Cartilage hair hypoplasia with cutaneous lymphomatoid granulomatosis.

Cartilage-hair hypoplasia (CHH) is an autosomal recessive chondrodysplasia characterized by short-stature, sparse hair and impaired cellular immunity. We describe a young girl who was diagnosed with CHH based on the findings of recurrent infections, short stature with metaphyseal chondrodysplasia, and a confirmed bi-allelic RMRP gene mutation. At 13 years, the patient developed an Epstein-Barr virus (EBV)-driven lymphoproliferative disorder involving the lung, which responded partially to chemotherapy. Simultaneously, she developed multiple indurated plaques involving her face, which had histological findings of granulomatous inflammation and EBV-associated low-grade lymphomatoid granulomatosis. The patient received a matched unrelated peripheral blood stem cell transplant at 15 years of age, and her immunological parameters and skin lesions improved. Lymphomatoid forms of granulomatosis and cutaneous EBV-associated malignancies have not been described previously in CHH. This case highlights the possibility of EBV-associated cutaneous malignancy in CHH.

A phase II window study of irinotecan (CPT-11) in high risk Ewing sarcoma: a Euro-E.W.I.N.G. study.

BACKGROUND: The prognosis for patients with nonpulmonary metastatic Ewing sarcoma remains poor with survival in the order of 15-20%. The need to introduce effective new agents into clinical practice is clear. Based on a preclinical rationale of responses in xenografts and backed by a phase I study in children, the Euro-E.W.I.N.G consortium planned a phase II window study of irinotecan in newly diagnosed high risk metastatic patients with Ewing sarcoma. PROCEDURES: Patients were recruited between April 2004 and December 2007. Two courses of irinotecan were administered at a dose of 600 mg/m(2) as a 1 hour infusion at 21 day intervals. Response evaluation was determined after the second course of treatment by radiological assessment of primary and metastatic sites and, where appropriate bone marrow sampling. RESULTS: Twenty-three patients were recruited. Two patients were deemed inevaluable for response. Five patients (24%) demonstrated a partial response. Grade 3 or 4 diarrhoea was seen in 4/43 course of treatment and was managed with loperamide. CONCLUSIONS: This is the first report of single agent irinotecan activity in an untreated population of patients with Ewing sarcoma. In common with other paediatric tumours and other camptothecin analogues such as topotecan, single agent activity is only modest. The exact role for the use of irinotecan in patients with ES, dose schedule and combinations with other agents still requires further investigation.

Rejection is less common in children undergoing liver transplantation for hepatoblastoma.

To compare the incidence of acute histologically proven rejection in children who have had a liver transplant for hepatoblastoma with a control group of children transplanted for biliary atresia (EHBA). A retrospective case notes based study was performed. Twenty patients were identified with hepatoblastoma who were transplanted at a single unit between 1991 and 2008. These were matched as closely as possible for age, gender, year of transplant and type of immunosuppression used to the control group transplanted for biliary atresia (n = 60). There was a significant decrease in rate of acute rejection as assessed by the rejection activity index (RAI) in the hepatoblastoma group (75% vs. 50%, respectively, p < 0.04). Chronic rejection was rare in both groups, but twice as common in the biliary atresia group. Equal levels of immunosuppression were achieved in both groups. Renal function was noted to be reduced one yr post-transplant in both groups, as previously reported. A modified immunosuppression regimen could be considered in children with hepatoblastoma undergoing liver transplantation.

Phase I/II study of single-agent lenvatinib in children and adolescents with refractory or relapsed solid malignancies and young adults with osteosarcoma (ITCC-050)☆.

