Childhood Acute Lymphoblastic Leukemia: Results of the Randomized Acute Lymphoblastic Leukemia Intercontinental-Berlin-Frankfurt-Münster 2009 Trial.

PURPOSE: The International Berlin-Frankfurt-Münster (BFM) study group conducted a study on pediatric acute lymphoblastic leukemia (ALL). Minimal residual disease (MRD) was assessed using flow cytometry (FCM), and the impact of early intensification and methotrexate (MTX) dose on survival was evaluated. PATIENTS AND METHODS: We included 6,187 patients younger than 19 years. MRD by FCM refined the risk group definition previously used in the ALL intercontinental-BFM 2002 study on the basis of age, WBC count, unfavorable genetic aberrations, and treatment response measured morphologically. Patients at intermediate risk (IR) and high risk (HR) were randomly assigned to protocol augmented protocol I phase B (IB) versus IB regimen. MTX doses of 2 versus 5 g/m2 every 2 weeks, four times, were evaluated in precursor B-cell-ALL (pcB-ALL) IR. RESULTS: The 5-year event-free survival (EFS ± SE) and overall survival (OS ± SE) rates were 75.2% ± 0.6% and 82.6% ± 0.5%, respectively. Their values in risk groups were standard risk (n = 624), 90.7% ± 1.4% and 94.7% ± 1.1%; IR (n = 4,111), 77.9% ± 0.7% and 85.7% ± 0.6%; and HR (n = 1,452), 60.8% ± 1.5% and 68.4% ± 1.4%, respectively. MRD by FCM was available in 82.6% of cases. The 5-year EFS rates in patients randomly assigned to protocol IB (n = 1,669) and augmented IB (n = 1,620) were 73.6% ± 1.2% and 72.8% ± 1.2%, respectively (P = .55), while those in patients receiving MTX doses of 2 g/m2 (n = 1,056) and MTX 5 g/m2 (n = 1,027) were 78.8% ± 1.4% and 78.9% ± 1.4%, respectively (P = .84). CONCLUSION: The MRDs were successfully assessed using FCM. An MTX dose of 2 g/m2 was effective in preventing relapse in non-HR pcB-ALL. Augmented IB showed no advantages over the standard IB.[Media: see text].

Predictive Factors for Gram-negative Versus Gram-positive Bloodstream Infections in Children With Cancer.

BACKGROUND: Identifying potential predictive factors for the type of bacteremia (Gram-negative vs. Gram-positive) in children with cancer would be crucial for the timely selection of the appropriate empiric antibiotic treatment. MATERIALS AND METHODS: Demographic, clinical, and laboratory characteristics of children with cancer and a bacterial bloodstream infection (BSI) (February 1, 2011 to February 28, 2018) in a tertiary pediatric oncology department were retrospectively examined and were correlated with the type of isolated bacteria. RESULTS: Among 224 monomicrobial bacterial BSI episodes, Gram-negative and Gram-positive bacteria were isolated in 110 and 114 episodes, respectively. Gram-negative bacteria were isolated significantly more frequently in girls (Gram-negative/Gram-positive ratio 1.7:1) versus boys (Gram-negative/Gram-positive ratio 0.72:1), P=0.002, in patients with previous BSI episodes (1.4:1) versus those without (0.8:1), P=0.042, and in children with hematologic malignancy (1.3:1) versus those who suffered from solid tumors (0.52:1), P=0.003. Gram-negative BSI episodes were more frequently correlated with a lower count of leukocytes, P=0.009, neutrophils, P=0.009 and platelets, P=0.002, but with significantly higher C-reactive protein (CRP) levels, P=0.049. Female sex, hematologic malignancy, and higher CRP levels remained independent risk factors for Gram-negative BSI in the multivariate analysis. Among neutropenic patients, boys with solid tumors and a recent central venous catheter placement appear to be at increased risk for Gram-positive BSI in the multivariate analysis. CONCLUSIONS: Although Gram-negative and Gram-positive BSIs are close to balance in children with cancer, Gram-negative bacteria are more likely to be isolated in girls, children with hematologic malignancies and those with higher CRP level at admission. In contrast, neutropenic boys with solid tumors and a recently placed central venous catheter may be at increased risk for Gram-positive BSI indicating probably the need for initially adding antibiotics targeting Gram-positive bacteria.

