Nimotuzumab and radiotherapy for treatment of newly diagnosed diffuse intrinsic pontine glioma (DIPG): a phase III clinical study.

BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) is a devastating cancer of childhood and adolescence. METHODS: The study included patients between 3 and 20 years with clinically and radiologically confirmed DIPG. Primary endpoint was 6-month progression-free survival (PFS) following administration of nimotuzumab in combination with external beam radiotherapy (RT). Nimotuzumab was administered intravenously at 150 mg/m2 weekly for 12 weeks. Radiotherapy at total dose of 54 Gy was delivered between week 3 and week 9. Response was evaluated based on clinical features and MRI findings according to RECIST criteria at week 12. Thereafter, patients continued to receive nimotuzumab every alternate week until disease progression/unmanageable toxicity. Adverse events (AE) were evaluated according to Common Terminology Criteria for Adverse Events (CTC-AE) Version 3.0 (CTC-AE3). RESULTS: All 42 patients received at least one dose of nimotuzumab in outpatient settings. Two patients had partial response (4.8%), 27 had stable disease (64.3%), 10 had progressive disease (23.8%) and 3 patients (7.1%) could not be evaluated. The objective response rate (ORR) was 4.8%. Median PFS was 5.8 months and median overall survival (OS) was 9.4 months. Most common drug-related AEs were alopecia (14.3%), vomiting, headache and radiation skin injury (7.1% each). Therapy-related serious adverse events (SAEs) were intra-tumoral bleeding and acute respiratory failure, which were difficult to distinguish from effects of tumor progression. CONCLUSIONS: Concomitant treatment with RT and nimotuzumab was feasible in an outpatient setting. The PFS and OS were comparable to results achieved with RT and intensive chemotherapy in hospitalized setting.

Randomised Introduction of 2-CDA as Intensification during Consolidation for Children with High-risk AML--results from Study AML-BFM 2004.

BACKGROUND: The outcome in children and adolescents with high-risk (HR) acute myeloid leukemia (AML) is still unsatisfactory. Therefore, in study AML-BFM 2004 we aimed to improve outcome of HR-patients by adding moderately dosed 2-Chloro-2-Deoxyadenosine (2-CDA) to the respective consolidation treatment backbone without increasing toxicity. The aim was to improve prognosis especially in FAB M4/M5/MLL patients, who represent the largest subgroup of HR patients. PATIENTS AND METHODS: In total, 343 children and adolescents with HR-AML were randomized to receive or not 2-CDA (6 mg/m²/d, days 1, 3) in combination with cytarabine/idarubicine (AI=500 mg/m² cytarabine 5 days continuous infusion plus 7 mg/m²/d idarubicin, days 3 and 5). RESULTS: RESULTS for patients of the AI/2-CDA arm (n=168) vs. the AI-arm (n=175) were similar: 5-year overall survival 68±4 vs. 72±4%, plogrank=0.38, event-free survival 53±4 vs. 49±4%, plogrank=0.77; cumulative incidence of relapse at 5 years: 35±4 vs. 37±4%, p(Gray)=0.89. RESULTS in patients with MLL rearrangement or FAB M4/M5 were also similar in the treatment groups. In addition, toxicities did not differ between the two arms. CONCLUSION: We conclude that additional, moderate dose 2-CDA does not improve prognosis in HR-patients when given during consolidation treatment. Its effect might be too low in this multidrug regimen, where the strongest effects are achieved during induction, or the chosen dose of 2-CDA might have been too low.

Treatment of recurrent primitive neuroectodermal tumors (PNET) in children and adolescents with high-dose chemotherapy (HDC) and stem cell support: results of the HITREZ 97 multicentre trial.

