Invasive mucormycosis during treatment for acute lymphoblastic leukaemia-successful management of two life-threatening diseases.

A 5-year-old patient treated for acute lymphoblastic leukaemia (ALL) developed proven pulmonary invasive fungal disease (IFD) due to Actinomucor elegans. While completing ALL treatment according to AIEOP ALL protocol 2009 for further 15 months, antifungal treatment with liposomal amphotericin B and intermittent additional posaconazole was continued until immune reconstitution 7 months after the end of ALL treatment. Repeated imaging guided treatment decisions. Twenty-six and 19 months after the end of ALL treatment and antifungal treatment, respectively, the patient is still in the first complete remission and shows no signs of active invasive fungal disease (IFD).

Primary renal neuroblastoma metastasizing into liver and lungs with tumor thrombus extension into the right atrium.

Neuroblastomas are malignant tumors of the sympathetic nervous system. Areas of manifestation most commonly involve the abdomen, neck, thorax and pelvis. Primary renal neuroblastomas are extremely rare, only a few case reports exist worldwide, and even those are discussed controversially.We present the case of a 6-year-old girl with a renal tumor and a tumor thrombus extending into the right atrium, which radiologically appeared to be a Wilms tumor. Since the lesion did not respond to nephroblastoma-specific therapy, a biopsy from one of the liver metastases was taken, revealing the revised diagnosis of a clear cell renal cell carcinoma. Histopathology of the reference center, however, described a primary renal neuroblastoma. After adjusting the chemotherapy tumornephrectomy including the complete venous thrombus could be performed without any complications.Neuroblastoma originating from a kidney is an absolute rarity that can easily be misdiagnosed as Wilms tumor, especially, if a typical tumor thrombus with extension into the inferior vena cava is seen. Therefore neuronspecific enolase in serum as well as vanillylmandelic acid and homovanillic acid in the urine should be determined in all patients when Wilms tumor is assumed. To the best of our knowledge, this is the first published case of a primary renal neuroblastoma with a tumor thrombus extending into the right atrium.

Incidence and clinical course of radionecrosis in children with brain tumors. A 20-year longitudinal observational study.

Radionecrosis (RN) in children treated for brain tumors represents a potentially severe long-term complication. Its diagnosis is challenging, since magnetic resonance imaging (MRI) cannot clearly discriminate between RN and tumor recurrence. A retrospective single-center study was undertaken to describe the incidence and clinical course of RN in a cohort of 107 children treated with external radiotherapy (RT) for various brain tumors between 1992 and 2012. During a median follow-up of 4.6 years (range 0.29-20.1 years), RN was implied by suspicious MRI findings in in 5 children (4.7 %), 5-131 months after RT. Suspicion was confirmed histologically (1 patient) or substantiated by FDG positron-emission tomography (FDG-PET, 2 patients) or by FDG-PET and MR spectroscopy (1 patient). Before developing RN, all 5 patients had received cytotoxic chemotherapy in addition to RT. In addition to standard treatment protocols, 2 patients had received further chemotherapy for progression or relapse. Median radiation dose expressed as the biologically equivalent total dose applied in 2 Gy fractions (EQD2) was 51.7 Gy (range 51.0-60.0 Gy). At RN onset, 4 children presented with neurological symptoms. Treatment of RN included resection (n = 1), corticosteroids (n = 2) and a combination of corticosteroids, hyperbaric oxygen (HBO) and bevacizumab (n = 1). One patient with asymptomatic RN was not treated. Complete radiological regression of the lesions was observed in all patients. Clinical symptoms normalized in 3 patients, whereas 2 developed permanent severe neurological deficits. RN represents a severe long-term treatment complication in children with brain tumors. The spectrum of clinical presentation is wide; ranging from asymptomatic lesions to progressive neurological deterioration. FDG-PET and MR spectroscopy may be useful for distinguishing between RN and tumor recurrence. Treatment options in patients with symptomatic RN include conservative management (steroids, HBO, bevacizumab) and surgical resection.

Hemophagocytic syndrome in children with acute monoblastic leukemia-another cause of fever of unknown origin.