Toxoplasma gondii: How fatal is it in pediatric allogeneic bone marrow transplantation setting?

Toxoplasmosis is a disease of the immunocompetent population. However, cases of toxoplasma infection associated with immunosuppression have been reported, especially the first months after transplantation. Limited data are available about toxoplasma infection, occurring even many months post-transplant in pediatric patients with nonmalignant and malignant diseases. We report the cases of three patients with early and late disseminated toxoplasmosis and review the literature.

A prospective study on the epidemiology and clinical significance of viral respiratory infections among pediatric oncology patients.

Respiratory infections in oncology are both common and potentially severe. However, there is still a gap in the literature, regarding the epidemiology of viral respiratory infections in children with cancer. We prospectively enrolled 224 patients, from September 2012 to August 2015. The cohort included children with hematologic or solid malignancies receiving chemotherapy, or undergoing hemopoietic stem cell transplantation, outpatients/inpatients exhibiting signs/symptoms of febrile/afebrile upper/lower respiratory infection. Viral infection was diagnosed by detection of ≥1 viruses from a sample at time of enrollment, using the CLART® PneumoVir kit (GENOMICA, Spain). Α detailed questionnaire including demographics and medical history was also completed. Samples were processed in batches, results were communicated as soon as they became available. Children recruited in whom no virus was detected composed the no virus detected group. Viral prevalence was 38.4% in children presenting with respiratory illness. A single virus was found in 30.4%, with RSV being the most frequent. Viral coinfections were detected in 8%. Children with viral infection were more likely to be febrile upon enrollment and to present with lower respiratory signs/symptoms. They had longer duration of illness and they were more likely to receive antibiotics/antifungals. Only 22% of children with influenza received oseltamivir. Mortality was low (2.7%), however, pediatric intensive care unit (PICU) admission and death were correlated with virus detection. In our study mortality was low and PICU admission was related to virus identification. Further research is needed to clarify whether antibiotics in virus-proven infection are of value and underline the importance of oseltamivir's timely administration in influenza.

BCL2L12 improves risk stratification and prediction of BFM-chemotherapy response in childhood acute lymphoblastic leukemia.

Background Risk-adjusted treatment has led to outstanding improvements of the remission and survival rates of childhood acute lymphoblastic leukemia (ALL). Nevertheless, overtreatment-related toxicity and resistance to therapy have not been fully prevented. In the present study, we evaluated for the first time the clinical impact of the apoptosis-related BCL2L12 gene in prognosis and risk stratification of BFM-treated childhood ALL. Methods Bone marrow specimens were obtained from childhood ALL patients upon disease diagnosis and the end-of-induction (EoI; day 33) of the BFM protocol, as well as from control children. Following total RNA extraction and reverse transcription, BCL2L12 expression levels were determined by qPCR. Patients' cytogenetics, immunophenotyping and minimal residual disease (MRD) evaluation were performed according to the international guidelines. Results BCL2L12 expression was significantly increased in childhood ALL and correlated with higher BCL2/BAX expression ratio and favorable disease markers. More importantly, BCL2L12 expression was associated with disease remission, while the reduced BCL2L12 expression was able to predict patients' poor response to BFM therapy, in terms of M2-M3 response and MRD≥0.1% on day 15. The survival analysis confirmed the significantly higher risk of the BFM-treated patients underexpressing BCL2L12 at disease diagnosis for early relapse and worse survival. Lastly, evaluation of BCL2L12 expression clearly strengthened the prognostic value of the established disease prognostic markers, leading to superior prediction of patients' outcome and improved specificity of BFM risk stratification. Conclusions The expression levels of the apoptosis-related BCL2L12 predict response to treatment and survival outcome of childhood ALL patients receiving BFM chemotherapy.

Immune response to influenza vaccination in children with cancer.