Early studies with high-dose chemotherapy for treatment of relapsed cerebral PNET had shown modest efficacy but considerable toxicity. The HIT97 national trial tested a nonrandomized but stratified relapse protocol using either intensive chemotherapy, potentially high dose, or oral chemotherapy. 72 patients (59 disseminated) whose primary treatment had been surgery (97 %), radiotherapy (88 %), and/or chemotherapy (95 %) were enrolled in the intensive chemotherapy arm at diagnosis of relapse or resistance. As a window for this study they received two courses of a 96-hour infusion with carboplatin and etoposide. A response (complete or partial remission) was documented by MRI. Responders received two more cycles of this therapy and stem cell collection, before they received HDC (carboplatin, etoposide, thiotepa) and stem cell support. All possibilities of local therapy were to be explored and applied. After two courses of chemotherapy there was a 52 % response rate (41/72 patients). The median PFS and OS for all 72 patients were 11.6 and 21.1 months. Patients with medulloblastoma had a longer PFS and OS (12.6 and 22.6 months) than those with other PNETs (3.1 and 12.3 months). Favourable prognostic features were no new signs of clinical impairment and localised disease at relapse diagnosis. For the 27 patients who received HDC the median PFS and OS were 8.4 and 20.2 months, respectively. HDC did not benefit patients with resistant cerebral PNET and was associated with profound haematological and mucosal toxicity (90-100 % grade III, IV), infections (50 % grade III and IV) and severe ototoxicity (50 % grade III, 12.5 % grade IV). Treatment related mortality was 8 %. There was low long-term survival and only 2/72 patients are in continuous remission. Adding HDC in patients who responded to the initial courses of chemotherapy did not improve survival. Patients with relapsed cerebral PNET who respond to conventional chemotherapy do not profit from further augmentation to HDC.

Bloodstream infections in paediatric cancer patients. Prospective comparative study in 2 university hospitals.

BACKGROUND: Preventive approaches (including those related to care of long term central venous catheters, CVADs) and the incidence of bloodstream infections (BSI) in 2 German university affiliated paediatric oncology units. PATIENTS AND METHODS: Non-interventional prospective observational study using the Oncoped surveillance module. Center A included 85 patients in 31 months and Center B 84 patients in 21 months. The populations did not differ in terms of age, gender, malignancy and disease status (first illness vs. relapse). Center A used ports (46 %) and 2 different Broviac catheters (54 %), in Center B nearly all patients with a CVAD had Broviacs (96 %). 30 BSI (24 patients) were diagnosed in Centre A and 28 BSI (22 patients) in Center B. Patients with relapsed malignancy experienced more BSI (51.4 % vs. 20.9 %; p = 0.001). Incidence rates were significantly lower in Center A (3.47 vs. 7.93 BSI/1000 CVAD days; p = 0.037). Poisson regression analysis revealed a significant lower incidence density (BSI/100 inpatient days) for all BSI in Center A (RR 0.47 CI95 0.27-0.81, p = 0.006). Overall, 52 % of all pathogens detected in blood cultures in Center A were Gram-positive (57 % in Center B) and 48 % Gram-negative (43 in Center B). One ALL patient without a CVAD died due to overwhelming sepsis caused by an ESBL-producing E. cloacae isolate. CONCLUSION: Paediatric cancer treatment centers differ substantially in regard to management of CVADs and in other preventive strategies. The most important use of local surveillance data is longitudinal internal assessment in close cooperation with microbiology and hospital hygiene experts.

[Transient splenial lesion in influenza A H1N1 2009 infection]. / Transiente Spleniumläsion bei Influenza-A-H1N1-09-Infektion.

Severe neurologic complications have been rarely reported during novel pandemic influenza A(H1N1) virus infections. We describe the case of an 10-year-old boy with new onset seizures and proven influenza A(H1N1) 2009 infection showing a reversible hyperintense lesion in the splenium of the corpus callosum on T2-weighted and FLAIR magnetic resonance images without contrast enhancement. Transient splenial lesions have been described in the context of virus encephalopathy and do not require specific treatment.

Renal cell carcinoma with Xp11.2 translocation in a 7-year-old boy.

BACKGROUND: More than 90% of pediatric renal tumors are nephroblastomas while renal cell carcinomas (RCC) are rare in children (< 5%). PATIENT: According to the clinical diagnoses of a nephroblastoma stage IV a 7-year-old boy with a kidney tumor and peripheral pulmonary lesion was preoperatively treated for 8 weeks with Vincristine, Actinomycin D and Adriamycin. The resected kidney displayed a RCC with Xp11.2 translocation. There was no tumor regression and the pulmonary lesion was no longer detectable. Hence chemotherapy was put to a halt. CONCLUSION: Fine needle aspiration biopsy (FNA) would have allowed to adjust the tumor subtype. Prognosis of pediatric RCC with translocation seems more favourable than without translocation though definitive evidence will only be possible by documentation in a clinical diagnose-related register.

Aortobifemoral embolism in an 18-year old patient following cisplatin and 5-fluorouracil chemotherapy for nasopharyngeal carcinoma.

