Favorable outcome in children and adolescents with a high proportion of advanced phase disease using single/multiple autologous or matched/mismatched allogeneic stem cell transplantations.

We determined the indication, outcome, and risk factors of single and multiple hematopoietic stem cell transplantation(s) (HSCT) in children and adolescents mostly with advanced disease. Forty-one out of 483 patients (8.5 %; median age 9 years) diagnosed at the University of Leipzig with hematological and oncological diseases required HSCT from 1999 to 2011. Patients had overall survival (OS) of 63 ± 10 and 63 ± 16 %, event-free survival (EFS) of 57 ± 10 and 42 ± 16 %, relapse incidence (RI) of 39 ± 10 and 44 ± 18 % and nonrelapse mortality (NRM) of 4 ± 4 and 13 ± 9 % at 10 years after one or more allogeneic and autologous HSCT, respectively. One patient in CR1 and five with advanced disease received two HSCT. Four of the six patients maintained/achieved CR for a median of 13 months. Three died of progression and one of NRM. Two patients had a third HSCT and one survived in CR +231 days after HSCT. Risk factors for OS and EFS were disease stage at HSCT and EBMT risk score. Center (pediatric or JACIE accredited pediatric/adult) was not a determinant for survival. Pediatric single and multiple HSCT are important curative approaches for high-risk malignant diseases with low NRM. Efforts to reduce high RI remain the major aim.

Allo-SCT using BU, CY and melphalan for children with AML in second CR.

Based on the results from the AML-BFM 98 trial, hematopoietic SCT (HSCT) is recommended for children with AML in second CR only. Here, we retrospectively analyze interphase data of children who underwent HSCT after myeloablative conditioning with BU, CY, and melphalan (BuCyMel) for AML in second remission (CR2) between 1998 and 2009. Out of 152 children, transplant data were available on 109 individuals. Sixty out of 109 children (55%) received BuCyMel. Median age at HSCT was 12.2 years (range 3.0; 18.3). GVHD prophylaxis mostly consisted of CsA and short term MTX with or without antithymocyte globulin. Matched-sibling donors were used for 6/60 analyzed recipients, the remainder either received grafts from matched unrelated (30/60) or mismatched donors. OS after 5 years was 62% (s.e. 6%), relapse incidence 35% (18/60 children) and treatment-related mortality accounted for 12% (7/60) of fatal events. In conclusion, even taking into account possible selection bias in this retrospective analysis, HSCT in CR2 using BuCyMel resulted in a respectable OS. Based on this data the prospective, controlled and centrally monitored AML SCT-BFM 2007 trial has started to recruit patients in January 2010 aiming to generate valid outcome data for further strategy decisions.

Long-term follow-up of children conditioned with Treosulfan: German and Austrian experience.

We report the long-term follow-up of children transplanted with Treosulfan (TREO)-based conditioning in Germany and Austria. Nine centres reported a total of 109 transplantations. Patients were stratified according to the paediatric TRM risk score derived from the paediatric BMT registry (PRST) and compared with the historical transplant population of this registry. Underlying diseases were malignancies, immunodeficiencies, and haematologic and metabolic disorders. TREO total dose ranged from 21-42 g/m(2). Additional conditioning drugs included fludarabine, thiotepa, melphalan, CY and/or TBI. EFS at 3 years for non-malignant and malignant diseases was 88% and 49%, respectively. Leukaemia patients in remission had a survival of 51% at 3 years; nonremission patients relapsed and died within 18 months. TRM and OS in the low-risk groups 0 and 1 were similar to PRST controls. TRM in the high-risk groups 2 and 3 was markedly lower (9% vs 28% and 13% vs 53%, respectively) than in the PRST group, but OS was similar. In conclusion, TREO-based conditioning regimens in children resulted in excellent engraftment and long-term survival in nonmalignant disease. In high-risk malignancy, low acute toxicity was followed by low TRM but it did not translate into increased survival.

Systemic sarcoidosis after cardiac transplantation in a 9-year-old child.

Sarcoidosis is a granulomatous disease of unknown etiology and is only rarely seen in infants and children. We present the case of a 9-year-old boy who developed sarcoidosis with multi-organ involvement 9 years after cardiac transplantation for Shone complex. The patient was on immunosuppressive therapy with tacrolimus and mycophenolate mofetil. He presented with severe respiratory distress due to marked mediastinal lymphadenopathy and bilateral pulmonary infiltrates in association with fatigue, low-grade fever, hepatosplenomegaly and generalized lymphadenopathy. Lymph node histology showed non-caseating epitheloid cell granulomas and giant cells. Initialization of therapy with prednisolone resulted in prompt clinical recovery and resolution of all symptoms except for the development of mild pulmonary fibrosis. Tapering of the steroids led to recurrence of mediastinal lymphadenopathy 5 months after the initial disease, which responded to an increase in steroid dose. The clinical course, the medical management, and the possible role of immunosuppression in the etiology of the disease are discussed.