The aim of this study was to evaluate the ability of influenza immunization to evoke a protective immune response among children with cancer. We evaluated 75 children with cancer who received influenza vaccination. Hemagglutination Inhibition Antibody titers were determined before and after vaccination. The protective rates after vaccination were 79% for H1N1, 75% for H3N2 and 59% for influenza B virus whereas the seroconversion rates were 54%, 44% and 43% respectively. The differences pre- and post-vaccination were significant regardless the method which was used: seroprotection changes, seroconversion and geometric mean titers analyses. Variables such as the pre-vaccination antibody titers, the time when the responses were measured after the vaccination, the age and the type of malignancy as well as the absolute lymphocyte count were found to be correlated with the immune response but the findings were different for each vaccine subunit. In conclusion, influenza vaccination provides protection in a remarkable proportion of pediatric cancer patients whereas this protection is more obvious against H1N1 and H3N2 compared to influenza B. The immune response after vaccination is significant and seems to be influenced by a variety of factors.

Voriconazole Antifungal Prophylaxis in Children With Malignancies: A Nationwide Study.

BACKGROUND: Antifungal prophylaxis (AFP) is recommended in at-risk hematology-oncology patients. We evaluated the safety of AFP with voriconazole (VRC) in pediatric hematology/oncology patients. MATERIALS AND METHODS: A retrospective study of VRC AFP in children with malignancies hospitalized in all 7 Greek pediatric hematology/oncology centers during 2008 to 2012 was conducted. Patients' demographics, outcome, and adverse event (AE) data were recorded. RESULTS: Four hundred twenty-nine VRC AFP courses in 249 patients (median age 6 y, 55% boys) were studied. The most common underlying diseases were acute lymphoblastic leukemia (51%), non Hodgkin lymphoma (8.6%), and acute myeloid leukemia (7.7%). The median number of VRC courses per patient was 1.7, whereas the median VRC dose was 7 mg/kg (range, 5 to 7 mg/kg) every 12 hours. During the last 2 weeks before AFP, 51% of the patients had received corticosteroids, 43% suffered from severe neutropenia, and 17.3% from mucositis. The median duration of VRC AFP was 17 days (range, 1 to 31 d). A single breakthrough fungemia due to Candida glabrata was recorded. Only 1 patient died due to the underlying disease. The most common AEs reported in 70/429 (16.3%) courses with ≥1 AE were elevated liver enzymes (50%), hypokalemia (24.3%), and ophthalmological disorders (14.3%). The median time of AE onset was 5 days (range, 1 to 21 d). Among 70 AEs reported, 38.5%, 48.4%, and 12.8% were of grade I, II, and III, respectively. CONCLUSIONS: VRC prophylaxis in pediatric hematology/oncology patients appears to be well tolerated.

Multifocal Aeromonas Osteomyelitis in a Child with Leukemia.

Aeromonas hydrophila is a Gram negative organism causing both intestinal and extraintestinal disease. The case of a 14-year-old girl with underlying immunodeficiency and leukemia who developed systemic A. hydrophila infection is described in this report. While in deep bone marrow aplasia she developed fever, severe pain in the lower extremities, and swelling of the left femur. Blood culture showed Escherichia coli and A. hydrophila whereas pus culture from the soft tissue swelling showed the presence of A. hydrophila. Imaging studies showed diffuse osteolytic lesions. Patient received 5 months of intravenous and oral antibiotics and she improved clinically whereas the radiology findings persisted.

Optic pathway glioma in children: 10 years of experience in a single institution.

Optic pathway glioma (OPG) is a rare brain tumor that occurs more commonly during early childhood and is frequently associated with neurofibromatosis type 1 (NF1). In this study, our aim was to describe the characteristics, management, and outcome of patients with OPG. We retrospectively analyzed the clinical charts of all children diagnosed with OPG at our institution from 2003 to 2013. Twenty children (11 boys and 9 girls, median age: 5 and 3/12 years; NF1: 15/20) were diagnosed with OPG. The diagnosis was based on magnetic resonance imaging (MRI) findings. A biopsy was useful in 3 patients. The main reason for seeking medical advice was decreased vision (7/20 patients), whereas in 10/20 patients, the diagnosis was established during the routine follow-up for their NF1. Fifteen patients demonstrated MRI findings of optic nerve involvement and/or chiasmal tumor, whereas in 5 children, postchiasmal structures were also involved. Sixteen patients (16/20) received carboplatin-based regimens, whereas 4/20 patients were only under close observation. Six patients showed deterioration of visual acuity and/or imaging findings at the end of treatment and/or during their follow-up. Three of them (3/6) underwent tumor resection, whereas 1 (1/6) received radiation treatment. None of our patients had total blindness from both eyes. Half of our patients were diagnosed during follow-up for their NF1, the incidence of which was high in our group. Our data suggest that chemotherapy helps in the preservation of vision in the majority of children.