BACKGROUND: We report results from the phase I dose-finding and phase II expansion part of a multicenter, open-label study of single-agent lenvatinib in pediatric and young adult patients with relapsed/refractory solid tumors, including osteosarcoma and radioiodine-refractory differentiated thyroid cancer (RR-DTC) (NCT02432274). PATIENTS AND METHODS: The primary endpoint of phase I was to determine the recommended phase II dose (RP2D) of lenvatinib in children with relapsed/refractory solid malignant tumors. Phase II primary endpoints were progression-free survival rate at 4 months (PFS-4) for patients with relapsed/refractory osteosarcoma; and objective response rate/best overall response for patients with RR-DTC at the RP2D. RESULTS: In phase I, 23 patients (median age, 12 years) were enrolled. With lenvatinib 14 mg/m2, three dose-limiting toxicities (hypertension, n = 2; increased alanine aminotransferase, n = 1) were reported, establishing 14 mg/m2 as the RP2D. In phase II, 31 patients with osteosarcoma (median age, 15 years) and 1 patient with RR-DTC (age 17 years) were enrolled. For the osteosarcoma cohort, PFS-4 (binomial estimate) was 29.0% [95% confidence interval (CI) 14.2% to 48.0%; full analysis set: n = 31], PFS-4 by Kaplan-Meier estimate was 37.8% (95% CI 20.0% to 55.4%; full analysis set) and median PFS was 3.0 months (95% CI 1.8-5.4 months). The objective response rate was 6.7% (95% CI 0.8% to 22.1%). The patient with RR-DTC had a best overall response of partial response. Some 60.8% of patients in phase I and 22.6% of patients in phase II (with osteosarcoma) had treatment-related treatment-emergent adverse events of grade ≥3. CONCLUSIONS: The lenvatinib RP2D was 14 mg/m2. Single-agent lenvatinib showed activity in osteosarcoma; however, the null hypothesis could not be rejected. The safety profile was consistent with previous tyrosine kinase inhibitor studies. Lenvatinib is currently being investigated in osteosarcoma in combination with chemotherapy as part of a randomized, controlled trial (NCT04154189), in pediatric solid tumors in combination with everolimus (NCT03245151), and as a single agent in a basket study with enrollment ongoing (NCT04447755).

Fifty years of paediatric malignant bone tumours in the West Midlands, UK, 1957-2006: incidence, treatment and outcome.

Malignant bone tumours in the paediatric age group (0-14 years) are uncommon; various aetiological theories exist and few reports of incidence, age and sex distributions have been published. We examined the incidence of childhood malignant bone tumours in one large single region of the UK over an extended period of 50 years. The West Midlands specialist regional children's tumour registry holds data on all malignancies and benign brain tumours in children under 15 years in the West Midlands region, which has a population of around 1 million children. Demographic and clinical data have been abstracted and diagnoses reviewed by a panel of expert pathologists. During the period 1957-2006, 259 cases of malignant paediatric bone tumours were diagnosed. There were 153 osteosarcomas, 78 Ewing sarcomas and 28 other primary bone tumours. The overall age standardised rate was 4.66, with no increase over time, although there was a significant increase in the incidence of Ewing sarcomas in the period 1965-92. Sixty-eight per cent of tumours were in patients over 10 years, whereas the incidence in patients under 10 years showed a non-significant increase. Survival rates increased dramatically post-chemotherapy introduction, with Ewing sarcoma demonstrating better survival overall. This is a large study giving an overview of malignant bone tumours in the childhood population of a single region over an extended period, showing results consistent with national reports. It also examines late effects, which were mostly mobility/orthopaedic, although almost one-fifth of patients had cardiac problems and five went on to develop second malignancies.

Congenital mesoblastic nephroma: a single-centre series.

BACKGROUND: Congenital mesoblastic nephroma is a rare disease. Treatment is surgical in the first instance. Chemotherapy has traditionally been thought not to have a role. Recent literature suggests a 50% mortality rate for recurrent/metastatic disease. MATERIALS AND METHODS: This study is a retrospective case review of prospectively collected data. Demographics, histopathology, treatment, outcomes and follow up were reviewed. RESULTS: Nine patients, 6 male and 3 female, were included. The median age at presentation was one month (range 0-7 months); follow-up was for a median of 21.5 months (range 16-79 months). Two patients had mixed and classical subtypes and the other five had the cellular subtype. Surgery was completed by an open procedure in eight patients and laparoscopically in one. There were three recurrences; two were local and one was pulmonary. Recurrences were treated with a combination of chemotherapy, radiotherapy and surgery. One patient with recurrent disease died from acute-on-chronic respiratory failure secondary to lung irradiation but was disease free. The other eight are disease free, alive and well with no sequelae at latest follow-up. CONCLUSIONS: Surgery remains the mainstay of management with chemo- and radiotherapy reserved for unresectable tumours or adjuvant management of recurrent disease. Specimen-positive margins are not an indication for instituting chemotherapy. The tyrosine kinase pathway seems to be a potential target for future chemotherapeutic agents although it is too early to assess how that will impact on the management of congenital mesoblastic nephroma.

