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.

Bloodstream infection in paediatric cancer centres--leukaemia and relapsed malignancies are independent risk factors.

UNLABELLED: In a prospective multicentre study of bloodstream infection (BSI) from November 01, 2007 to July 31, 2010, seven paediatric cancer centres (PCC) from Germany and one from Switzerland included 770 paediatric cancer patients (58% males; median age 8.3 years, interquartile range (IQR) 3.8-14.8 years) comprising 153,193 individual days of surveillance (in- and outpatient days during intensive treatment). Broviac catheters were used in 63% of all patients and Ports in 20%. One hundred forty-two patients (18%; 95% CI 16 to 21%) experienced at least one BSI (179 BSIs in total; bacteraemia 70%, bacterial sepsis 27%, candidaemia 2%). In 57%, the BSI occurred in inpatients, in 79% after conventional chemotherapy. Only 56 % of the patients showed neutropenia at BSI onset. Eventually, patients with acute lymphoblastic leukaemia (ALL) or acute myeloblastic leukaemia (AML), relapsed malignancy and patients with a Broviac faced an increased risk of BSI in the multivariate analysis. Relapsed malignancy (16%) was an independent risk factor for all BSI and for Gram-positive BSI. CONCLUSION: This study confirms relapsed malignancy as an independent risk factor for BSIs in paediatric cancer patients. On a unit level, data on BSIs in this high-risk population derived from prospective surveillance are not only mandatory to decide on empiric antimicrobial treatment but also beneficial in planning and evaluating preventive bundles. WHAT IS KNOWN: • Paediatric cancer patients face an increased risk of nosocomial bloodstream infections (BSIs). • In most cases, these BSIs are associated with the use of a long-term central venous catheter (Broviac, Port), severe and prolonged immunosuppression (e.g. neutropenia) and other chemotherapy-induced alterations of host defence mechanisms (e.g. mucositis). What is New: • This study is the first multicentre study confirming relapsed malignancy as an independent risk factor for BSIs in paediatric cancer patients. • It describes the epidemiology of nosocomial BSI in paediatric cancer patients mainly outside the stem cell transplantation setting during conventional intensive therapy and argues for prospective surveillance programmes to target and evaluate preventive bundle interventions.

Stromal cells as trend-setters for cells migrating into the lymph node.

Lymph node stromal cells are known to be immunorelevant during inflammation and tolerance. Differences between peripheral lymph nodes and mesenteric lymph nodes are important for an efficient and effective immune defense. Stromal cells were considered to be perfectly adapted to their draining area and not changeable concerning their expression pattern. Here we show that stromal cells can change their profile after isolation and transplantation into a different draining area. Subsequently, these newly organized lymph nodes are able to induce not only a region-specific but also an antigen-specific immune response. Thus, stromal cells are trend-setters for immune cells in producing a microenvironment that allows an optimized immune defense.

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.

The intestinal micro-environment imprints stromal cells to promote efficient Treg induction in gut-draining lymph nodes.

De novo induction of Foxp3⁺ regulatory T cells (Tregs) is particularly efficient in gut-draining mesenteric and celiac lymph nodes (mLN and celLN). Here we used LN transplantations to dissect the contribution of stromal cells and environmental factors to the high Treg-inducing capacity of these LN. After transplantation into the popliteal fossa, mLN and celLN retained their high Treg-inducing capacity, whereas transplantation of skin-draining LN into the gut mesenteries did not enable efficient Treg induction. However, de novo Treg induction was abolished in the absence of dendritic cells (DC), indicating that this process depends on synergistic contributions of stromal and DC. Stromal cells themselves were influenced by environmental signals as mLN grafts taken from germ-free donors and celLN grafts taken from vitamin A-deficient donors did not show any superior Treg-inducing capacity. Collectively, our observations reveal a hitherto unrecognized role of LN stromal cells for the de novo induction of Foxp3⁺ Tregs.

Skin tolerance is supported by the spleen.