Prayer and blessings focused for healing is the most popular complementary intervention in a paediatric oncology unit in Greece.

PURPOSE: Increasing numbers of children with cancer are using complementary and alternative medicine (CAM) therapies. Our aim was to estimate the rate of use, the beliefs of users and non-users and factors related with the use of CAM among Greek families. METHODS: A self-reported questionnaire was given to parents of 184 children with cancer. We assessed the rate of use, types of CAM therapies and factors potentially associated with the use of CAM. RESULTS: Based on the 110 questionnaires which were completed (59.8% of the families), 23 families (21%) had used at least one complementary treatment. The most common forms were: spiritual healing/prayer/blessings 18/23 (78%), art therapies 4, dietary supplements 3, massage 3, homeopathy 2, and herbals 2. The reasons given for use included: making the child stronger 17/23 (48%, hope of stopping the cancerous process 11/23 (49%), and coping with side effects 6/23 (26%). Among the reasons given by the parents for not using CAM therapies the most common (84%) was the effective conventional treatment and, therefore, there was no need for CAM use. Another 24% reported that were unaware of these "alternative" and "complementary" therapies and a further 7% had considered using them but finally they didn't. In bivariate analysis, the use of CAM was not associated either with age, sex, nationality, education or occupation of the parents at the time of the survey, or with diagnosis, mode of therapy or age of the child at diagnosis. CONCLUSIONS: The use of CAM therapies by Greek families for their children with cancer does not appear to be very popular, although the experiences of those who did use them were generally positive.

Overexpression of BCL2 and BAX following BFM induction therapy predicts ch-ALL patients' poor response to treatment and short-term relapse.

PURPOSE: The identification of childhood acute lymphoblastic leukemia (ch-ALL) patients who are at a higher risk of chemotherapy resistance and relapse is essential for successful treatment decisions, despite the application of novel therapies. The aim of the study is the evaluation of BCL2 and BAX expression for the prognosis of ch-ALL patients treated with Berlin-Frankfurt-Münster (BFM) backbone protocol. METHODS: Bone marrow specimens were obtained at the time of diagnosis and on day 33 following BFM treatment induction from 82 ch-ALL patients, as well as from 63 healthy children. Following extraction, total RNA was reverse transcribed and BCL2 and BAX expression levels were determined by qPCR. RESULTS: BCL2 expression and BCL2/BAX ratio were strongly upregulated in ch-ALL compared to healthy children and were correlated with favorable prognostic disease features. Increased levels of BCL2 and BAX expression were associated with disease remission, as ch-ALL patients with lower expression ran a significantly higher risk of M2-M3 response, positive MRD and poor survival outcome. Moreover, the upregulation of BCL2 and BAX following BFM treatment induction was shown to represent an independent predictor of patients' short-term relapse, which was further confirmed in ch-ALL patients with favorable prognostic markers. CONCLUSIONS: In conclusion, BCL2 and BAX could be effectively used for an enhanced prediction of BFM-treated patients' outcome.

Malignant peripheral nerve sheath tumors in children with neurofibromatosis type 1.