Migration of CD18-deficient neutrophils in vitro: evidence for a CD18-independent pathway induced by IL-8.

Neutrophils isolated from a child with severe leukocyte adhesion deficiency 1 (LAD1) had a complete absence of expression of the CD11/CD18 beta2 integrin family of adhesion molecules, and were shown to be deficient in the in vitro adhesion and migration properties. However, we found that interleukin-8 (IL8), a potent chemoattractant for neutrophils, and sputum sol phase induced these LAD1 neutrophils to migrate through an endothelial cell layer in vitro, and confirmed that this migration was CD18-independent. These findings add to evidence of CD18-independent mechanisms of neutrophil recruitment, in particular neutrophil infiltration into the lungs, where IL8 may be an important recruitment factor.

Granulocyte colony-stimulating factor in established febrile neutropenia: a randomized study of pediatric patients.

PURPOSE: Infection in neutropenic patients is potentially life-threatening and carries important implications for hospital resource use. Prophylactic administration of cytokines may reduce the severity of neutropenia, but involves the treatment of all patients for the possible benefit of a minority. This study evaluates whether treatment with cytokines in the setting of established febrile neutropenia will influence outcome and be potentially more cost-effective. PATIENTS AND METHODS: In a double-blind study, pediatric patients with fever and severe neutropenia were randomized to receive granulocyte colony-stimulating factor ([G-CSF] filgrastim; 5 microg/kg/d) or placebo, in addition to antibiotics. The study protocol required a resolution of fever and a neutrophil count > or = 0.2 x 10(9)/L for hospital discharge. Patients could be randomized for up to four independent febrile episodes. A total of 186 episodes of febrile neutropenia were investigated. RESULTS: Patients randomized to G-CSF had a shorter hospital stay (median, 5 v 7 days; P = .04) and fewer days of antibiotic use (median, 5 v 6 days; P = .02). G-CSF-treated patients also had more rapid neutrophil recovery and higher neutrophil levels at discharge. The 2-day reduction in hospital stay reduced the median bed cost by 29% per patient admission (P = .04). CONCLUSION: Under the clinical guidelines of our institution, the use of G-CSF in the treatment of established febrile neutropenia produced a small but significant reduction in the time that children required antibiotics and hospital admission, with possible cost savings.

Prospective validation of renal function-based carboplatin dosing in children with cancer: A United Kingdom Children's Cancer Study Group Trial.

PURPOSE: Carboplatin dosing in adults with cancer is based on renal function. The purpose of the current study was to validate a previously developed pediatric carboplatin-dosing formula. PATIENTS AND METHODS: Thirty-eight pediatric patients were randomized to receive a carboplatin dose calculated according to surface area or a renal function-based dosing formula. On the next course of therapy, the alternative dosing method was used for each patient. Carboplatin pharmacokinetics (based on free plasma platinum concentrations) were measured after both courses. RESULTS: The mean observed areas under the carboplatin concentration-versus-time curve (AUCs) after renal function- and surface area-based dosing were 98% and 95% of the target AUCs, respectively. The variation in the observed AUC was significantly less after renal function-based dosing (F test, P =.02), such that 74% of courses had an observed AUC within +/- 20% of the target value, versus 49% for courses after dosing according to surface area. Only one of 22 courses at the center with the most experience with renal function-based dosing was associated with an AUC outside +/- 20% of the target value, versus nine of 22 courses after surface area-based dosing in the same center. There was a relationship (r(2) =.71) between carboplatin AUC and thrombocytopenia in 10 neuroblastoma patients treated with a combination of carboplatin, vincristine, etoposide, and cyclophosphamide. CONCLUSION: Renal function-based carboplatin dosing in children results in more consistent drug exposure than surface area-based drug administration.