After cisplatin / 5-fluorouracil chemotherapy for nasopharyngeal carcinoma, an 18-year female patient developed aortobifemoral embolism. Besides chemotherapy, additional risk factors for arterial thromboembolic events were smoking, contraceptive medication and adjuvant antiemetic treatment with dexamethasone. Thrombophilia screening was negative. Thromboembolic complications during or after cisplatin have been reported in a frequency of 17.6 % in lung cancer patients, and in 8.4 % of patients with germ cell tumors. The incidence of arterial thromboembolic events was 9.3 % and 1.7 %, respectively. The pathogenesis of cisplatin induced thromboembolism is thought to be caused by endothelial damage leading to endothelial cell dysfunction, increased von Willebrand factor plasma levels, and hypomagnesaemia.

Compassionate use of bevacizumab (Avastin) in children and young adults with refractory or recurrent solid tumors.

BACKGROUND: The aim of this study was to evaluate feasibility and toxicity of bevacizumab (Avastin), a monoclonal antibody directed against the vascular endothelial growth factor in children and young adults. PATIENTS AND METHODS: Fifteen patients (male: n = 8; female: n = 7; median age, 14.6 years) received bevacizumab for recurrent or progressive solid tumors (carcinoma: n = 3; neuroblastoma: n = 2; astrocytoma grade III: n = 2; rhabdomyosarcoma: n = 2; nephroblastoma: n = 2; benign vascular tumors: n = 2; synovial sarcoma: n = 1; and malignant hemangiopericytoma: n = 1) on a compassionate basis. Bevacizumab was administered at 5-10 mg/kg body weight intravenously every 2-3 weeks. Most patients received chemotherapy in addition to bevacizumab. Duration of bevacizumab therapy ranged from 1.5 to 23 months. RESULTS: Bevacizumab-related side-effects were mild and included hypertonia (n = 2), proteinuria/hematuria (n = 2), epistaxis (n = 2), local erythema (n = 1), and defective wound healing and ascites (n = 1). Radiographic objective responses (partial responses) were observed in two patients with astrocytoma grade III and in one patient each with neuroblastoma and pleomorphic rhabdomyosarcoma, respectively. CONCLUSIONS: Bevacizumab seems to have a good acute safety profile and some antitumor activity in heavily pretreated children and young adults with recurrent solid tumors. Prospective clinical trials are urgently needed to further evaluate the safety and efficacy of bevacizumab in pediatric patients.

Proton Therapy for Craniopharyngioma - An Early Report from a Single European Centre.

AIMS: Proton beam therapy (PBT) is being increasingly used for craniopharyngioma. We describe our early outcome of patients treated with PBT. MATERIALS AND METHODS: Between August 2013 and July 2016, 18 patients with craniopharyngiomas were treated with 54 Cobalt Gray Equivalent (CGE) in 30 fractions over 6 weeks at our centre. The early outcome of 16 patients included in a registry study was analysed. Radiological response was assessed by RECIST criteria and the disease- and treatment-related toxicities were scored according to the CTCAE 4.0. RESULTS: All patients are alive at a median follow-up of 32.6 months (range 9.2-70.6 months) from initial diagnosis. The median age at PBT was 10.2 years (range 5.4-46.9 years). One patient progressed 8.7 months after PBT and subsequently had complete resection of the tumour. At a median follow-up of 18.4 months after PBT, five patients remained in complete remission, four in partial remission and seven with stable disease. The most common adverse effects during PBT were grade 1 (cutaneous in seven patients and fatigue in six patients). There were no treatment-related grade 3 toxicities. CONCLUSIONS: Our early results are encouraging and comparable with the limited literature on PBT for craniopharyngioma.

Genotype-outcome correlations in pediatric AML: the impact of a monosomal karyotype in trial AML-BFM 2004.