PURPOSE: Intensification of antileukemic treatment and progress in supportive management have improved the survival rates of children with acute myeloid leukemia (AML). However, morbidity and early mortality in these patients are still very high, especially in children with acute monoblastic leukemia (AML FAB M5). Inflammatory syndromes complicating the management of these children after application of cytosine arabinoside and due to hyperleukocytosis at initial presentation have been reported. Hemophagocytic lymphohistiocytosis (HLH) has been described as a serious and life-threatening acute complication during treatment of different oncologic entities; however, data on HLH in children with AML FAB M5 are extremely rare. METHODS: A retrospective study of all children with AML FAB M5 treated at our institution between 1993 and 2013 was performed to describe the clinical characteristics of patients who developed an inflammatory syndrome with HLH during oncologic treatment. RESULTS: Three of 10 children developed an inflammatory syndrome with fever, elevation of C-reactive protein, hyperferritinemia, elevation of soluble interleukin-2, and hemophagocytosis during prolonged aplasia following the first cycle of chemotherapy not responding to broad-spectrum antibiotics. No infectious agents could be identified; the initial symptoms occurred 17, 18, and 28 days after diagnosis of AML, respectively. The children immediately responded to dexamethasone; however, the same syndrome was observed again after the second cycle of chemotherapy and, in one patient, also after the third cycle. CONCLUSIONS: Treating physicians should be aware of an inflammatory syndrome resembling HLH in children with monoblastic leukemia since this problem might extremely complicate management and supportive care of these children. The co-incidence of monoblastic leukemia with HLH might be explained by cytokines released from the monoblastic leukemic cells themselves.

Fatal EBV infection and variable clinical manifestations in an XLP-1 pedigree - rapid diagnosis of primary immunodeficiencies may save lives.

Two related boys who died from fulminant infectious mononucleosis were diagnosed with X-linked lymphoproliferative disease type 1 (XLP-1). Family screening (n=17) identified 6 female mutation carriers and 2 more XLP-1 patients in whom, despite recurrent infections, agammaglobulinemia, and Hodgkin's Disease, the genetic basis had been unknown; demonstrating that awareness and early genetic testing are crucial to reveal underlying primary immunodeficiencies and improve outcome. Furthermore, XLP should be included routinely in the differential diagnosis of severe hypogammaglobulinemia and/or lymphoma in males.

Granulomatous amebic encephalitis in a child with acute lymphoblastic leukemia successfully treated with multimodal antimicrobial therapy and hyperbaric oxygen.

Acanthamoeba is the causative agent of granulomatous amebic encephalitis, a rare and usually fatal disease. We report a child with acute lymphoblastic leukemia who developed brain abscesses caused by Acanthamoeba during induction therapy. Multimodal antimicrobial chemotherapy and hyperbaric oxygen therapy resulted in complete resolution of symptoms and of pathology as seen by magnetic resonance imaging.

Stem cell transplantation in 6 children with parvovirus B19- induced severe aplastic anaemia or myelodysplastic syndrome.

Parvovirus B19 (PVB19) induced severe aplastic anaemia (SAA) or myelodysplastic syndrome (MDS) is rare, and haematopoietic stem cell transplantation (HSCT) in this condition has not been reported so far. 6 children with SAA (n=4) or MDS (n=2) caused by acute PVB19 infection underwent HSCT under the protection of intravenous immunoglobulines. The 4 children with SAA received matched HLA bone marrow from a sibling (n=3) or peripheral unrelated blood stem cells (n=1). 1 patient had delayed erythrocyte engraftment, whereas 3 patients had an uneventful transplantation course. HSCT in one of the 2 children with MDS was complicated by poor graft function, the other patient engrafted without complications. In conclusion, HSCT in children with PVB19 induced SAA or MDS is feasible, even though some patients may develop delayed engraftment or prolonged poor graft function.

TCERG1L allelic variation is associated with cisplatin-induced hearing loss in childhood cancer, a PanCareLIFE study.

In children with cancer, the heterogeneity in ototoxicity occurrence after similar treatment suggests a role for genetic susceptibility. Using a genome-wide association study (GWAS) approach, we identified a genetic variant in TCERG1L (rs893507) to be associated with hearing loss in 390 non-cranial irradiated, cisplatin-treated children with cancer. These results were replicated in two independent, similarly treated cohorts (n = 192 and 188, respectively) (combined cohort: P = 5.3 × 10-10, OR 3.11, 95% CI 2.2-4.5). Modulating TCERG1L expression in cultured human cells revealed significantly altered cellular responses to cisplatin-induced cytokine secretion and toxicity. These results contribute to insights into the genetic and pathophysiological basis of cisplatin-induced ototoxicity.

Evaluating bleeding severity in children with newly diagnosed immune thrombocytopenia: a pilot study.

BACKGROUND: Childhood immune thrombocytopenia (ITP) is a bleeding disorder characterized by decreased platelet counts. Assessment of the individual bleeding risk during the course of the disease would allow more accurately guiding treatment-related decisions in these patients. PATIENTS AND METHODS: We conducted a pilot study and prospectively evaluated platelet counts and bleeding signs using an established bleeding (Buchanan) score in 30 patients with newly diagnosed ITP at 3 different time points (at diagnosis [TP1], on day 2-3 [TP2], and on day 5-8 [TP3]) during the first week after diagnosis. 15 patients received immune modulatory therapy. RESULTS: Median platelet counts at the 3 different time points were 13, 19, 32×10 (9)/L (untreated patients) and 2, 7, 37×10 (9)/L (treated patients). Corresponding median cumulative bleeding scores were 5, 2, 0 (untreated patients) and 7, 6, 2 (treated patients). Cumulative median bleeding scores and platelet counts were inversely correlated in treated and untreated patients at all 3 time points. Cumulative median bleeding scores significantly decreased in both groups. CONCLUSIONS: Bleeding signs in children with newly diagnosed ITP rapidly improve within one week after diagnosis. Serial grading of bleeding severity seems to be useful to comprehensively assess and monitor the individual bleeding risk in these patients, but has to be evaluated and validated in a larger cohort.