The repeated application of antigens results in the induction of tolerance. Lymph nodes are responsible for this reaction by producing suppressor cells. Using an in vivo transplantation model, we showed recently that stromal cells from different lymph nodes induce different cell populations for suppression, which all produce a tolerogenic phenotype. In this study, we were interested in the role of the spleen in these tolerance reactions. Therefore, tolerance was induced via feeding or injecting ovalbumin several times in control and splenectomized mice. The delayed-type hypersensitivity (DTH) was measured as well as the cell subset composition of the spleen. The spleen of peripherally tolerized mice showed higher proliferation activity and a specific antibody production compared with orally tolerized mice, where regulatory T cells were predominantly found. Tolerance induction after removal of the spleen resulted in a reduced DTH response in antigen fed animals, whereas skin tolerance induction failed. In conclusion, the results illustrate that lymph nodes from different areas employ their individual pathways for similar immune reactions, and the spleen is part of this reaction initiated at the peripheral site.

Lymph node dissection--understanding the immunological function of lymph nodes.

Lymph nodes (LN) are one of the important sites in the body where immune responses to pathogenic antigens are initiated. This immunological function induced by cells within the LN is an extensive area of research. To clarify the general function of LN, to identify cell populations within the lymphatic system and to describe the regeneration of the lymph vessels, the experimental surgical technique of LN dissection has been established in various animal models. In this review different research areas in which LN dissection is used as an experimental tool will be highlighted. These include regeneration studies, immunological analysis and studies with clinical questions. LN were dissected in order to analyse the different cell subsets of the incoming lymph in detail. Furthermore, LN were identified as the place where the induction of an antigen-specific response occurs and, more significantly, where this immune response is regulated. During bacterial infection LN, as a filter of the lymph system, play a life-saving role. In addition, LN are essential for the induction of tolerance against harmless antigens, because tolerance could not be induced in LN-resected animals. Thus, the technique of LN dissection is an excellent and simple method to identify the important role of LN in immune responses, tolerance and infection.

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.

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.

Sexual precocity associated with an abdominal tumor in an African boy.

We report a 3 year-old boy in Tanzania with an abdominal mass and isosexual precocity due to an hCG-secreting hepatoblastoma. Due to the limited availability of local diagnostic testing, surgery and chemotherapy were completed before immunohistochemical and endocrine results were available.

[Pediatric renal cell carcinoma. A rare differential diagnosis of Wilms' tumor]. / Das Nierenzellkarzinom beim Kind. Eine seltene Differenzialdiagnose zum Wilms-Tumor.

Renal cell carcinoma (RCC) is a very rare pediatric disease and should be treated as an entity of its own because of differences in symptoms, therapy, and prognosis from the adult form of the disease. Our objective is to discuss the difficulties in clinical diagnosis, prognosis, and therapy of this very rare disease in children and to provide a review of the current literature.

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.

Effect of medical honey on wounds colonised or infected with MRSA.

Full healing was achieved in seven consecutive patients whose wounds were either infected or colonised with methicillin-resistant Staphylococcus aureus. Antiseptics and antibiotics had previously failed to irradicate the clinical signs of infection.

Marked elevation in homocysteine and homocysteine sulfinic acid in the cerebrospinal fluid of lymphoma patients receiving intensive treatment with methotrexate.

OBJECTIVE: Interference of methotrexate (MTX) with the metabolism of homocysteine may contribute to MTX neurotoxicity. In this pilot study we measured the concentration of homocysteine and related metabolites in the cerebrospinal fluid (CSF) of patients with primary central nervous system lymphoma undergoing intensive treatment with MTX. MATERIAL AND METHODS: CSF samples from lymphoma patients (n = 4) were drawn at the end of high-dose MTX infusions (3-5 g/m2/24 h, HDMTX) and one day after intraventricular injections of MTX (3 mg, ICVMTX) or cytarabine (30 mg) and analyzed for homocysteine, cysteine, sulfur-containing excitatory amino acids (cysteine sulfinic acid, cysteic acid, homocysteine sulfinic acid and homocysteic acid), S-adenosylmethionine, 5-methyltetrahydrofolate and MTX. The concentration of homocysteine, cysteine and sulfur-containing excitatory amino acids were also measured in the CSF of a reference population not exposed to MTX. The Wilcoxon signed rank-test and the Friedman test were used to compare concentrations of homocysteine and its metabolites at various time-points during chemotherapy. Comparison of patient and control samples were performed using the Mann-Whitney U-test. Allelic variants of homocysteine metabolism previously shown to influence MTX neurotoxicity (MTHFR c.677C>T, MS c.2756A>G and Tc2 c.776C>G) were also analyzed. RESULTS: After application of HD- and ICVMTX, the CSF homocysteine concentrations in the lymphoma patients were markedly elevated and significantly higher than those in the control group (p < 0.05, Mann-Whitney U-test), whereas 5-methyltetrahydrofolate was depleted. A rapid elevation of homocysteine sulfinic acid, a sulfur-containg amino acid which was not detected in the CSF of the control group, was observed. One patient developed confluent white matter brain changes visible using MRI. This patient had the lowest concentration of S-adenosylmethionine in the CSF and carried two risk alleles for MTX neurotoxicity. CONCLUSIONS: In this pilot study, MTX administered either intravenously or intraventricularly, induced marked biochemical alterations in the CSF. Whether these changes can be used to predict MTX-induced neurotoxicity at an early stage in treatment needs to be elucidated in larger clinical trials.

