Critical incidents, nocturnal supervision, and caregiver knowledge on SUDEP in patients with Dravet syndrome: A prospective multicenter study in Germany.

OBJECTIVE: The aim was to investigate the monitoring, interventions, and occurrence of critical, potentially life-threatening incidents in patients with Dravet syndrome (DS) and caregivers' knowledge about sudden unexpected death in epilepsy (SUDEP). METHODS: This multicenter, cross-sectional study of patients with DS and their caregivers in Germany consisted of a questionnaire and prospective diary querying the disease characteristics and demographic data of patients and caregivers. RESULTS: Our analysis included 108 questionnaires and 82 diaries. Patients with DS were 49.1% male (n = 53), with a mean age of 13.5 (SD ± 10.0 years) and primary caregivers were 92.6% (n = 100) female, with a mean age of 44.7 (SD ± 10.6 years). Monitoring devices were used regularly by 75.9% (n = 82) of caregivers, and most monitored daily/nightly. Frequently used devices were pulse oximeters (64.6%), baby monitors (64.6%), thermometers (24.1%), and Epi-Care (26.8%). Younger caregiver and patient age and history of status epilepticus were associated with increased use of monitoring, and 81% of monitor users reported having avoided a critical incident with nocturnal monitoring. The need for resuscitation due to cardiac or respiratory arrest was reported by 22 caregivers (20.4%), and most cases (72.7%) were associated with a seizure. Caregivers reported frequently performing interventions at night, including oropharyngeal suction, oxygenation, personal hygiene, and change of body position. Most caregivers were well informed about SUDEP (n = 102; 94%) and monitored for a lateral or supine body position; however, only 39.8% reported receiving resuscitation training, whereas 52.8% (n = 57) knew what to do in case the child's breathing or heart activity failed. SIGNIFICANCE: Critical incidents and the need for resuscitation are reported frequently by caregivers and may be related to high mortality and SUDEP rates in DS. Resuscitation training is welcomed by caregivers and should be continuously provided. Oxygen monitoring devices are frequently used and considered useful by caregivers.

Prognostic Factors in High-Grade Osteosarcoma of theExtremities or Trunk: An Analysis of 1,702 Patients Treatedon Neoadjuvant Cooperative Osteosarcoma Study GroupProtocols.

PURPOSE: To define prognostic factors for response and long-term outcome for a wide spectrum of osteosarcomas, extending well beyond those of the typical young patient with seemingly localized extremity disease. PATIENTS AND METHODS: A total of 1,702 consecutive newly diagnosed patients with high-grade osteosarcoma of the trunk or limbs registered into the neoadjuvant studies of the Cooperative Osteosarcoma Study Group before July 1998 were entered into an analysis of demographic, tumor-related, and treatment-related variables, response, and survival. The intended therapeutic strategy included preoperative and postoperative chemotherapy with multiple agents as well as surgery of all operable lesions. RESULTS: Axial tumor site, male sex, and a long history of symptoms were associated with poor response to chemotherapy in univariate and multivariate analysis. Actuarial 10-year overall and event-free survival rates were 59.8% and 48.9%. Among the variables assessable at diagnosis, patient age (actuarial 10-year survival ≥ 40, 41.6%; < 40, 60.2%; P = .012), tumor site (axial, 29.2%; limb, 61.7%; P < .0001), and primary metastases (yes, 26.7%; no, 64.4%; P < .0001), and for extremity osteosarcomas, also size (≥ one third, 52.5%; < one third, 66.7%; P < .0001) and location within the limb (proximal, 49.3%; other, 63.9%; P < .0001), had significant influence on outcome. Two additional important prognostic factors were treatment related: response to chemotherapy (poor, 47.2%; good, 73.4%; P < .0001) and the extent of surgery (incomplete, 14.6%; macroscopically complete, 64.8%; P < .0001). All factors except age maintained their significance in multivariate testing, with surgical remission and histologic response emerging as the key prognostic factors. CONCLUSION: Tumor site and size, primary metastases, response to chemotherapy, and surgical remission are of independent prognostic value in osteosarcoma.

