were observed, whereas patients with incompletely resected or metastasized APP were treated with six chemotherapy courses (etoposide and vincristine, combined with either carboplatin or cyclophosphamide). Risk-adapted radiotherapy was given only to patients older than 3 years of age. Of the 106 patients with a centrally confirmed CPT histology, 30 had APP, 42 CPP and 34 CPC. APP patients were significantly younger (median = 0.7 years) than patients with CPP or CPC (both medians = 2.3 years). Complete resection was achieved in 68 (64%) patients (79% in CPP, 63% in APP, and 47% in CPC). Metastases were present at diagnosis in 17% of APP patients, 5% of CPP patients, and 21% of CPC patients. All nine APP patients who received postoperative chemotherapy showed an early response after two cycles: two had complete remission, four had partial response, and three had stable disease. In the observation group of 15 patients, one event was seen, and all patients were alive. In the treatment group, one patient with a metastasized tumor and incompletely resected APP died. While APP was defined histologically, median percentages of both the Ki-67/MIB-1 proliferation marker and the p53 tumor suppressor protein increased across the three histological subtypes (from CPP to APP and then CPC), suggesting that the subtypes comprise an ordinal categorization of increasingly severe CPT tumors. This ordering was reiterated by clinical outcome in the 92 patients treated per the study protocol, with 5-year EFS rates of 92% in 39 CPP patients, 83% in 24 APP patients, and 28% in 29 CPC patients. A similar ordering was seen when all 106 patients were evaluated for EFS. APP responded favorably to chemotherapy. The intermediate position of APP between CPP and CPC was supported by the clinical data.

Imaging and spectroscopic findings in meningioangiomatosis.

Meningioangiomatosis (MA) is an uncommon brain tumor. The role of imaging techniques is underscored in cases where the tumor location makes resection (or even biopsy) dangerous. We report the case of a child with an MA tumor located deep in the right sylvian fissure. A computed tomography (CT) scan showed calcifications in a highly vascular lesion with surrounding edema. Magnetic resonance spectroscopy (MRS) showed a distinct choline (Cho) peak, which usually suggests a proliferating tumor. Fluorodeoxyglucose positron emission tomography (FDG-PET) showed the lesion lacked hypermetabolic features. These radiological features should put MA in the differential diagnosis.

Histone acetylation resulting in resistance to methotrexate in choroid plexus cells.

Choroid plexus carcinomas are rare tumors that typically occur in young children. Prognosis is poor, and very little information is available to optimize treatment protocols. We used a cell culture model to evaluate whether combining chemotherapeutic agents such as methotrexate with histone deacetylase inhibitors (HDACI) such as valproic acid and MS-275 could improve efficacy. Valproic acid increased the cytotoxicity of radiation and of all the chemotherapeutic agents in Z310 and SV11 mouse choroid plexus cell lines, with the exception of methotrexate. Both HDACIs made choroid plexus cells resistant to this folate antagonist. Searching for a molecular explanation, we found that thymidylate synthase was up regulated when the cells were incubated with HDACI. We also confirmed this finding in human choroid plexus carcinoma cells. Methotrexate should not be combined with HDACI in the treatment of choroid plexus carcinoma.

Treatment of early childhood medulloblastoma by postoperative chemotherapy and deferred radiotherapy.

To investigate the utility of postoperative chemotherapy in delaying radiotherapy and to identify prognostic factors in early childhood medulloblastoma, we studied children younger than 3 years of age registered to the HIT-SKK'87 (Therapieprotokoll für Säuglinge und Kleinkinder mit Hirntumoren [Brain Tumor Radiotherapy for Infants and Toddlers with Medulloblastoma] 1987) trial who received systemic interval chemotherapy until craniospinal radiotherapy was applied at 3 years of age or at relapse, from 1987 to 1993. Children with postoperative residual tumor or metastatic disease received systemic induction chemotherapy prior to interval chemotherapy. Twenty-nine children were eligible for analyses (median age, 1.7 years; median follow-up, 12.6 years). In children without macroscopic metastases, rates (+/-SEM) for 10-year progression-free survival (PFS) and overall survival (OS) were 52.9% +/- 12.1% and 58.8% +/- 11.9% (complete resection), and 55.6% +/- 16.6% and 66.7% +/- 15.7% (incomplete resection), compared with 0% and 0% in children with macroscopic metastases. Survival was superior in nine children with desmoplastic or extensive nodular histology compared with 20 children with classic medulloblastoma (10-year PFS, 88.9% +/- 10.5% and 30.0% +/- 10.3%, p = 0.003; OS, 88.9% +/- 10.5% and 40.0% +/- 11.0%, p = 0.006). Eleven of 12 children with tumor progression during chemotherapy had classic medulloblastoma. After treatment, IQ scores were inferior compared with nonirradiated children from the subsequent study, HIT-SKK'92. Classic histology, metastatic disease, and male gender were independent adverse risk factors for PFS and OS in 72 children from HIT-SKK'87 and HIT-SKK'92 combined. In terms of survival, craniospinal radiotherapy was successfully delayed especially in young children with medulloblastoma of desmoplastic/extensive nodular histology, which was a strong independent favorable prognostic factor. Because of the neurocognitive deficits of survivors, the emerging concepts to avoid craniospinal radiotherapy should rely on the histological medulloblastoma subtype.

Aberrant MGMT (O6-methylguanine-DNA methyltransferase) promoter methylation in choroid plexus tumors.

Aberrant methylation of the MGMT (O6-methylguanine-DNA methyltransferase) DNA-repair gene is a predictive marker for the response to chemotherapy with alkylating agents (e.g., temozolomide) in malignant gliomas. Since temozolomide is considered for the treatment of choroid plexus tumors, MGMT promoter methylation status was retrospectively assessed in 36 choroid plexus tumors using methylation specific PCR, combined bisulfite restriction analysis (COBRA), and clone sequencing. By methylation specific PCR, all samples demonstrated a signal for MGMT methylation. COBRA confirmed >10% methylation of CpGs 17 and 31 in 58% of tumors. Clone sequencing of six cases methylated by COBRA confirmed aberrant methylation including a previously recognized enhancer element. In conclusion, MGMT promoter methylation is frequent in choroid plexus tumors and can be quantified using COBRA. Determination of MGMT promoter methylation status might be useful for the stratification of patients for alkylator-based treatments in future clinical trials.

Pediatric giant cell glioblastoma: New insights into a rare tumor entity.

Little is known about giant cell glioblastoma (GCG) in pediatric patients. The present study identified 18 pediatric patients with centrally reviewed GCG from the HIT-GBM database of the Gesellschaft für Paediatrische Onkologie und Haematologie in Germany, Austria, and Switzerland. Clinical and epidemiological data were compared with those of 178 pediatric patients with centrally reviewed glioblastoma multiforme (GBM) from the same database. In this unique series, median age, male preference, and median clinical history did not differ significantly between pediatric GCG and GBM patients. GCG showed a stronger predilection for cerebral hemispheres than did GBM, which may only partly explain the higher percentage of gross total tumor resections in GCG patients. Most surprising, the widely distributed hypothesis that GCG may imply a better prognosis than GBM could not be substantiated for our pediatric series. Future studies with larger patient numbers and molecular pathological analyses are still needed to corroborate the present findings and further elucidate the biology of GCG in children.