Treatment with caspofungin in immunocompromised paediatric patients: a multicentre survey

OBJECTIVES: Although a paediatric dosage has not been established, caspofungin is occasionally used in paediatric patients. We conducted a multicentre retrospective survey to obtain data on immunocompromised paediatric patients considered to require caspofungin therapy. METHODS: The survey identified 64 patients (median age: 11.5 years; 25 females, 39 males) with haematological malignancies (48), marrow failure (9), solid tumours (3), haematological disorders (2) and congenital immunodeficiency (2) who received caspofungin for proven (17), probable (14) and possible (17) invasive fungal infections or empirically (16). Caspofungin was administered until intolerance or maximum efficacy at dosages individually determined by the responsible physician for refractory infection (38), intolerance of other agents (10) or as best therapeutic option (16). RESULTS: The 64 patients received caspofungin for a median of 37 days (range 3-218) as single agent (20) or in combination (44). The median daily maintenance dosage was 1.07 mg/kg (95% CI 1.09-1.35; range 0.40-2.92) or 34.3 mg/m2 (95% CI 32.3-37.3; range 16.3-57.5). In none of the patients was therapy discontinued due to adverse events (AEs). Clinical AEs were mild to moderate and observed in 34 patients (53.1%). While mean glutamate pyruvate transaminase and glutamate oxalate transaminase values were slightly (P < 0.005) higher at the end of treatment (EOT), serum bilirubin, alkaline phosphatase and creatinine values were not different from baseline. Complete responses, partial responses or stabilization were observed in 5/7/3 of 17 patients with proven, in 3/4/3 of 14 patients with probable and in 7/6/1 of 15 evaluable patients with possible invasive infections. Thirteen of 16 patients on empirical therapy completed without breakthrough infection. Overall survival was 75% at the EOT and 70% at 3 months post-EOT, respectively. CONCLUSIONS: Caspofungin displayed favourable safety and tolerance and may have useful antifungal efficacy in severely immunocompromised paediatric patients.     

Binding kinetics of 123I[ADAM] in healthy controls: a selective SERT radioligand

[123I]ADAM (2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine) is a promising radioligand for in-vivo quantification of serotonin transporters (SERT) using single photon emission computed tomography (SPECT) in man. We performed tracer kinetic analysis in various brain regions to determine the optimum equilibrium time for SERT quantification with [123I]ADAM and SPECT. Radiosyntheses of [123I]ADAM were performed at MAP Medical Technologies Oy, Tikkakoski, Finland. Thirty healthy male volunteers (21-41 yr) received between 104 and 163 MBq [123I]ADAM intravenously as a bolus. Consecutively, multiple SPECT scans were performed between 14 and 420 min post-injection (p.i.) using a Siemens Multispect 3 camera. Reconstruction was performed applying filtered back projection with a Butterworth filter (cut-off 0.7, order 7) in 128x128 matrices. Regions of interest (ROI) were drawn manually on the individual T1-weighted magnetic resonance image (MRI) comprising midbrain/hypothalamus for specific binding to SERT, and the cerebellum as reference region. After re-orientation to the MRI, the ROI template was applied to SPECT studies. We generated time-activity curves for the ROI and calculated the ratio countstarget/countscerebellum minus 1 (=V3') as a measure for specific SERT binding. Counts were corrected for applied activity, acquisition time and body-weight. Peak uptakes were observed between 14 and 50 min after bolus injection. Counts per voxel were highest in the midbrain/hypothalamus, 798 (max. 872, min. 728), whereas 462 counts per voxel (max. 599, min. 412) were measured in the cerebellum at a mean time of 31 min p.i. Stable values for V3' reached 205-320 min p.i. Mean peak V3' value was 1.43 (95% CI 171-230) for the midbrain/hypothalamus at 205 min p.i. [123I]ADAM is a useful ligand for in-vivo quantification of human SERT by means of SPECT, with a comparatively better signal-to-noise ratio compared to beta-CIT. Our data suggest that the acquisition time for the SPECT scan is optimally, under pseudo-equilibrium conditions, between 205-320 min post-bolus injection of the tracer.     