We conducted a cytogenetic analysis of 642 children with de novo acute myeloid leukemia (AML) treated on the AML-Berlin-Frankfurt-Münster (BFM) 04 protocol to determine the prognostic value of specific chromosomal aberrations including monosomal (MK+), complex (CK+) and hypodiploid (HK+) karyotypes, individually and in combination. Multivariate regression analysis identified in particular MK+ (n=22) as a new independent risk factor for poor event-free survival (EFS 23±9% vs 53±2% for all other patients, P=0.0003), even after exclusion of four patients with monosomy 7 (EFS 28±11%, P=0.0081). CK+ patients without MK had a better prognosis (n=47, EFS 47±8%, P=0.46) than those with MK+ (n=12, EFS 25±13%, P=0.024). HK+ (n=37, EFS 44±8% for total cohort, P=0.3) influenced outcome only when t(8;21) patients were excluded (remaining n=16, EFS 9±8%, P<0.0001). An extremely poor outcome was observed for MK+/HK+ patients (n=10, EFS 10±10%, P<0.0001). Finally, isolated trisomy 8 was also associated with low EFS (n=16, EFS 25±11%, P=0.0091). In conclusion, monosomal karyotype is a strong and independent predictor for high-risk pediatric AML. In addition, isolated trisomy 8 and hypodiploidy without t(8;21) coincide with dismal outcome. These results have important implications for risk stratification and should be further validated in independent pediatric cohorts.

Surveillance for nosocomial and central line-related infections among pediatric hematology-oncology patients.

OBJECTIVE: To determine the incidence of all nosocomial infections (NIs) in pediatric hematology-oncology patients, as well as central venous access device (CVAD)-associated infections acquired during home care. DESIGN: Prospective surveillance study. SETTING: The Pediatric Hematology and Oncology Department at the University Hospital Bonn. PATIENTS: All patients admitted from January through October 1998 (surveillance period). METHODS: Standardized surveillance system based on the Centers for Disease Control and Prevention's National Nosocomial Infections Surveillance System. RESULTS: A total of 143 patients were hospitalized for 3,701 days (776 admissions) during the surveillance period. Of the 40 NIs detected, 26 were CVAD-related, with 21 bloodstream infections (BSIs) and 5 local infections. Four were Clostridium difficile-associated diarrheal illnesses, 3 were pneumonias, and 7 were other infections. The incidence of NIs was 10.8 per 1,000 patient-days (5.2 NIs/100 admissions). The overall CVAD-related BSI rate was 7.4 per 1,000 utilization days, without a significant difference between implanted infusion ports and tunneled catheters. In addition, 7 CVAD-related infections occurred during home care. All 8 BSIs associated with tunneled catheters and 13 (76%) of the 17 BSIs associated with ports were acquired nosocomially. For inpatients and outpatients combined, the exit sites of tunneled catheters were more likely to become locally infected than were the needle entry sites of ports (relative risk, 8.0; P=.007). In 30 (75%) of the 40 NIs, the affected patients had severe neutropenia (<500/mm3) at the time of infection. CONCLUSIONS: Most NIs in the pediatric hematology-oncology patients were associated with CVAD devices. Although many infections in this high-risk population may not be preventable through infection control measures, the careful evaluation of specific infection rates permits the identification of risk factors that may be targeted by infection control programs. Prospective surveillance for NIs on pediatric oncology units is an indispensable tool for this internal quality control.

Accidental iatrogenic intoxications by cytotoxic drugs: error analysis and practical preventive strategies.

OBJECTIVES: Drug errors are quite common. Many of them become harmful only if they remain undetected, ultimately resulting in injury to the patient. Errors with cytotoxic drugs are especially dangerous because of the highly toxic potential of the drugs involved. For medico-legal reasons, only 1 case of accidental iatrogenic intoxication by cytotoxic drugs tends to be investigated at a time, because the focus is placed on individual responsibility rather than on system errors. The aim of our study was to investigate whether accidental iatrogenic intoxications by cytotoxic drugs are faults of either the individual or the system. The statistical analysis of distribution and quality of such errors, and the in-depth analysis of contributing factors delivered a rational basis for the development of practical preventive strategies. METHODS: A total of 134 cases of accidental iatrogenic intoxication by a cytotoxic drug (from literature reports since 1966 identified by an electronic literature survey, as well as our own unpublished cases) underwent a systematic error analysis based on a 2-dimensional model of error generation. Incidents were classified by error characteristics and point in time of occurrence, and their distribution was statistically evaluated. The theories of error research, informatics, sensory physiology, cognitive psychology, occupational medicine and management have helped to classify and depict potential sources of error as well as reveal clues for error prevention. RESULTS: Monocausal errors were the exception. In the majority of cases, a confluence of unfavourable circumstances either brought about the error, or prevented its timely interception. Most cases with a fatal outcome involved erroneous drug administration. Object-inherent factors were the predominant causes. A lack of expert as well as general knowledge was a contributing element. In error detection and prevention of error sequelae, supervision and back-checking are essential. Improvement of both the individual training and work environment, enhanced object identification by manufacturers and hospitals, increased redundancy, proper usage of technical aids, and restructuring of systems are the hallmarks for error prevention. CONCLUSIONS: Errors follow general patterns even in oncology. Complex interdependencies of contributing factors are the rule. Thus, system changes of the working environment are most promising with regard to error prevention. Effective error control involves adapting a set of basic principles to the specific work environment. The work environment should allow for rectification of errors without penalty. Regular and ongoing intra-organisational error analysis needs to be an integral part of any error prevention strategy. However, it seems impossible to totally eliminate errors. Instead, if the environment guarantees timely error interception, most sequelae are avoided, and errors transform into a system-wide learning tool.