European collaboration in trials of new agents for children with cancer.

Childhood cancer is a relatively rare disease, representing just 1% of all malignancies. Within Europe, this represents some 12,000 new cases each year, with approximately 1600 a year in the United Kingdom and 1800 in France. International collaboration in phase III trials of childhood cancer has been the norm for many years, traditionally within Europe, but, largely because of organisational considerations, phase I and II trials have only been conducted on a national basis. With overall cure rates in the region of 70%, relatively few children are available for these early drug trials. Access to new drugs is also a major problem. Against this background, a United Kingdom (UK)/French 'new agent' collaboration was established, expanding subsequently into a wider European grouping. This paper documents the history of that collaboration, the outcomes and future challenges.

Macrophage inhibition of collagen-induced platelet aggregation.

Collagen was incubated with cells or media fractions of mouse peritoneal macrophage cultures, and its aggregating effect on human platelets was tested. Incubation with lysates of cultured cells completely abolished the normal collagen-induced platelet aggregation, while incubation with media fractions only caused partial inhibition. The latter inhibition was more pronounced after macrophage phagocytosis of latex particles, while endocytosis of endotoxin had no effect. Corresponding macrophage cultures were also tested for specific collagenase activity, using 14C-glycine labelled collagen as substrate. Collagenase activity was found in the culture media fractions only, and the enzyme activity could be enhanced by endocytosis of latex as well as endotoxin. It appears that the effect of macrophage lysates and media on collagen-platelet interaction cannot be ascribed only to secretion of collagenase from macrophages.

Different effects of ethanol on particle phagocytosis via different receptors in human monocytes.

Endocytosis of test particles by human blood monocytes (Mo) was tested in the presence of ethanol (80 mM). Phagocytosis via the Fc (IgG)- or C3b receptors (R) was assessed by an assay in which IgG- or C3b coated sheep erythrocytes (E) were used as test particles. Latex particles were tested in parallel with opsonized E. Phagocytosis of IgG-E was reduced to 67 +/- 5% of control (= without ethanol), while the corresponding value for C3b-E was 164 +/- 26% controls. Phagocytosis of latex particles was not affected by ethanol exposure (91 +/- 8% of control). The receptor functions were also tested without ethanol present during the assays. In this part of the study, Mo were incubated with or without ethanol in autologous serum for 15 min at 37 degrees C. After washing the cells free of ethanol, binding properties of the Fc-R or C3b-R were assessed by a rosette assay. Preincubation with ethanol reduced Fc-R binding, while attachment to C3b-R seemed to be more effective. The experiments thus indicate different effects of ethanol treatment in vitro on phagocytic receptors in human Mo. Control experiments revealed no direct effect of ethanol on the test particles.

Molecular cytogenetic characterization of two non-MYCN amplified neuroblastoma cell lines with complex t(11;17).

The pediatric tumor neuroblastoma is characterized by a very variable, and at times unpredictable, pattern of clinical behavior, ranging from a benign localized tumor to an aggressive malignancy with poor prognosis. Standard clinical and pathological assessments do not always differentiate reliably between tumor subtypes and, therefore, genetic markers are now playing an increasingly important role in treatment decisions. MYCN oncogene amplification, for example, provides a useful marker of poor prognosis. However, less than one-half of all patients who present with, or who later develop, metastatic disease show MYCN amplification. Consequently, the identification of characteristic patterns of genetic alteration in the remaining tumors is of importance. In this report, we describe two new cell lines that we have established from metastatic, non-MYCN amplified, advanced stage neuroblastomas. These cell lines show a number of features in common, including unbalanced translocation between 11q and 17q, loss of 3p, 4p and 11q and gain of 17q. Therefore, they provide a valuable resource for the characterization of genetic pathways leading to aggressive tumor growth in non-MYCN amplified neuroblastomas.