Incidence of tumor lysis syndrome in children with advanced stage Burkitt's lymphoma/leukemia before and after introduction of prophylactic use of urate oxidase.

To evaluate the clinical benefit of the prophylactic use of urate oxidase in children with non-Hodgkin's lymphoma (NHL), we analyzed the incidence and complications of tumor lysis syndrome (TLS) in children with B-cell acute lymphoblastic leukemia (B-ALL) or stage III/IV Burkitt's lymphoma and a lactate dehydrogenase (LDH) level > or =500 U/l before and after the introduction of a protocol amendment to use urate oxidase for the prophylaxis of TLS. Data from 1791 children with NHL enrolled in the two subsequent multicenter studies NHL-BFM 90 and 95 were evaluated. The presence of the side effects TLS, anuria, sepsis, and other complications during the first 2 weeks after admission were registered. Until March 1996, no urate oxidase was used (period 1). From November 1997 all children with B-ALL or stage III and IV B-NHL and LDH > or =500 U/l should receive urate oxidase prophylactically (period 3). In between (period 2), urate oxidase was given in a minority of hospitals therapeutically. Initial chemotherapy was identical. Altogether, 78 children (4.4%) developed a TLS. Patients with B-ALL had the highest risk to develop a TLS (26.4%) followed by B-ALL/Burkitt's lymphoma and a LDH > or =500 U/l (14.9%). In period 1, 16.1% and 9.2% of the latter children developed a TLS or anuria, respectively, compared to 12.3% and 6.2% in period 3 ( p=NS). The incidence of sepsis remained unchanged (5.0% vs 4.6%). In children with B-ALL the differences in the incidence of TLS and anuria between period 3 and period 1 were more pronounced, reaching significance for anuria (15.4% vs 3.8%, p=0.03). Our results suggest that patients with the highest risk to develop a TLS might benefit from the prophylactic use of urate oxidase.

[Familial Mediterranean fever]. / Familiäres Mittelmeerfieber.

BACKGROUND: Familial Mediterranean fever (FMF) is characterized by febrile attacks, acute abdominal pain, pleuritis or arthritis and predominantly observed in ethnic groups of the Mediterranean area (Sephardic Jews, Turks, Armenians). Its most ominous manifestation is amyloidosis potentially leading to chronic renal failure. FMF is an inherited disorder caused by mutations of the FMF-gene, which first was described in 1997. CASE REPORT: We report a 10-year old turkish boy and his family presenting with an increased blood sedimentation rate (WBC) and recurrent attacks of acute abdominal pain. A molecular analysis was carried out, confirming a typical mutation of the FMF-gene. The patient remained free of symptoms after starting therapy with colchicine. CONCLUSION: Investigation of the FMF gene enables an early diagnosis in case of clinical suspect findings, subsequent colchicine administration may prevent amyloidosis.

[Hereditary fructose intolerance (HFI) as cause of isolated gamma GT rise in a 5-year old boy with hepatomegaly]. / Hereditäre Fruktoseintoleranz (HFI) als Ursache einer isolierten gamma GT-Erhöhung bei einem 5-jährigen Jungen mit Hepatomegalie.

The diagnosis of HFI is easily missed during childhood. It should be suspected in children presenting with hepatomegaly and an isolated increase in GGT. A carefully taken nutritional history forms the basis of the diagnosis of HFI which can be confirmed by molecular analysis with a sensitivity of > 95%. I.v. fructose tolerance tests and liver biopsies often can be omitted.

Mercury intoxication presenting with hypertension and tachycardia.

An 11 year old girl presented with hypertension and tachycardia. Excess urinary catecholamine excretion suggested phaeochromocytoma but imaging studies failed to demonstrate a tumour. Other symptoms included insomnia and weight loss, and she was found to have a raised concentration of mercury in blood and urine. Mercury intoxication should be considered in the differential diagnosis of hypertension with tachycardia even in patients presenting without the skin lesions typical of mercury intoxication and without a history of exposure.

Influence of induction of HSP70 on the cytotoxicity of oxazaphosphorine compounds and cisplatin.