Frequency, clinical and dermoscopic features of benign papillomatous melanocytic naevi (Unna type).

BACKGROUND: Most previous studies on melanocytic naevi have not distinguished between the different types of naevi, except for some studies trying to define atypical naevi. No large, population-based studies on papillomatous or Unna-type melanocytic naevi have been performed. OBJECTIVES: To investigate the dermoscopic and clinical features of papillomatous naevi and to study some of the factors which could potentially influence their development. METHODS: Seven hundred and seven caucasians aged 1-82 years participated in a screening campaign at open-air recreation facilities in Austria. The volunteers underwent a total body examination by experienced dermatologists and answered a questionnaire. Clinical and dermoscopic images of one representative papillomatous naevus per person were taken. RESULTS: Twenty-nine per cent of the volunteers exhibited papillomatous naevi, the highest frequency being found in young adults. No correlation between the frequency of papillomatous naevi and gender, skin type, sunburns, sunbed use or hormonal factors was found. Most lesions were brown papules (median diameter 5.0 mm), located on the trunk. Dermoscopy showed a predominance of homogeneous and globular pattern, multifocal hypo/hyperpigmentation and comma vessels. Of the papillomatous naevi, 9.8% showed suspicious scores with dermoscopic algorithms. CONCLUSIONS: The lack of exogenous influencing factors and the predominance of globular dermoscopic pattern strengthen the hypothesis that papillomatous naevi belong to the same spectrum as small congenital melanocytic naevi. As the role of papillomatous naevi as precursors of melanoma remains unclear and they are frequently not recognized by the patients, one should perform dermoscopy of papillomatous naevi during skin cancer screening.

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.

False positive serum levels of (1-3)-ß-D-Glucan after infusion of intravenous immunoglobulins and time to normalisation.

OBJECTIVES: (1-3)-ß-D-Glucan (BDG) is a marker for invasive fungal diseases (IFD). Administration of intravenous immunoglobulin preparations (IVIG) has been reported to lead to false positive BDG serum levels >80 pg/ml. The aim of the study was to determine the time interval between IVIG infusion and normalisation of BDG serum levels. METHODS: In 22 paediatric haemato-/oncologic patients, we analysed 92 BDG serum levels obtained within 4 weeks after IVIG administration (0.5 to 1 g/kg body weight), correlated them to 54 IVIG episodes and compared them to 76 BDG levels obtained in 29 patients without IVIG administration in the 4 weeks prior to BDG analyses (control group). RESULTS: BDG peak levels within 3 days after IVIG ranged from 21.47 to 660.38 (median 201.4) pg/ml. BDG serum levels at 7, 14 and 21 days (+/-1 day each) after IVIG infusion were significantly higher than BDG serum levels in the control group (p < 0.001 each). By days 7, 14, and 21 (+/-1 day each) after IVIG infusion, BDG serum levels have normalized (<80 pg/ml) in 64.0%, 76.5% and 100%, respectively. CONCLUSIONS: IVIG administration leads to false positive BDG levels in the vast majority of patients. Elevated BDG levels may be detectable for more than two weeks after IVIG administration, while BDG levels normalized within 3 weeks in all patients. Therefore, BDG should not be used to diagnose IFD within three weeks after IVIG administration.

Management of chronic immune thrombocytopenia in children and adolescents: lessons from an Austrian national cross-sectional study of 81 patients.