Sleep quality, anxiety, symptoms of depression, and caregiver burden among those caring for patients with Dravet syndrome: a prospective multicenter study in Germany.

BACKGROUND: This study measured sleep quality among caregivers of patients with Dravet syndrome (DS) and assessed the impacts of mental health problems and caregiver burden on sleep quality. METHODS: This multicenter, cross-sectional study of patients with DS and their caregivers throughout Germany consisted of a questionnaire and a prospective 4-week diary querying disease characteristics, demographic data, living conditions, nocturnal supervision, and caregivers' work situations. Sleep quality was assessed using the Pittsburgh Sleeping Quality Index (PSQI). The Hospital Anxiety and Depression Scale (HADS) and the Burden Scale for Family Caregivers (BSFC) were used to measure anxiety, symptoms of depression, and caregiver burden. RESULTS: Our analysis included 108 questionnaires and 82 four-week diaries. Patients with DS were 49.1% male (n = 53), with a mean age of 13.5 ± 10.0 years. Caregivers were 92.6% (n = 100) female, with a mean age of 44.7 ± 10.6 years. The overall mean PSQI score was 8.7 ± 3.5, with 76.9% of participants (n = 83) scoring 6 or higher, indicating abnormal sleep quality. The HADS for anxiety and depression had overall mean scores of 9.3 ± 4.3 and 7.9 ± 3.7, respectively; 61.8% and 50.9% of participants scored above the cutoff value of 8 for anxiety and depression, respectively. Statistical analyses revealed caregiver anxiety levels and patients' sleep disturbances as major factors influencing PSQI scores. The overall mean BSFC score of 41.7 ± 11.7 indicates a moderate burden, with 45.3% of caregivers scoring 42 or higher. CONCLUSIONS: Sleep quality is severely affected among caregivers of patients with DS, correlating with anxiety, comorbidities, and patients' sleep disturbances. A holistic therapeutic approach should be implemented for patients with DS and their caregivers, focusing on the sleep quality and mental health of caregivers. TRIAL REGISTRATION: German Clinical Trials Register (DRKS), DRKS00016967. Registered 27 May 2019, http://www.drks.de/DRKS00016967.

A European pilot study in Dravet Syndrome to delineate what really matters for the patients and families.

We aimed to identify caregivers' opinions on the outcome measures that matter in clinical trials in individuals with Dravet syndrome (DS). We conducted a prospective European multicenter study based on an 11 closed questions survey developed by the French reference center for rare epilepsies and DS patients' advocacy groups. Items included questions on seizures and daily life outcomes that a clinical trial on a therapy for individuals with DS should target. Statistical analyses were performed to evaluate the impact of the country of residence and of the patients' age. The survey was answered by 153 caregivers (68%: France, 28%: Germany, and 24%: Italy) off individuals with DS. Individuals with DS included 86 males (mean age of 11.4 [interquartile: 7-20.4] years). Families ranked as important almost all the items proposed. However, items related to daily life had the highest rank in all three countries compared to items about seizures (P = 0.02). Increase in individuals' age was associated with a higher age at diagnosis (ρ = 0.26, P = 0.02), and a lower impact of seizure duration (ρ = -0.25, P = 0.005) and on the need of hospital referral (ρ = -0.26, P = 0.005). These data can help tailor patient-centered outcome measures in future clinical and real-life trials for DS.

Validation of a predictive model for identifying an increased risk for thromboembolism in children with acute lymphoblastic leukemia: results of a multicenter cohort study.