Purpose. Malignant peripheral nerve sheath tumors (MPNSTs) are rare in children and account for approximately 5-10% of all soft tissue sarcomas in adults. MPNSTs may occur independently but individuals with neurofibromatosis type 1 (NF1) have a significantly increased risk. Our aim is to present patients with MPNST treated in our department. Cases and Results. In this report we present 4 cases of MPNSTs (3 females: 13, 12, and 13 years old and 1 male: 10 years old) arising in patients with NF1. All of them presented with an enlarging mass and pain at diagnosis. Tumor was located in the buttock, the spinal cord, the trunk, and the left leg proximal to the heel. Wide excision of the tumor and radiotherapy were applied to all and adjuvant chemotherapy was given to three of them after the disease was progressed. All four died 32, 18, 10, and 22 months after diagnosis with progressive disease locally and pulmonary metastases in two of them. Conclusions. In conclusion, MPNSTs arising in patients with NF1 are high grade sarcomas with short survival. Individuals with NF1 should be followed closely in order to identify early the development of MPNSTs. Aggressive surgery and complete excision significantly improves disease-free survival. The usefulness of radiation therapy in MPNSTs is not determined although all patients will receive radiation therapy at some stage of the disease. The role of chemotherapy is unclear.

A novel karyotype in acute myeloid leukemia with basophilia.

Acute basophilic leukemia is a distinct entity of Acute Myeloid Leukemia (AML) with primary differentiation to basophils. Increased basophil count has been described in AML cases with translocation t(6;9)(p23;q34) or other chromosomal abnormalities. We describe a 15-year old female teenager with AML and excess peripheral blood and bone marrow basophils. Her white blood cell count at diagnosis was 15.4 G/L with 53% basophils and 17% blasts. The bone marrow cytogenetics analysis did not reveal any of the usual abnormalities. The karyotype showed two closely related leukemic clones: the first (16 metaphases), with a total of 48 chromosomes, had an extra chromosome 8 with deletion of the long arm and an additional 21 (48,XX, +del(8)(q24.2q24.3), t21[16]), while the second clone (2 metaphases), with a total of 47 chromosomes, did not contain the extra 21 chromosome (47, sl, -21[2]). In summary, in this case of AML-M2 with excess basophils, there is a novel chromosomal abnormality, not previously reported in this entity.

Detection of acquired hemoglobinopathy in children with hematological malignancies at disease onset: results form a national referral centre.

Abnormal hemoglobin synthesis is usually inherited but may also arise as a secondary manifestation of a hematological neoplasia. The objective of this study is to identify the presence of acquired hemoglobinopathy in children diagnosed with hematological malignancies and compare these against healthy controls. Prospective matched case-control study held from 2010 to 2012. For each patient with hematological malignancy two healthy controls matched on gender, age and race were recruited. Patients with other co-morbidities were excluded. All samples underwent supravital staining and high-performance liquid chromatography (HPLC) electrophoresis. Following identification of abnormal results, molecular genetic testing for all α- and ß-thalassemia mutations prevalent in the Greek population was performed. Other causes of anemia were ruled out based on specific testing. A total of 44 (32 males) patients with a mean age of 7.1 years were enrolled in the study. Hematological disorders included acute lymphocytic leukemia (24), acute myeloid leukemia (8), non-Hodgkin lymphoma (8), Hodgkin disease (3), and Langerhans cell histiocytosis (1). Following exclusion of congenital hemoglobinopathies, atypical HPLC electrophoretic findings persisted in 18.1 % of the patient group, compared to 0 % in the control group (p < 0.001). The patient group showed marked microcytic anemia (p < 0.01) and detection of small inclusions (p = 0.034) on supravital staining. Comparison of the HPLC findings between the groups demonstrated significantly lower percentages of HbA (p = 0.02), normal HbA2 and higher percentage of fast moving Hb bands (p = 0.04) in the patient group. Interestingly, the majority of these patients belonged to the high-risk group. Acquired hemoglobinopathy is recognized in adult patients. This is a novel study describing evidence of abnormal erythropoiesis in children with hematological malignancies and in particular those classified as high-risk cancer patients according to international criteria.

Differences between younger and older patients with childhood hodgkin lymphoma.

From 1979 to 2006, 74 children with Hodgkin's lymphoma were treated at our center. Among them, 15 (14 boys and 1 girl) and 59 (33 boys and 26 girls) patients were younger and older than 8 years, respectively. Six (40%) children among younger patients and 26 (44%) among older patients had advanced stage disease. We detected 3 (20%) relapses among younger patients and 5 (8.5%) among the older patients. All of younger patients are alive whereas three of the older patients have died. Second malignancy developed in one and three children among younger and older patients, respectively. The only difference that was detected concerning the age was a male predominance among the younger patients.