Chronic immune thrombocytopenia (cITP) is often associated with an underlying predisposition towards autoimmunity, recognition of which is relevant to guide treatment. International recommendations on diagnostic steps and therapeutic measures of cITP in childhood exist. However, due to the low prevalence (1-2/100,000) and a variation of availability of immunological and hematological tests and treatments across pediatric units, we postulated that these guidelines are not uniformly adhered to and that immune dysregulation syndromes remained undiscovered. To delineate the current management of children and adolescents with cITP in Austria, we performed a nationwide cross-sectional study. Between 2011 and 2014, 81 children with cITP were seen at seven centers (median age 8.75 years; range 1-17; female:male ratio 47:34) at 641 visits during 180 patient years after diagnosis of cITP (>12 months ITP duration). Additional diagnoses were noted, most frequently immune or autoimmune disorders, hematologic diseases, or infections (in 37.3%, including Evans syndrome, autoimmune lymphoproliferative syndrome, systemic lupus erythematosus, and Fanconi anemia), or other symptoms like bi- or pancytopenia (n=9), lymphoproliferation or granulomatous inflammation (n = 3). Both decision to treat as well as choice of treatment varied: smaller centers tended to observe more frequently, larger centers applied a pattern of treatment modalities that appeared to depend less on bleeding tendency than on center policy. More than 50% of therapeutic interventions occurred in bleedings scores ≤2 (of 5), suggesting a strong psychosocial intention to treat. Platelet increment upon 479 therapeutic interventions of eight types was evaluated, with multiple treatment approaches being pursued sequentially in refractory patients. These data confirm the hypothesis of heterogeneous diagnostic and therapeutic management of cITP in Austrian children and corroborate the need for (1) a precise panel of parameters to exclude underlying disorders and (2) for biomarkers to predict treatment response.

Non-radiotherapy conditioning with stem cell transplantation from alternative donors in children with refractory severe aplastic anemia.

Conditioning including total body/lymphoid irradiation is widely used to prevent graft rejection in patients with refractory severe aplastic anemia (SAA) undergoing hemopoietic cell transplantation (HCT) from alternative donors and or after graft manipulation. To reduce regimen-related toxicity we transplanted three children with refractory SAA after conditioning with radiotherapy-free regimens. Conditioning included fludarabine 175-180 mg/m2 in all patients. In addition, patient 1 (failing two previous grafts) received thiotepa 10 mg/kg and Campath-1H 60 mg/m2; patient 2 cyclophosphamide 120 mg/kg, thiotepa 15 mg/kg and OKT-3 0.1 mg/kg/day for 4 weeks; and patient 3 cyclophosphamide 120 and ATG 90 mg/kg. Stem cell source was unmanipulated marrow from the same unrelated donor as for the two previous transplantations in patient 1 and CD34+-purified peripheral blood stem cells from an HLA-matched unrelated donor and from the haploidentical mother in patients 2 and 3. Only patient 1 received graft-versus-host disease (GVHD) prophylaxis with cyclosporine A and mycophenolate mofetil. Follow-up is now 30, 51, and 15 months. None of the patients developed GVHD. All patients have normal counts with complete donor chimerism. Fludarabine-based conditioning is powerfully immunosuppressive and may be used for children with refractory SAA undergoing HCT from alternative donors even after rejection following previous HCT.

Screening for neuroblastoma in late infancy by use of EIA (enzyme-linked immunoassay) method: 115000 screened infants in Austria.

The aim of this study was to investigate the feasibility of a neuroblastoma screening programme for children in late infancy, based on collaboration of general paediatricians and practitioners in Austria, using the technique of enzyme-linked immunoassay (EIA) for biochemical analyses. Analysis of catecholamine metabolites in spot urine samples by EIA with high performance liquid chromatography as a backup was undertaken. Austrian infants (median age 8.7 months) were screened. Overall compliance was 30%. The EIA method had a high rate (6.7%) of false-positive results. 28 infants were admitted to hospital. In 15 cases, neuroblastoma was found (four stage 1, five stage 2B, six stage 3). The EIA method can be used for neuroblastoma screening, but requires a backup analytical technique in order to avoid unnecessary hospital admissions. The stage distribution and biological features of neuroblastomas diagnosed by screening at a later age are different from those detected by earlier screening. Screening in late infancy might be of more benefit than early screening.

Unrecognized pulmonary embolism presenting as disseminated intravascular coagulation.

Six patients are described in whom disseminated intravascular coagulation of uncertain cause was found to be due to occult pulmonary embolism. The peripheral blood smear showed thrombocytopenia in all patients and schistocytes in four. Coagulation studies revealed increased levels of fibrinogen/fibrin degradation products (six of six patients), positive results for fibrin monomer (five patients), prolonged thrombin times (four patients), hypofibrinogenemia (three patients), prolonged prothrombin times (two patients), and decreased plasma coagulation factors (two patients). Pulmonary embolism was confirmed by lung scanning or pulmonary angiography. Institution of full-dose heparin therapy was associated with hemostatic and clinical improvement in all patients. The association of disseminated intravascular coagulation with occult pulmonary embolism merits recognition since full-dose heparinization is required for successful therapy.

Hermansky-Pudlak syndrome: a clinicopathologic study.

The Hermansky-Pudlak syndrome is a rare disease characterized by multisystemic involvement. Seven families with the disorder were identified in the Puerto Rican population of one municipal hospital, suggesting that the incidence in the Puerto Rican community is sufficient to warrant both dissemination of information about the disease and further investigation. The present study was an attempt to achieve both of these goals.