Among risk factors for developing thromboembolism (VTE) in children with acute lymphoblastic leukemia were Escherichia coli asparaginase, concomitant steroid use, presence of central venous lines, and thrombophilic abnormalities. Developing a predictive model for determining children at increased risk would be beneficial in targeting interventional studies to high-risk groups (HRGs). Predictive variables were incorporated into a risk assessment model, which was evaluated in 456 children and then validated in 339 patients. VTE risk by score was no greater than 2.5 for low-risk group (LRG) and greater than 2.5 for HRG. VTE rates at 3.5 months (validation cohorts) were 2.5% in LRG and 64.7% in HRG. In multivariate analysis adjusted for age, duration of asparaginase administration, enoxaparin prophylaxis, and T-immunophenotype, the HRG was significantly associated with VTE compared with the LRG (hazard/95% confidence interval [CI], 8.22/1.85-36.53). Model specificity was 96.2% and sensitivity was 63.2%. As secondary objective we investigated the use of enoxaparin for VTE prophylaxis in the HRG. HRG patients without enoxaparin prophylaxis showed a significantly reduced thrombosis-free survival compared with children on low-molecular-weight heparin (LMWH). On the basis of the high specificity, the model may identify children with leukemia at risk of VTE. LMWH may help prevent VTE in the HRG; this warrants assessment in larger cooperative clinical trials.

Periosteal osteosarcoma--a European review of outcome.

Periosteal osteosarcoma is a rare primary malignant bone tumour. Treatment is by surgical excision, but controversy remains about the value of chemotherapy. The members of the European Musculo Skeletal Oncology Society (EMSOS) collaborated to produce a dataset of 119 patients. The predominant site for the tumour was the femur, followed by the tibia. All but 2 patients underwent surgery, with 9 requiring amputation and the others having limb salvage. A total of 81 patients had chemotherapy, of whom 50 had neoadjuvant chemotherapy. There was no standard chemotherapy regime, but all patients receiving chemotherapy were given doxorubicin combined with at least one other agent. The overall survival was 89% at 5 years and 83% at 10 years. Eight patients developed local recurrence, of whom 5 died. Survival was related to appearance of local recurrence (P < 0.0001) but no other single factor. The use of chemotherapy was not shown to be a prognostic factor, but was used in two-thirds of the patients in this study.

Delaying surgery with chemotherapy for osteosarcoma of the extremities.

Osteosarcoma is the most frequent primary cancer of bone. When treated by surgery alone, it is almost invariably followed by metastatic dissemination and death. This dismal prognosis can be improved dramatically by including chemotherapy in an interdisciplinary regimen. Today, two-thirds of patients with localised extremity primaries can achieve long-term survival with such intensive multimodal therapy. This article provides a summary overview of current pharmacotherapy in osteosarcoma of the extremities, focussing on the approach of preoperative 'neoadjuvant' chemotherapy and thus, the potential benefits and pitfalls of delaying surgery. Prospective, multi-institutional trials are essential in guaranteeing that as many patients as possible can benefit from modern, efficacious interdisciplinary therapeutic regimens and that further progress can be made.

Primary metastatic osteosarcoma: presentation and outcome of patients treated on neoadjuvant Cooperative Osteosarcoma Study Group protocols.

PURPOSE: To determine demographic data and define prognostic factors for long-term outcome in patients presenting with high-grade osteosarcoma of bone with clinically detectable metastases at initial presentation. PATIENTS AND METHODS: Of 1,765 patients with newly diagnosed, previously untreated high-grade osteosarcomas of bone registered in the neoadjuvant Cooperative Osteosarcoma Study Group studies before 1999, 202 patients (11.4%) had proven metastases at diagnosis and therefore were enrolled onto an analysis of demographic-, tumor-, and treatment-related variables, response, and survival. The intended therapeutic strategy included pre- and postoperative multiagent chemotherapy as well as aggressive surgery of all resectable lesions. RESULTS: With a median follow-up of 1.9 years (5.5 years for survivors), 60 patients were alive, 37 of whom were in continuously complete surgical remission. Actuarial overall survival rates at 5 and 10 (same value for 15) years were 29% (SE = 3%) and 24% (SE = 4%), respectively. In univariate analysis, survival was significantly correlated with patient age, site of the primary tumor, number and location of metastases, number of involved organ systems, histologic response of the primary tumor to preoperative chemotherapy, and completeness and time point of surgical resection of all tumor sites. However, after multivariate Cox regression analysis, only multiple metastases at diagnosis (relative hazard rate [RHR] = 2.3) and macroscopically incomplete surgical resection (RHR = 2.4) remained significantly associated with inferior outcomes. CONCLUSION: The number of metastases at diagnosis and the completeness of surgical resection of all clinically detected tumor sites are of independent prognostic value in patients with proven primary metastatic osteosarcoma.