Induction of HSP70 and thermotolerance may also decrease the cytotoxicity of cytostatic agents or their combination with hyperthermia in clinically used thermochemotherapy. HSP70 and thermotolerance were induced by hyperthermia (42 degrees C, 1 h) in two human tumor cell lines in vitro and in vivo. The influence of thermotolerance on the cytotoxicity of CDDP and the oxazaphosphorine compounds Mafo and Ifo and their combination with hyperthermia (42 degrees C or 43 degrees C, 1 h) were studied. The results show that neither thermotolerance nor HSP70 affects the tumor cell sensitivity to CDDP or oxazaphosphorine compounds. However, the additive effect of hyperthermia and CDDP was found to be attenuated in thermotolerant cells. The cytotoxicity of oxazaphosphorine compounds combined with hyperthermia was not altered after preheating, suggesting a different mechanism may be responsible for the drug-hyperthermia interaction of CDDP and oxazaphosphorine compounds. There were no differences between in vitro and in vivo results suggesting mechanisms at the cellular level being responsible for the influence of thermotolerance on drug- and drug-hyperthermia action.

Effects of Cisplatin and mafosfamide on the interphase microtubular cytoskeleton of a human breast-cancer cell-line, mx-1, in-vitro - a fine-structure and antitubulin immunofluorescence study.

Modem therapy of solid tumors involves drugs such as cisplatin (CDDP) and mafosfamide (MAFO) that interact with the DNA. Hyperthermia facilitates the effectiveness of these drugs for the management of aggressive metastatic tumors. To evaluate the extent of cellular damage caused by anti-tumor drugs under hyperthermic conditions, we have examined the microtubular cytoskeleton in a human breast cancer line, MX-1, at two different temperatures: 37 and 42 degrees C. A mouse monoclonal antibody to beta-tubulin and a rabbit polyclonal antibody to gamma-tubulin were used in combination with indirect immunofluorescence. The former antibody stains the entire microtubular cytoskeleton, whereas the latter antibody detects microtubule-organizing centres. Untreated cells possessed a rich interphase cytoskeleton. The antibody against gamma-tubulin detected one to two distinct spots in mononucleate cells and a cluster of spots in multinucleate cells. Microtubules were usually not focused towards the gamma-tubulin-containing material. At 42 degrees C more cells were damaged when compared with cells treated at 37 degrees C. The drug effects were, however, highly variable. There were cells that appeared unaffected by a single treatment while other cells had almost completely lost their microtubules. Concomitantly, gamma-tubulin-containing clumps had formed in the highly damaged cells. Electron microscopy of ultrathin sections revealed a range of structural changes of cytoplasmic components including mitochondrial defects after CDDP treatment.

Effects of temperature on the therapeutic efficacy and pharmacokinetics of ifosfamide.

The influence of tumor temperature (28, 32, 37, 39, 41, or 43 degrees C for 1 h) on the therapeutic efficacy of i.v. single bolus injections of ifosfamide (IFO) (32, 65, 125, or 250 mg/kg body weight) in human tumor xenografts (MX1 breast carcinoma) grown in nude mice (n = 240) was studied. Tumor temperature was controlled by water bath immersion. Sixty days after treatment the percentage of tumor-free survival was determined. For example, at 37 degrees C IFO in a dose of 65 mg/kg body weight led to 10% tumor-free survival in the treated animals. At 43 degrees C the same dose resulted in 60% tumor-free survival. A clear drug dose- and temperature-dependent increase of the therapeutic efficacy of an active oxazaphosphorine compound was also demonstrated in vitro. The concentrations of IFO and of 4-hydroxyifosfamide in blood and tumors at different body temperatures (controlled by water bath immersion) were determined over 120 min and WBC counts were obtained. The half-lives and the areas under the curve for IFO in blood were not significantly different at 37 degrees C and 41 degrees C. Since the half-life of IFO depends mainly on hepatic metabolism, the similarity of half-lives and of areas under the curve for IFO at 37 degrees C and 41 degrees C indicates a constant activation rate. However, significantly lower plasma concentrations of the activated drug at a liver (body) temperature of 41 degrees C, compared with 37 degrees C, were found, indicating a higher elimination rate. The concentration of the activated drug in the tumors within the initial 60 min at 41 degrees C, however, exceeded by > 2-fold that at 37 degrees C. The bone marrow toxicity of the same drug dose did not significantly increase with body temperature.

[Enlarged iliopsoas bursa. A rare cause of inguinal mass]. / Forstøorret bursa iliopsoatica. Sjelden årsak til kul i lysken.

Bursa iliopsoatica is a well-defined anatomical structure lying under the corresponding muscle on the pelvis and hip joint. If it becomes large, it can be an uncommon cause of an inguinal mass with symptoms from compressed neighbour structures. An enlarged bursa can be associated with arthritis and arthrosis of the hip. We describe a patient with an inguinal tumour, with radicular pain, and discuss the diagnostic approach, pathogenesis and treatment.