Validation of variants in SLC28A3 and UGT1A6 as genetic markers predictive of anthracycline-induced cardiotoxicity in children.

BACKGROUND: The use of anthracyclines as effective antineoplastic drugs is limited by the occurrence of cardiotoxicity. Multiple genetic variants predictive of anthracycline-induced cardiotoxicity (ACT) in children were recently identified. The current study was aimed to assess replication of these findings in an independent cohort of children. PROCEDURE: . Twenty-three variants were tested for association with ACT in an independent cohort of 218 patients. Predictive models including genetic and clinical risk factors were constructed in the original cohort and assessed in the current replication cohort. RESULTS: . We confirmed the association of rs17863783 in UGT1A6 and ACT in the replication cohort (P = 0.0062, odds ratio (OR) 7.98). Additional evidence for association of rs7853758 (P = 0.058, OR 0.46) and rs885004 (P = 0.058, OR 0.42) in SLC28A3 was found (combined P = 1.6 × 10(-5) and P = 3.0 × 10(-5), respectively). A previously constructed prediction model did not significantly improve risk prediction in the replication cohort over clinical factors alone. However, an improved prediction model constructed using replicated genetic variants as well as clinical factors discriminated significantly better between cases and controls than clinical factors alone in both original (AUC 0.77 vs. 0.68, P = 0.0031) and replication cohort (AUC 0.77 vs. 0.69, P = 0.060). CONCLUSIONS: . We validated genetic variants in two genes predictive of ACT in an independent cohort. A prediction model combining replicated genetic variants as well as clinical risk factors might be able to identify high- and low-risk patients who could benefit from alternative treatment options.

Familial bone marrow monosomy 7. Evidence that the predisposing locus is not on the long arm of chromosome 7.

Loss of expression of a tumor-suppressing gene is an attractive model to explain the cytogenetic and epidemiologic features of cases of myelodysplasia and acute myelogenous leukemia (AML) associated with bone marrow monosomy 7 or partial deletion of the long arm (7q-). We used probes from within the breakpoint region on 7q-chromosomes (7q22-34) that detect restriction fragment length polymorphisms (RFLPs) to investigate three families in which two siblings developed myelodysplasia with monosomy 7. In the first family, probes from the proximal part of this region identified DNA derived from the same maternal chromosome in both leukemias. The RFLPs in these siblings diverged at the more distal J3.11 marker due to a mitotic recombination in one patient, a result that suggested a critical region on 7q proximal to probe J3.11. Detailed RFLP mapping of the implicated region was then performed in two additional unrelated pairs of affected siblings. In these families, DNA derived from different parental chromosome 7s was retained in the leukemic bone marrows of the siblings. We conclude that the familial predisposition to myelodysplasia is not located within a consistently deleted segment on the long arm of chromosome 7. These data provide evidence implicating multiple genetic events in the pathogenesis of myelodysplasia seen in association with bone marrow monosomy 7 or 7q-.

Importance of nutrition in pediatric oncology.

A nutritional perspective within pediatric oncology is usually just related to the supportive care aspect during the management of the underlying malignancy. However, nutrition has a far more fundamental importance with respect to a growing, developing child who has cancer as well as viewing cancer from a nutritional cancer control perspective. Nutrition is relevant to all components of cancer control including prevention, epidemiology, biology, treatment, supportive care, rehabilitation, and survivorship. This article briefly describes this perspective of nutrition within a cancer control context and is a summary of the presentation at the "1st International SIOP-PODC Workshop on Nutrition in Children with Cancer" held in Mumbai.

Rationale and recommendations for the irradiation of blood products.

Blood products are often irradiated to prevent proliferation of lymphocytes which could cause graft-vs.-host disease in immunocompromised recipients. The effects of irradiation on the function of blood components is discussed. It is concluded that 1500 rad is sufficient to prevent lymphocyte proliferation and production of graft-vs.-host disease in vivo, although 10 to 20% of lymphocytes are still capable of proliferation in vitro after 1500 rad. Neutrophils and erythrocytes are extremely radioresistant and their function is unaffected by 1500 rad. There is limited data to suggest that platelet yields may be slightly reduced following irradiation. Guidelines for the use of irradiated blood products are suggested.

Primary hemochromatosis in children: report of three newly diagnosed cases and review of the pediatric literature.

Hereditary hemochromatosis was diagnosed in three asymptomatic siblings following the unexpected finding of elevated serum iron concentrations. This diagnosis was confirmed by hepatic biopsy. Repeated phlebotomies resulted in a significant decline of serum iron and ferritin concentrations and a decrease of hepatic iron content. This report and a review of the literature indicate that the diagnosis of hereditary hemochromatosis must be considered more frequently in childhood. Organ dysfunction from iron overload may be minimized in children by the early commencement of regular phlebotomy.

Myelodysplasia and leukemia syndrome with monosomy 7: a genetic perspective.