Osteosarcoma of the pelvis: experience of the Cooperative Osteosarcoma Study Group.

PURPOSE: To define patients and tumor characteristics as well as therapy results, patients with pelvic osteosarcoma who were registered in the Cooperative Osteosarcoma Study Group (COSS) were analyzed. PATIENTS AND METHODS: Sixty-seven patients with a high-grade pelvic osteosarcoma were eligible for this analysis. Fifteen patients had primary metastases. All patients received chemotherapy according to COSS protocols. Thirty-eight patients underwent limb-sparing surgery, 12 patients underwent hemipelvectomy, and 17 patients did not undergo definitive surgery. Eleven patients received irradiation to the primary tumor site: four postoperatively and seven as the only form of local therapy. RESULTS: Local failure occurred in 47 of all 67 patients (70%) and in 31 of 50 patients (62%) who underwent definitive surgery. Five-year overall survival (OS) and progression-free survival rates were 27% and 19%, respectively. Large tumor size (P =.0137), primary metastases (P =.0001), and no or intralesional surgery (P <.0001) were poor prognostic factors. In 30 patients with no or intralesional surgery, 11 patients with radiotherapy had better OS than 19 patients without radiotherapy (P =.0033). Among the variables, primary metastasis, large tumor, no or intralesional surgery, no radiotherapy, existence of primary metastasis (relative risk [RR] = 3.456; P =.0009), surgical margin (intralesional or no surgical excision; RR = 5.619; P <.0001), and no radiotherapy (RR = 4.196; P =.0059) were independent poor prognostic factors. CONCLUSION: An operative approach with wide or marginal margins improves local control and OS. If the surgical margin is intralesional or excision is impossible, additional radiotherapy has a positive influence on prognosis.

Genetic imbalances revealed by comparative genomic hybridization in osteosarcomas.

Osteosarcomas are the most frequent bone sarcomas. The molecular chromosomal aberrations in osteosarcomas were analyzed by comparative genomic hybridization (CGH). We studied 47 frozen tumors (41 primary samples, 6 relapses) in osteosarcoma patients registered in the Cooperative Osteosarcoma Study (COSS) protocol. Genomic imbalances were detected in 40 of 41 primary tumors and 6 of 6 relapsed tumors. Gains were more frequent than losses (ratio of 1.3:1). The median number of changes was 16 and 12 in primary and relapsed osteosarcomas, respectively. The median number of aberrations in primary high-grade osteosarcomas (17.0) was significantly higher than in low- or intermediate-grade osteosarcoma subtypes (3.0) (p = 0.038). The most frequent gains included 8q, 1p21-p31 and 1q21-q24, and the most frequent losses were 10q, 5q and 13q. High-level gains were observed on 8q23-q24, 17p13 and 1q21-q24. A gain of 19p (p < 0.001) or loss of 9p (p = 0.027) was more frequent in poor responders than in good responders. Univariate analysis revealed that patients with primary metastases (p = 0.002), poor histologic responses (p = 0.005), high-level gains of 19p (p = 0.012) or losses of 13q14 (p = 0.042) had significantly lower event-free survival (EFS), whereas patients with a loss of 5q (p = 0.007) or a loss of 10q21-22 (p = 0.017) had significantly higher EFS than patients without these aberrations. Multivariate analysis demonstrated that primary metastasis, loss of 13q14 and loss of 5q were independent prognostic factors. The findings of our study seem to be useful for evaluating the prognosis of patients and may finally lead to treatment strategies based on genetic background of osteosarcoma.