Piperacillin-tazobactam in pediatric cancer patients younger than 25 months: a retrospective multicenter survey.

Piperacillin-Tazobactam (Pip-Taz) is an evidence-based empirical treatment of febrile neutropenia in adolescents and adults. No data are available in pediatric cancer patients <25 months of age. In this retrospective, multicenter data survey, the analysis focuses on safety, tolerance, and efficacy. The daily dose administered was 240 mg/kg given in three equally divided doses. Data on 156 Pip-Taz treatment courses in 69 children <25 months from five pediatric cancer treatment centers (2001-2005) were analyzed. The median duration of treatment with Pip-Taz was 5 days (range, 1-23 days; 1-12 Pip-Taz courses per patient). Pip-Taz was started on the first day of fever in 90% of all courses, in 6% in the first 72 h, and in 4% as second- or third-line agent. Forty-five percent of all patients were neutropenic. In all patients, the outcome was favorable independent whether Pip-Taz was given as monotherapy (42 courses; 27%) or in combination. Overall, Pip-Taz was well tolerated and discontinued due to adverse events in only two patients who experienced non-life-threatening allergic reactions (skin rash and wheezing). The results of this study are preliminary due to the methodological limitations of a retrospective survey. Taking this bias into consideration, Pip-Taz appears to be a safe, and feasible alternative in pediatric cancer patients with febrile neutropenia <25 months of age suggesting that the inclusion of children of all age groups in future prospective controlled studies evaluating Pip-Taz is justified.

[Coating with plasma-deposited functionalized diamond-like carbon to decrease encrustations on urological implants]. / Plasmadeponierte funktionalisierte Kohlenstoffschichten zur Minderung von Inkrustationen auf urologischen Implantaten.

The double-J stents used today for palliative artificial urinary diversion very often show extreme formation of encrustations, even a short time after implantation. Despite increased scientific material development, the complication rate has not really been strongly influenced. Grant-aided by the German Federal Ministry of Education and Research, we chose a new interdisciplinary and translational approach by coating standard stent materials with plasma-deposited amorphous diamond-like carbon. These stents show clearly reduced rates of encrustation in vitro. Ongoing clinical trials demonstrate a further enhancement of this effect in vivo. The underlying mechanisms are being investigated by extending the established in vitro model, thereby pushing research in this field to a new level.

[The human bocavirus: pathogen in airway infections?]. / Das humane Bocavirus: Erreger von Atemwegsinfektionen?

The human Bocavirus (HBoV), the second member of the parvovirus family, which displays pathogenicity in humans, has been described in 2005 by Allander et al.. It seems to be distributed worldwide and has been isolated mainly in infants and children with respiratory tract infection. This review covers all studies published on HBoV to February 2007 and discusses this emerging viral pathogen from the perspective of inpatient medical treatment centers.

[Human Metapneumovirus in hospitalized children - a review]. / Das humane Metapneumovirus als Erreger von Atemwegsinfektionen bei hospitalisierten Kindern - eine Ubersicht.