Acquired monosomy 7 is a frequent finding in myelodysplastic syndromes, including acute myelogenous leukemia. A subset of these patients has been described with an apparently distinct condition: myelodysplasia and leukemia syndrome with monosomy 7 (MLSM7). We report 2 brothers, 3 and 5 years of age, with MLSM7 and review other reports of familial occurrence. Genetic factors appear to be important in the cause of MLSM7, but the reported families do not fit neatly into any monogenic pattern. Recognition of the frequently familial nature of this condition requires hematological evaluation and genetic counseling for the families of patients with MLSM7.

The effect of desmopressin acetate (DDAVP) on postoperative blood loss after cardiac operations in children.

We investigated the effect of an intraoperative desmopressin acetate infusion on blood loss after cardiac operation in 60 children, by using a prospective, randomized, double-blind trial. Thirty patients received a desmopressin dose of 0.3 microgram/kg intravenously over 15 minutes at the conclusion of cardiac bypass, and 30 received a saline placebo. The two groups were comparable with respect to age, sex, cardiac lesion, presence of cyanosis, and prevalence of Down's syndrome. Results showed no significant difference in postoperative blood loss between the two groups (30.5 +/- 37.9 ml/kg in the placebo group versus 40.0 +/- 33.1 ml/kg in the desmopressin group). Postoperative bleeding time, total urine output, postinfusion hemodynamics, and postoperative coagulation studies did not differ significantly between the two groups. We conclude that postbypass desmopressin infusion does not reduce blood loss in children undergoing cardiac operations.

Allogeneic bone marrow transplantation for an adolescent with polycythemia vera.

Polycythemia vera is a rare clonal disorder of the bone marrow haematopoietic stem cell. We present the case of an adolescent female with polycythemia vera, who was treated with a curative HLA-matched allogeneic bone marrow transplant.

Breast metastases after bone marrow transplantation for rhabdomyosarcoma.

Two adolescent females with metastatic alveolar rhabdomyosarcoma underwent intensive chemoradiotherapy and bone marrow transplantation, one autologous and one allogeneic. Recurrence was detected in the breasts of both patients, the first at autopsy and the other as the only site of treatment failure. Breast masses after bone marrow transplantation should be thoroughly investigated for metastatic disease in patients with rhabdomyosarcoma.

Thalidomide in the management of chronic graft-versus-host disease in children following bone marrow transplantation.

Chronic graft-versus-host disease (GVHD) is the major complication in patients surviving > 100 days post-allogeneic bone marrow transplantation and occurs in 30% of pediatric patients. It is most prevalent 1-2 years post-transplant. Treatment involves corticosteroids and other immunosuppressive therapy which may affect growth and increase the likelihood of infectious complications. We report five children with severe corticosteroid-dependent chronic GVHD treated with thalidomide 12-25 mg/kg/day. Response to therapy was based on resolution of symptoms of chronic GVHD and withdrawal of other immunosuppressive therapy. All the children showed clinical response to thalidomide with cessation or diminution in other immunosuppressive medication. Side-effects were minimal and no patient developed peripheral neuropathy. All patients are alive 48-65 months post-transplantation. Thalidomide is a safe and effective drug for the treatment of chronic GVHD in children and may avoid the use of long-term corticosteroid therapy.

Acute aluminum toxicity after continuous intravesical alum irrigation for hemorrhagic cystitis.

An encephalopathy and cardiomyopathy developed in a seventeen-year-old girl with chemotherapy-induced renal failure while receiving an intravesical aluminum infusion for hemorrhagic cystitis. Premortem serum and postmortem tissue aluminum levels were markedly elevated. It is likely that her inability to excrete absorbed aluminum contributed to her death. Aluminum infusions should be used with caution in patients with renal failure.

Beta 2-microglobulin levels in cerebrospinal fluid of children with leukemia and lymphoma.

Beta 2-microglobulin levels were determined in the cerebrospinal fluid (CSF) of 119 children (ages 1 1/2 to 18 years) with malignant conditions; 87 with acute lymphoblastic leukemia, 9 with acute myeloblastic leukemia, 15 with lymphoma, and 8 with solid tumours. A total of 491 CSF specimens and 202 serum specimens were analyzed over a 12-month period. The mean CSF beta 2-microglobulin and serum beta 2-microglobulin were 1.11 +/- 0.58 mg/L and 1.5 +/- 0.64 mg/L respectively and were not different from the mean CSF (1.20 +/- 0.45 mg/L) and serum beta 2-microglobulin levels (1.70 +/- 0.45 mg/L) found in control patients. Meningeal leukemia was diagnosed on the basis of cytology in 7 patients. No elevation of CSF beta 2-microglobulin was found in any specimen at the time of CNS disease. Eleven other patients showed a transient rise in CSF beta 2-microglobulin above the reference range (greater than 2.1 mg/L). No evidence of CNS involvement was found in any of these patients. Five of these patients had received a combination of intrathecal methotrexate and irradiation therapy within the previous 4 months. A transient rise in CSF beta 2-microglobulin (2-3-fold increase over baseline CSF levels), which did not exceed the upper limit of the reference range was seen in 5 of 7 other children receiving the above therapy. Our study fails to demonstrate the usefulness of CSF beta 2-microglobulin for the diagnosis of CNS metastases but suggests that a transient elevation of CSF beta 2-microglobulin may occur after intrathecal methotrexate and irradiation therapy.