Prognostic significance of (18)F-FDG and (99m)Tc-methylene diphosphonate uptake in primary osteosarcoma.

UNLABELLED: The purpose of this retrospective analysis was to evaluate the prognostic significance of both initial glucose metabolism as measured by (18)F-FDG PET and osteoblastic activity as measured by (99m)Tc-methylene diphosphonate (MDP) bone scintigraphy in osteosarcoma. METHODS: In 29 patients (18 male, 11 female; age range, 5-41 y) with primary osteosarcoma, (18)F-FDG uptake and (99m)Tc-MDP uptake were measured semiquantitatively (average and maximum tumor-to-nontumor ratios [T/NT(av) and T/NT(max), respectively]) using PET and bone scintigraphy at the time of diagnosis. After chemotherapy, the patients underwent surgery for their primary tumor, and the response was determined histologically. Cumulative overall survival and event-free survival were determined by clinical and imaging follow-up of 7-72 mo (median, 28 mo). RESULTS: Clinical and imaging follow-up revealed that the disease relapsed or failed to achieve complete remission in 9 patients and that 6 patients died of the disease. Both overall and event-free survival were significantly better in patients with a low (18)F-FDG T/NT(max) (less than the median) than in patients with a high (18)F-FDG T/NT(max) (at least the median). The negative relationship of (18)F-FDG T/NT(av), (99m)Tc-MDP T/NT(max), and (99m)Tc-MDP T/NT(av) with overall and event-free survival did not reach a level of significance. (18)F-FDG uptake values correlated moderately and positively with (99m)Tc-MDP uptake values, but a level of significance was reached only between (18)F-FDG T/NT(max) and (99m)Tc-MDP T/NT(av). CONCLUSION: The initial glucose metabolism of primary osteosarcoma as measured by (18)F-FDG PET using T/NT(max) provides prognostic information. High (18)F-FDG uptake correlates with poor outcome. Thus, (18)F-FDG uptake may be complementary to other well-known factors in judging the prognosis in osteosarcoma.

Osteosarcoma of the spine: experience of the Cooperative Osteosarcoma Study Group.

BACKGROUND: Due to the low incidence rate, the optimal strategy for the treatment of patients with spinal osteosarcoma is unknown. METHODS: Twenty-two patients with osteosarcoma of the spine (15 with tumors of the sacrum and 7 with tumors at other sites) who received chemotherapy according to the Cooperative Osteosarcoma Study Group protocol were analyzed. Six patients presented with metastasis, and 16 patients had no evidence of metastasis at the time of entry into the protocol. Of 12 patients who underwent excision of their tumors, 2 patients underwent wide excision, 3 patients underwent marginal excision, and 7 patients underwent intralesional excision. Eight patients received irradiation: Six patients received conventional radiotherapy only, one patient received neutron beam therapy, and one patient received samarium-153-ethylene diamine tetramethylene phosphonate therapy. Follow-up ranged between 24 months and 105 months (median, 47 months). RESULTS: The median survival was 23 months, and three patients have survived without disease for > 6 years. Patients with primary metastases (P = 0.004), large tumors (P = 0.010), and sacral tumors (P = 0.048) had lower overall survival compared with patients who had no metastasis, small tumors, and nonsacral tumors, respectively. There was a significant difference in overall survival between 5 patients who underwent either wide or marginal surgery and 17 patients who underwent either intralesional surgery or no surgery (P = 0.033). Among 17 patients who underwent no surgery or intralesional surgery, overall survival tended to be better in 7 patients who received irradiation compared with the overall survival in 10 patients who did not receive irradiation (P = 0.059). CONCLUSIONS: Patients with metastases, a large tumors, and sacral tumors had a poor prognosis in the current study with small numbers of patients. Wide or marginal excision of the tumor improved survival. Patients with osteosarcoma of the spine should be treated with a combination of chemotherapy and at least marginal excision for those with surgically accessible tumors. Postoperative radiotherapy may be beneficial.