Decreased Fc-receptor binding in human monocytes exposed to ethanol in vitro.

Human blood monocytes were incubated with or without ethanol (14 mM-220 mM, initial concentration) in non-sealed wells in an atmosphere of 5% CO2 in air for various time periods. The actual ethanol concentration was assayed in the media at the beginning and at the end of each incubation period. No change in ethanol content was found after 5 or 15 min incubation, while a reduction to about 70% of the initial concentration was observed after 6 hr incubation. Binding of IgG-opsonized particles to the Fc-receptors was tested after ethanol exposure of the cells. An initial concentration of 14 or 28 mM ethanol caused no difference from controls, neither did incubation in 55 mM ethanol for 5 min. Monocyte incubated in 55 mM ethanol for 15 min showed reduced binding of particles, and further reduction was obtained by increasing the ethanol concentration. Six hr incubation in 55 mM ethanol caused no further reduction in binding capacity. Reduced binding of test particles to Fc-receptors after ethanol incubation was demonstrated with variable amounts of test particles, as well as variable length of the binding assay period. There was no change in viability, morphology or spreading ability of the monocytes after ethanol treatment.

Orthotopic liver transplantation for unresectable hepatoblastoma: a single center's experience.

BACKGROUND/PURPOSE: Complete surgical resection after chemotherapy is the definitive treatment for hepatoblastoma. However, orthotopic liver transplantation (OLT) is now accepted as a treatment modality for patients with unresectable tumours. The aim of this study was to review a single center's experience of OLT for unresectable hepatoblastoma. METHODS: A retrospective review of 8 patients with unresectable hepatoblastoma who were referred for liver transplantation was conducted. RESULTS: The patients assessed had an age range of 5 to 105 months at presentation; median, 24 months, (5 boys; 3 girls). Two patients have familial adenomatous polyposis, and one has right hemihypertrophy. All 8 patients had received standard chemotherapy according to SIOP (International Society of Pediatric Oncology) protocols. Extrahepatic metastases were found in 3 patients at diagnosis, but none had detectable metastases at the time of OLT. Four patients continued chemotherapy while awaiting OLT. Three patients received whole grafts, and 5 received reduced grafts. The median follow-up period was 22 months (range, 2 to 78 months). Five patients are alive and well, although 1 patient had a second OLT for biliary cirrhosis secondary to biliary stricture at 6 years. Three patients died: one 26 days post OLT of sepsis and two of disease recurrence at 22 months and 70 months posttransplant. The actuarial survival rate is 88% and 65% at 1 and 5 years, respectively, whereas the overall survival rate is 62.5%. CONCLUSION: OLT for unresectable hepatoblastoma without extra hepatic metastases is highly successful with a low recurrence rate.

The state of research into children with cancer across Europe: new policies for a new decade.

Overcoming childhood cancers is critically dependent on the state of research. Understanding how, with whom and what the research community is doing with childhood cancers is essential for ensuring the evidence-based policies at national and European level to support children, their families and researchers. As part of the European Union funded EUROCANCERCOMS project to study and integrate cancer communications across Europe, we have carried out new research into the state of research in childhood cancers. We are very grateful for all the support we have received from colleagues in the European paediatric oncology community, and in particular from Edel Fitzgerald and Samira Essiaf from the SIOP Europe office. This report and the evidence-based policies that arise from it come at a important junction for Europe and its Member States. They provide a timely reminder that research into childhood cancers is critical and needs sustainable long-term support.

Anaplastic large cell lymphoma of bone--is it a bad tumor?

A teenage boy presented with a CD30-positive anaplastic large cell lymphoma (ALCL) affecting his scapula and was successfully treated with chemotherapy. His clinical features and outcome were compared with other cases described in the literature. A further review of 11 ALCL cases with bony involvement treated in the UK since 1990, including two with primary bone disease, did not suggest an unfavorable treatment outcome. This finding will need to be confirmed by further study on a larger patient cohort with primary bone ALCL.