Alopecia areata and multifocal bone involvement in a young adult with Hodgkin's disease

A 17-year-old girl presented with a 3 month history of alopecia areata, a generalized scaling skin, enlargement of the inguinal lymph nodes and severe back pain. Staging procedures revealed multifocal bone disease and generalized lymphadenopathy. The diagnosis of nodular sclerosing Hodgkin's disease was established by biopsies of the os ileum and a left inguinal lymph node. Complete clinical remission was achieved after 2 OPPA (vincristine, prednisone, procarbazine, and doxorubicin) and 4 COPP (cyclophosphamide, vincristine, prednisone, and procarbazine) cycles and treatment completed with involved-field irradiation. After the completion of therapy, skeletal lesions had mostly resolved or become sclerotic and the patient had normal hair regrowth and skin appearance. Conclusively, this case illustrates that alopecia areata may occur as a paraneoplastic phenomenon or an autoimmune process related to the deranged cellular immune system in children and adolescents with Hodgkin's disease.     

Mixed lineage leukemia-rearranged childhood pro-B and CD10-negative pre-B acute lymphoblastic leukemia constitute a distinct clinical entity.

PURPOSE: Mixed lineage leukemia (MLL) abnormalities occur in approximately 50% of childhood pro-B acute lymphoblastic leukemia (ALL). However, the incidence and type of MLL rearrangements have not been determined in common ALL (cALL) and CD10+ or CD10- pre-B ALL. EXPERIMENTAL DESIGN: To address this question, we analyzed 29 patients with pro-B ALL, 11 patients with CD10- pre-B ALL, 23 pre-B, and 26 cALL patients with CD10 on 20% to 80%, as well as 136 pre-B and 143 cALL patients with CD10 > or = 80% of blasts. They were all enrolled in four Austrian ALL multicenter trials. Conventional cytogenetics were done to detect 11q23 abnormalities and in parallel the potential involvement of the MLL gene was evaluated with a split apart fluorescence in situ hybridization probe set. RESULTS: We found that 15 of 29 pro-B ALL, 7 of 11 CD10- pre-B ALL, and 1 of 2 French-American-British classification L1 mature B-cell leukemia cases had a MLL rearrangement. However, no 11q23/MLL translocation was identified among the CD10+ pre-B and cALL patients. MLL-rearranged pro-B and CD10- pre-B ALL cases had similar clinical and immunophenotypic (coexpression of CDw65 and CD15) features at initial diagnosis. CONCLUSIONS: The striking similarities between the two CD10- ALL subsets imply that CD10- pre-B ALL variants may represent pro-B ALL cases that maintained the propensity to rearrange and express their immunoglobulin heavy chain rather than actual pre-B ALL forms transformed at this later stage of B-cell differentiation. However, direct experimental data are needed to confirm this observation.     

Neuroblastoma cells provoke Schwann cell proliferation in vitro

BACKGROUND: A subset of human neuroblastomas (NBs) has the capacity to mature completely, imitating sympathetic ganglia. Previously, we showed that the neuronal population in spontaneously maturing NBs usually has a near-triploid DNA content without 1p deletions, and we concluded that the constantly diploid Schwann cells (SCs) do not belong to the neoplastic component of these tumours. We therefore hypothesised that NB cells are able to stimulate SC proliferation, and that SCs trigger NB differentiation. PROCEDURE: We performed in vitro experiments to test this model and to test whether SCs can also influence the growth of aggressive NBs. Human SCs were co-cultivated with NB tumours and cell lines, and were harvested after defined time intervals. Proliferative activity of the SCs and the NB cells was determined by visualisation of 5-bromo-2'-deoxyuridine (BrdU) incorporation or Ki-67 staining. Neurite outgrowth and neurofilament (NF) expression were analysed immunocytochemically and apoptotic rate was determined by a terminal deoxynucleotidyl transferase-mediated dUTP-X fluorescein nick end labelling (TUNEL) assay. RESULTS: Human NB tumours or cell lines unequivocally increased the proliferation of SCs in vitro. In cocultivated NB cells, the proliferative activity was not altered in the first days of cocultivation, although neurite outgrowth and NF expression were enhanced. However, after 10 days, the mitotic rate of neuroblastic cells decreased and the apoptotic rate showed a marked increase. CONCLUSIONS: The results of the cocultivation experiments provide an experimental hint that the in vivo growth of SCs in NBs is caused by the neoplastic neuroblasts, and they also indicate that cells from peripheral nerves can influence the growth of aggressive NB cells if cocultivated.     