Prognostic factors in high-grade osteosarcoma of the extremities or trunk: an analysis of 1,702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols.

PURPOSE: To define prognostic factors for response and long-term outcome for a wide spectrum of osteosarcomas, extending well beyond those of the typical young patient with seemingly localized extremity disease. PATIENTS AND METHODS: A total of 1,702 consecutive newly diagnosed patients with high-grade osteosarcoma of the trunk or limbs registered into the neoadjuvant studies of the Cooperative Osteosarcoma Study Group before July 1998 were entered into an analysis of demographic, tumor-related, and treatment-related variables, response, and survival. The intended therapeutic strategy included preoperative and postoperative chemotherapy with multiple agents as well as surgery of all operable lesions. RESULTS: Axial tumor site, male sex, and a long history of symptoms were associated with poor response to chemotherapy in univariate and multivariate analysis. Actuarial 10-year overall and event-free survival rates were 59.8% and 48.9%. Among the variables assessable at diagnosis, patient age (actuarial 10-year survival > or = 40, 41.6%; < 40, 60.2%; P =.012), tumor site (axial, 29.2%; limb, 61.7%; P <.0001), and primary metastases (yes, 26.7%; no, 64.4%; P <.0001), and for extremity osteosarcomas, also size (> or = one third, 52.5%; < one third, 66.7%; P <.0001) and location within the limb (proximal, 49.3%; other, 63.9%; P <.0001), had significant influence on outcome. Two additional important prognostic factors were treatment related: response to chemotherapy (poor, 47.2%; good, 73.4%; P <.0001) and the extent of surgery (incomplete, 14.6%; macroscopically complete, 64.8%; P <.0001). All factors except age maintained their significance in multivariate testing, with surgical remission and histologic response emerging as the key prognostic factors. CONCLUSION: Tumor site and size, primary metastases, response to chemotherapy, and surgical remission are of independent prognostic value in osteosarcoma.

Peak plasma concentrations of doxorubicin in children with acute lymphoblastic leukemia or non-Hodgkin lymphoma.

PURPOSE: The peak plasma concentrations seem to play an important role in the toxicity of the anthracyclines. As there are only limited data in the literature about the distribution of doxorubicin in children, we assessed the peak plasma concentrations of doxorubicin in pediatric patients. PATIENTS AND METHODS: We collected 87 plasma samples at the end of infusion from 27 children with acute lymphoblastic leukemia (ALL) or non-Hodgkin lymphoma (NHL) treated with 30 mg/m(2) doxorubicin as a 1- or 2-h infusion once weekly for four weeks in the ALL-BFM 95 or NHL-BFM 95 protocol. Plasma concentrations of doxorubicin were quantified by capillary electrophoresis, and the peak plasma levels for a uniform 2-h infusion were calculated. RESULTS: The geometric mean of all samples was 273 microg/l with a geometric coefficient of variation of 46.0%. This is in accordance with the peak plasma concentrations expected from simulations based on literature data from adults. High inter-individual as well as substantial intra-individual variability was observed. Girls had slightly higher peak plasma levels than boys. Age, weight, and body mass index as well as laboratory parameters had no influence on the peak plasma concentrations. No cumulation of doxorubicin during therapy was observed. CONCLUSION: The peak plasma concentrations are similar in adults and children for both the absolute values as well as the variability; this indicates that there are no major differences in the distribution of doxorubicin in children and adults.