The human Metapneumovirus (HMPV) has been discovered by von den Hoogen et al. in 2001 and seems to play an important role as etiologic agent in childhood respiratory tract infections in particular involving infants after the 6th month of life and toddlers. Duly considering the hitherto published studies and retrospective analysis of two HMPV seasons (2002-2004) at our institution this review focuses on children, who had to be hospitalized due to HMPV infection. The analysis confirmed, that among those patients there is a high proportion of children with pre-existing risk factors for a complicated clinical course, a high proportion of children with bronchiolitis or pneumonia and a relevant proportion of children with HMPV related apnoeas, most prevalent in the prematurely born. Although the first HMPV infection takes place somewhat later in infancy, the data do not show that HMPV infection is in general milder than RSV infection in hospitalized children. Clinical symptoms and radiological signs do not permit tentative conclusions on the causative agent. This underlines the necessity of specific diagnostic efforts (in case of HMPV with PCR). HMPV may cause lobar or segmental pneumonias difficult to distinguish from bacterial lower respiratory tract infection. Children admitted to the hospital with an acute exacerbation of asthma bronchiale or cystic fibrosis should not only be tested for RSV but also for HMPV. Prospective studies investigating specific therapeutic interventions or describing the impact and prevention of nosocomial HMPV in fection are awaited for. There has been one report of a meningoencephalitis possibly related to HMPV. Thus, liquor samples in such cases should be tested for HMPV too.

Influence of prolonged use of intravenous administration sets in paediatric cancer patients on CVAD-related bloodstream infection rates and hospital resources.

BACKGROUND: To assess the effects of extending the routine intravenous administration set (IVAS) change-interval from 72 h (group 1) to 7 days (group 2) on the incidence density for central venous access device (CVAD)-related bloodstream infections (BSIs) and on resource expenditures in a singlecentre pilot study. PROCEDURE: Prospective pre-/post-intervention comparison of two consecutive 12-month surveillance periods (2001-2003) in a 17-bed paediatric oncology tertiary care unit. IVAS changes and nosocomial infections (NIs) were prospectively analysed using a standardized unit-based surveillance system (Oncopaed NI). RESULTS: All 175 eligible patients were enrolled, 96 in group 1 and 79 in group 2. Both groups had similar distributions of primary diagnoses and risk factors. The proportion of IVAS changes performed after 3 days increased from 5.6% to 22.5%, but only 8% of IVASs in group 2 were changed after 7 days. Most IVAS changes (64.8% in group 1 and 92.9% in group 2) were done because of therapeutic interventions (blood products, parenteral nutrition [TNP]) before the scheduled endpoint. Overall, the rates and incidence densities of NIs were significantly lower during the second period. The corresponding results for CVAD-related BSIs did not show significant differences. No death attributable to a NI occurred. The '7-day' strategy resulted in cost savings for devices (3,300 dollars/year) and of nursing time (23 working days/year). CONCLUSIONS: Extending the routine IVAS change-interval from 3 days to 7 days appears to be safe and cost-effective in a paediatric oncology unit with high infection control standards and continuous surveillance for NIs. These results do not prove that 7-day intervals prevent infections, but they do suggest that this policy probably is not harmful and that a prospectively randomized study with sufficient power is needed.

Diagnosis and treatment of catheter-related infections in paediatric oncology: an update.

Otherwise unexplained clinical signs of infection in patients with long-term tunnelled or totally implanted central venous access devices (CVADs) are suspected to be CVAD-associated. Diagnostic methods include catheter swabs, blood cultures and cultures of the catheter tip or port reservoir. In the case of a suspected CVAD-related bloodstream infection in paediatric oncology patients, in-situ treatment without prompt removal of the device can be attempted. Removal of the CVAD should be considered if bacteraemia persists or relapses > or = 72 h after the initiation of (in-vitro effective) antibacterial therapy administered through the line. Timely removal of the device is also recommended if the patient suffers from a complicated infection, or if Staphylococcus aureus, Pseudomonas aeruginosa, multiresistant Acinetobacter baumannii or Candida spp. are isolated from blood cultures. Duration of therapy depends on the immunological recovery of the patient, the pathogen isolated and the presence of related complications, such as thrombosis, pneumonia, endocarditis and osteomyelitis. Antibiotic lock techniques in addition to systemic treatment are beneficial for Gram-positive infections. Although prospectively controlled studies are lacking, the concomitant use of urokinase locks and taurolidine secondary prophylaxis seem to favour catheter salvage.