An international survey of nutritional practices in low- and middle-income countries: a report from the International Society of Pediatric Oncology (SIOP) PODC Nutrition Working Group.

BACKGROUND/OBJECTIVES: Optimal nutritional status is important in children with cancer, as it can influence clinical outcomes. To improve the nutritional health of children and adolescents receiving treatment for cancer residing in low income and middle-income countries (LMIC), we investigated nutrition practices among these nations' institutions providing treatment for childhood cancer. SUBJECT/METHODS: A cross-sectional survey of nutrition practice was administered to staff members at institutions providing treatment for children with cancer between 2011 and 2012. Countries classified as low income and middle income were divided by geographical region. Final analysis was performed with 96 surveys, which included 27 institutions from Asia, 27 institutions from Latin America and Caribbean, 27 institutions from Africa and 15 institutions from Europe. RESULTS: The study found that 55% of institutions had a dietician available on their service. Access to dieticians, lack of nutrition resources and lack of nutrition education of staff were the main barriers to providing nutrition care in LMIC. Half of the institutions performed nutritional assessment at diagnosis, and the methods used varied widely. Twenty-nine percent of all institutions used complementary and alternate therapies within their clinical practice, and 35% of institutions reported that nutrition education was provided to patients and families. CONCLUSIONS: Priority areas for improving the nutritional management in LMIC include the following: (1) improved nutrition education and assessment tools for doctors and nurses; (2) increased availability of nutrition education resources for families and patients; and (3) identification of the role of complementary and alternative therapies in closing gaps in symptom management in these institutions.

Importance of nutrition in pediatric oncology.

A nutritional perspective within pediatric oncology is usually just related to the supportive care aspect during the management of the underlying malignancy. However, nutrition has a far more fundamental importance with respect to a growing, developing child who has cancer as well as viewing cancer from a nutritional cancer control perspective. Nutrition is relevant to all components of cancer control including prevention, epidemiology, biology, treatment, supportive care, rehabilitation, and survivorship. This article briefly describes this perspective of nutrition within a cancer control context and is a summary of the presentation at the “1st International SIOP‑PODC Workshop on Nutrition in Children with Cancer” held in Mumbai.

Immunocytochemical evidence for an axonal localization of GABA in the optic nerves of rabbits, rats, and cats.

We have examined, by light-microscopic immunocytochemistry, the distribution of GABA in the optic nerves of adult rabbits, rats, and cats. Within the optic nerves, immunoreactivity for GABA was restricted to a small subset of axons; some axons were strongly labelled, others weakly labelled, whilst most axons were unlabelled. Glia and other non-neuronal elements were always unlabelled. Our ability to detect GABA in optic nerve axons of adult mammals contrasts with previous reports that indicate a lack of GABA immunoreactivity in such axons. We suggest that this discrepancy may be due to the sensitivity of our immunocytochemical techniques which enable us to detect low concentrations of GABA.

Auditory and ophthalmological findings in children with acute lymphoblastic leukemia.

The audiological and ophthalmological function in 59 children in continuous complete remission for at least 2 years since the completion of therapy for acute lymphoblastic leukemia was evaluated. Three of 42 tested had abnormal hearing assessments, but none was attributed to the leukemia or its treatment. Four of 54 patients had visual abnormalities: 3 had mild refractive errors and 1 patient had mild subcapsular cataracts consistent with steroid-induced cataracts. We conclude that as the frequency of visual and hearing impairment in these patients is low, it is not necessary to perform audiological or ophthalmological assessment during routine follow-up unless clinically indicated.

Low-dose fibrinolytic therapy in infants.

We describe three pediatric patients in whom locally infused streptokinase at a dose of 50 U/kg/hr was used successfully to treat thrombosis in a major artery, a major vein, and a systemic-to-pulmonary arterial graft. Complications, including hemorrhage and distal embolization, were minimized by careful monitoring of the coagulation status of the blood and by avoiding rapid infusions. Selective thrombolytic therapy appears to be as effective in infants as in adults. Because the dose required is reduced, the incidence of complications is lower than with systemic infusions.

Possible effects of growth hormone on development of acute lymphoblastic leukaemia.

Growth hormone (G.H.) or a G.H.-dependent somatomedin may be involved in the process of acute lymphoblastic leukaemia (A.L.L.). Growth hormone has a trophic effect on lymphoid tissue and also specific receptors on lymphocytes, most probably T cells. Hypophycess. Resting concentrations of G.H. and somatomedin activity are raised in some children with A.L.L. and may be reduced after remission is achieved. It is suggested that control of G.H. and/or somatomedin concentrations may be necessary for adequate treatment of some cases of A.L.L. in children.

Urogenital rhabdomyosarcoma in childhood.

Recent advances in chemotherapy and radiotherapy have improved the prognosis of urogenital rhabdomyosarcoma. Preliminary reports suggest that a mutilative operation may no longer be essential to cure this disease.