Successful treatment in a child with anaplastic large cell lymphoma and coexistence of pulmonary tuberculosis.

A 13-year-old girl was admitted to our department with a history of severe pain of her left axilla and fever. On physical examination, a block of lymph nodes in her left axilla, diffuse papular rash, and red-violet swelling of her supraclavicular and subclavian region were noted. Imaging investigations revealed left axillar and supraclavicular lymphadenopathy and a small nodular shade in the upper lobe of her left lung. A biopsy from an axillary lymph node established the diagnosis of anaplastic large cell lymphoma (ALCL), whereas DNA of Mycobacterium tuberculosis was detected by polymerase chain reaction (PCR) in the same tissue biopsy. Patient was started on chemotherapy for ALCL and achieved remission of all initially involved fields. Nevertheless, two new nodular lesions were detected in the left lower lobe. Biopsy revealed granulomas, and PCR was positive for M. tuberculosis. Our patient received treatment with the combination of isoniazid and rifampin (12 months), pyrazinamide (the first 2 months), and maintenance chemotherapy for her ALCL for one year simultaneously. Four years later, she is disease free for both mycobacterial infection and lymphoma. We are reporting this successful management of mycobacterial infection in a patient with ALCL despite intensive chemotherapy that the patient received at the same time.

Compliance with immunization against H1N1 influenza virus among children with cancer.

In this report, we describe the experience with immunization against pandemic influenza A H1N1 in children with cancer treated at a pediatric oncology department during the pandemic season (2009). According to the guidelines, vaccination of all children with cancer receiving chemotherapy as well as those who had completed treatment was scheduled. Among the 140 children who were eligible for immunization, 122 were immunized, achieving a compliance rate of 87% despite negative publicity and low vaccine uptake in the general population. The vaccine was tolerated and none of the vaccinated children developed influenza. It is concluded that high immunization rates can be achieved among pediatric oncology patients.

Acute megakaryoblastic leukemia with increased hematogones in children.

We describe 2 patients, a 4-month-old male and a 17-month-old female, with de novo acute megakaryoblastic leukemia with increased number of hematogones at diagnosis. Both children were admitted in the hospital with thrombocytopenia. The bone marrow smears in the first child revealed the presence of 60% cells with morphologic features consistent with acute megakaryoblastic leukemia. In the other, the initial bone marrow aspirate was dry tap but on the following aspirate 10% cells with lymphoblastic morphology could be seen. The bone marrow flow cytometry showed the presence of hematogones-38% in the first case and 20% in the second-with absence of blasts. Repeated bone marrow aspirates, trephines, and immunophenotypic as well as molecular studies, confirmed the diagnosis of M7. Both children were treated according to the Berlin-Frankfurt-Munster 2004 protocol.

Psychological problems in children with cancer in the initial period of treatment.

BACKGROUND: The increasing survival rate of children with cancer because of more refined treatments makes necessary the investigation of psychological burden for the young patients. OBJECTIVE: The aim of the study was to evaluate the development of psychological problems in children with cancer during the initial 6-month period of intensive treatment. METHODS: This prospective, comparative study was conducted at one of the largest Greek pediatric oncology units in Athens. The sample comprised 132 children with cancer treated during a 30-month period and 100 children with no cancer as control group. Data were collected using the Rutter instruments for parents and teachers. For patients, it was completed by their parents at 1 (T1), 3 (T2), and 6 months (T3) from diagnosis and by teachers at T3. In the control group, the questionnaire was completed by teachers and parents once. RESULTS: The comparison of total Rutter scores for patients at T1, T2, and T3, according to parents' responses, showed statistically significant difference (P < .001). The difference in scores for patients (at T3) and control subjects was also significant according to both parents' (P < .00001) and teachers' (P < .001) responses. Children with leukemia had higher score reduction during treatment (P = .009) compared with the rest. Only age had a marginal impact on score of patients at T1 (R = 0.04). CONCLUSIONS: Based on parental reports, children treated for cancer develop psychological problems during the period of intensive treatment. The development and evolution of these problems depend on their age and type of cancer. IMPLICATIONS FOR PRACTICE: This information can be used for relevant interventions in specific groups.