Structuring psychosocial care in pediatric oncology.

The requirements for high quality psychosocial care for children with cancer and their families are steadily increasing. As an additional supplement to medical and nursing care, psychosocial work has to consider both the requirements of the medical treatment and the associated stress factors. It is essential to structure the different possibilities of intervention in a way which guarantees the practice of psychosocial care within the ongoing medical care. This requires a standardized psychosocial care manual. In July 1994, a 'Manual for Psychological Care in Pediatric Oncology' was put into practice and has been continually improved in the Department of Pediatric Hematology/Oncology of the University of Bonn. It contains special indications for different standards of psychosocial care, is oriented according to the phases and situations of medical treatment, and consists of a health education program as well as special care measurements. The latter are related to both the stressors primarily caused by the requirements of familial adherence to medical and nursing care and the stressors primarily caused by factors of the individual or the familial life circumstances. The theoretical basis of this manual and concrete information for its use are described in this paper.

High-dose chemotherapy (HDCT) with auto-SCT in children with atypical teratoid/rhabdoid tumors (AT/RT): a report from the European Rhabdoid Registry (EU-RHAB).

A retrospective analysis of data from the European Rhabdoid Registry (EU-RHAB) was performed to describe the outcome of children with atypical teratoid/rhabdoid tumors (AT/RT) who underwent high-dose chemotherapy (HDCT) with auto-SCT. Nineteen patients (male, n=15; median age at diagnosis 21 months) were identified. Nine patients presented with metastatic disease at diagnosis. A partial or subtotal resection was achieved in 11, a total resection in five and a biopsy in three patients. Patients received a median of six chemotherapy cycles prior to HDCT. Additional radiotherapy was performed in 14 patients (first-line, n=9; following progression, n=5). Six patients underwent tandem auto-SCT. Disease status before HDCT was CR in six, PR in eight, stable disease in two and progressive disease (PD) in two patients (data missing, n=1). With a median follow-up of 16 months, 14 patients progressed. Estimated progression-free and OS at 2 years were 29% (±11%) and 50% (±12%), respectively. At last follow-up, eight patients were alive (first CR, n=4; second CR, n=2; PR, n=1; PD, n=1). Eleven patients died of PD. Median time-to-progression was 14 months. Selected patients with AT/RT might benefit from HDCT with radiotherapy. The definitive impact of this treatment modality has to be evaluated prospectively in a randomized trial.

Consequent and intensified relapse therapy improved survival in pediatric AML: results of relapse treatment in 379 patients of three consecutive AML-BFM trials.

Relapse remains the major cause of treatment failure in pediatric acute myeloid leukemia (AML). We analyzed the clinical characteristics, treatment response to relapse treatment and overall survival (OS) of 379 children with AML relapse treated according to three consecutive frontline protocols of the AML-Berlin/Frankfurt/Muenster study group (AML-BFM-87/-93/-98). Of 313 treated patients with data on remission status, 198 children (63%) achieved a second complete remission (CR2). There were no significant differences in remission rates and OS for the intensive reinduction treatment schedules used. The 5-year OS rate was 23% for the total group and 29% for patients treated with curative intent. OS rates increased with study periods from 18 to 34% (P(log rank)=0.012), whereas the proportion of patients receiving only palliative treatment decreased from 23 to 11% (P(CMH)=0.005). Late relapse, no allogeneic stem cell transplantation (SCT) in CR1, age <10 years and favorable cytogenetics were independent favorable prognostic factors for survival. Achievement of CR2 was the most important prognostic factor (OS 44 vs 3%; P(log rank)<0.0001). Overall, one-third of children with relapsed AML can be cured today. SCT in CR2 is recommended for most patients, although its impact on CR2 is discussed.