Mediastinal mass in childhood T-cell acute lymphoblastic leukemia: significance and therapy response

BACKGROUND: T-cell acute lymphoblastic leukemia (T-ALL) accounts for approximately 10-13% of childhood ALL cases. Patients with T-ALL frequently present with unfavorable features at diagnosis and thus are considered to have a higher risk to relapse. Within the last 10 years, the previously dismal prognosis of this ALL subtype has been improved by intensified chemotherapy. However, 30-40% of patients still relapse, so that additional prognostic factors such as the local response of the mediastinal mass to therapy might allow defining the patients at risk in a better manner. PROCEDURE: A retrospective analysis of 116 Austrian patients with T-ALL was performed to assess whether an initial mediastinal mass (70/116) and its response to chemotherapy as measured by thoracic X-rays (32/70) might predict outcome. RESULTS: Neither patients with a mediastinal tumor at the time of diagnosis nor patients with an incomplete response on day 35 or 70 of therapy had a worse prognosis, as compared with the group of patients with no initial tumor and complete regression on day 35 and 70. CONCLUSIONS: We failed to show that in children with T-ALL residual mediastinal tumors are of prognostic relevance. This might suggest that incomplete local response is not necessarily an indication for treatment intensification such as local irradiation, second-look operation, or high-dose chemotherapy with bone marrow rescue. However, due to the relatively small number of patients analyzed, our results have to be validated prospectively on a larger cohort of patients in future clinical trials.     

Rothia mucilaginosa bacteremia: A 10‐year experience of a pediatric tertiary care cancer center

Rothia mucilaginosa is part of the oral and upper respiratory tract flora. Usually, this gram‐positive coccus is not pathogenic; however, in the setting of immunosuppressed hosts, it can cause life‐threatening infections as an opportunistic pathogen. Among a cohort of 1511 hematologic‐oncologic patients at a pediatric tertiary care cancer center, we identified five cancer patients (0.35%) within a period of 10 years having a proven Rothia mucilaginosa bacteremia (1 culture positive: n = 3/5; > 1 culture positive: n = 2/5). With prompt and adequate antibiotic treatment, infection resolved rapidly before recovery of neutrophils and without any sequelae, suggesting that Rothia mucilaginosa bacteremia without organ involvement is not exceptionally problematic in pediatric cancer patients.     

Malignant non-Hodgkin's lymphoma of childhood and adolescence in Austria--therapy results between 1986 and 2000

Between 1986 and 2000 183 Austrian children and adolescents with non-Hodgkin's lymphoma (NHL) and mature B-cell acute leukemia (B-ALL) were enrolled in 3 consecutive studies of the Berlin-Frankfurt-Münster (BFM) Group. In trial NHL-BFM 86, patients were stratified according to the histologic subtype and clinical stage. In the succeeding studies NHL-BFM 90 and 95, treatment stratification was additionally based on the speed of tumor response to therapy and for children with B-cell NHL/B-ALL also on the pre-therapeutic serum lactic dehydrogenase level. Event-free survival rates were 84% +/- 6% in trial NHL-BFM 86 (n = 39) and 86% +/- 4% in both trials NHL-BFM 90 (n = 67) and NHL-BFM 95 (n = 77). Patients with lymphoblastic lymphoma (mainly with T-cell phenotypes) had an excellent prognosis with an ALL-type chemotherapy regimen (n = 49; relapse, n = 1), whereas an intensive, short-pulse therapy delivered within a 2- to 4-month period was found to be highly efficacious in children with B-cell NHL/B-ALL (n = 114; relapse, n = 6; progression, n = 5). Patients with anaplastic large cell lymphoma (ALCL) who were treated with similar alternating short courses of multi-agent chemotherapy had a less good outcome (n = 20; relapse, n = 6, progression, n = 3). Children with B-cell NHL and B-ALL who failed initial therapy also had a dismal prognosis (10/11 patients died). Local radiotherapy as a part of lymphoma therapy was completely abandoned in study NHL-BFM 90 and surgical interventions were confined to specific situations such as complete resection in localized B-cell NHL and ALCL, diagnostic biopsy and second-look operation. In conclusion, our results showed that the BFM treatment strategy for lymphoblastic lymphoma and B-cell NHL/B-ALL was highly successful in the majority of patients; however, optimal treatment for children with ALCL has not yet been defined. As a consequence, larger trials at an international level are necessary to find new prognostic markers that might define more precisely those patients who need further intensification of first-line treatment or novel therapy.     

Antibiotic prophylaxis with teicoplanin on alternate days reduces rate of viridans sepsis and febrile neutropenia in pediatric patients with acute myeloid leukemia

Intensive chemotherapy directed against acute myeloid leukemia of childhood is followed by profound neutropenia and high risk for bacterial and fungal infections, including viridans group streptococci as a common cause for gram-positive septicemia. Few retrospective studies have shown the efficacy of various antibiotic prophylactic regimens in children. We retrospectively studied 50 pediatric patients treated on the AML-BFM 2004 protocol between 2005 and 2015 at St. Anna Children’s Hospital and assessed the effect of antibiotic prophylaxis on the frequency of febrile neutropenia and bacterial sepsis. Fifty pediatric patients underwent 199 evaluable chemotherapy cycles. Viridans sepsis occurred after none of 98 cycles with prophylactic administration of teicoplanin/vancomycin in comparison to 12 cases of viridans sepsis among 79 cycles without systemic antibacterial prophylaxis (0 vs. 15 %, p?<?0.0001). In addition, there were significantly fewer episodes of febrile neutropenia in the teicoplanin/vancomycin group (44 % vs. no prophylaxis 82 %, p?<?0.0001). Severity of infection seemed to be worse when no antibiotic prophylaxis had been administered with a higher rate of intensive care unit treatment (0/98, 0 %, vs. 4/79, 5 %, p?=?0.038). So far, no increase of vancomycin-resistant enterococcus isolates in surveillance cultures was noticed. Antibiotic prophylaxis with teicoplanin (or vancomycin) appears safe and feasible and resulted in eradication of viridans sepsis and decreased incidence of febrile neutropenia in pediatric AML patients. The possibility to administer teicoplanin on alternate days on an outpatient basis or at home could contribute to patient’s quality of life and decrease health care costs.     

Early and reliable diagnosis of non-Hodgkin lymphoma in childhood and adolescence: contribution of cytomorphology and flow cytometric immunophenotyping

Non-Hodgkin lymphoma (NHL) represents one of the most rapidly growing malignancies in childhood and adolescence. About 80% of patients now are cured with adequate treatment. Serious complications at presentation due to tumor lysis syndrome or local tumor effects are commonly observed. Thus, a rapid diagnosis with the least invasive procedure enabling the initiation of early and specific therapy is necessary to diminish early fatality or persistent impairment. In 56 centrally registered patients with NHL, cytomorphologic analyses (FAB criteria) of May-Grünwald-Giemsa-stained touch imprints or malignant effusions and flow cytometric immunophenotyping (EGIL criteria) of fresh cell suspensions with a standardized panel of monoclonal antibodies were performed. The authors identified 23 patients with Burkitt lymphoma by the combination of FAB L3 morphology and a mature B-cell phenotype and 22 patients with lymphoblastic lymphoma by FAB L1/L2 morphology and a T-/B-cell precursor phenotype. They also found 11 patients with large cell lymphomas, 3 of them with anaplastic large cell lymphoma (T-cell phenotype; NPM/ALK-positive). In the remaining 8 patients diffuse large B-cell lymphoma was suspected by the combined use of cytologic and immunophenotypic findings (mature B-cell phenotype). In all cases with available solid tumor material (n = 42/56) the preliminary diagnosis was confirmed by histopathology. Burkitt lymphoma, lymphoblastic lymphoma, and, in a few cases, some large cell lymphomas could be classified reliably by cytomorphology and immunophenotyping of freshly obtained tumor cell material, enabling an early start of specific lymphoma treatment.