Deborah Schiff

Preponderance of Thiopurine S-Methyltransferase Deficiency and Heterozygosity Among Patients Intolerant to Mercaptopurine or Azathioprine

PURPOSE To assess thiopurine S-methyltransferase (TPMT) phenotype and genotype in patients who were intolerant to treatment with mercaptopurine (MP) or azathioprine (AZA), and to evaluate their clinical management. PATIENTS AND METHODS TPMT phenotype and thiopurine metabolism were assessed in all patients referred between 1994 and 1999 for evaluation of excessive toxicity while receiving MP or AZA. TPMT activity was measured by radiochemical analysis, TPMT genotype was determined by mutation-specific polymerase chain reaction restriction fragment length polymorphism analyses for the TPMT*2, *3A, *3B, and *3C alleles, and thiopurine metabolites were measured by high-performance liquid chromatography. RESULTS Of 23 patients evaluated, six had TPMT deficiency (activity < 5 U/mL of packed RBCs [pRBCs]; homozygous mutant), nine had intermediate TPMT activity (5 to 13 U/mL of pRBCs; heterozygotes), and eight had high TPMT activity (> 13.5 U/mL of pRBCs; homozygous wildtype). The 65.2% frequency of TPMT-deficient and heterozygous individuals among these toxic patients is significantly greater than the expected 10% frequency in the general population (P <.001, chi(2)). TPMT phenotype and genotype were concordant in all TPMT-deficient and all homozygous-wildtype patients, whereas five patients with heterozygous phenotypes did not have a TPMT mutation detected. Before thiopurine dosage adjustments, TPMT-deficient patients experienced more frequent hospitalization, more platelet transfusions, and more missed doses of chemotherapy. Hematologic toxicity occurred in more than 90% of patients, whereas hepatotoxicity occurred in six patients (26%). Both patients who presented with only hepatic toxicity had a homozygous-wildtype TPMT phenotype. After adjustment of thiopurine dosages, the TPMT-deficient and heterozygous patients tolerated therapy without acute toxicity. CONCLUSION There is a significant (> six-fold) overrepresentation of TPMT deficiency or heterozygosity among patients developing dose-limiting hematopoietic toxicity from therapy containing thiopurines. However, with appropriate dosage adjustments, TPMT-deficient and heterozygous patients can be treated with thiopurines, without acute dose-limiting toxicity.

Participation in pediatric oncology research protocols: Racial/ethnic, language and age-based disparities

Survival rates in pediatric oncology have improved dramatically, in part due to high patient participation in clinical trials. Although racial/ethnic inequalities in clinical trial participation have been reported in adults, pediatric data and studies comparing participation rates by socio‐demographic characteristics are scarce. The goal of this study was to assess differences in research protocol participation for childhood cancer by age, sex, race/ethnicity, parental language, cancer type, and insurance status.

Chorea, eosinophilia, and lupus anticoagulant associated with acute lymphoblastic leukemia

A child is reported with chorea as the initial presentation of acute lymphoblastic leukemia. Subsequent laboratory studies revealed marked eosinophilia and a lupus anticoagulant. No peripheral or central nervous system lymphoblasts were observed. The chorea, eosinophilia, and lupus anticoagulant all resolved once remission of the acute lymphoblastic leukemia was induced. It is suggested that acute lymphoblastic leukemia be included in the differential diagnosis of chorea and eosinophilia in childhood.

Methemoglobinemia associated with dapsone therapy in a child with pneumonia and chronic immune thrombocytopenic purpura.

This report describes a case of methemoglobinemia in association with dapsone therapy. The patient, an immunocompromised child with chronic immune thrombocytopenic purpura, presented with fever, cough, perioral cyanosis, bilateral lower lobe rales, and low O2 saturation by pulse oximetry (89%). His medications included prednisone and rituximab for chronic immune thrombocytopenic purpura, and dapsone for Pneumocystis carinii pneumonia prophylaxis. Because of his lack of dyspnea and tachypnea, and the temporal association of his perioral cyanosis with the initiation of dapsone therapy, a methemoglobin (MetHb) level was obtained and found to be elevated at 9.6%. The authors discuss the mechanism and treatment of methemoglobinemia secondary to dapsone. They also stress the importance of monitoring for signs and symptoms of methemoglobinemia in immunocompromised patients on dapsone therapy for P. carinii pneumonia prophylaxis.

Temozolomide and radiation for aggressive pediatric central nervous system malignancies.

This study describes the outcomes of children treated with combinations of temozolomide and radiation therapy for various aggressive central nervous system malignancies. Their age at diagnosis ranged from 1 to 15 years. Patients with focal disease were treated with concomitant temozolomide (daily 75 mg/m2) and three-dimensional conformal radiotherapy in a dose that ranged from 50 to 54 Gy, followed by temozolomide (200 mg/m2/d × 5 days/month in three patients, 150 mg/m2 × 5 days/ month in one patient). Patients with disseminated disease were treated with craniospinal radiation (39.6 Gy) before conformal boost. One patient received temozolomide (200 mg/m2 × 5 days/month) before craniospinal radiation, and one patient received temozolomide (daily 95 mg/m2) concomitant with craniospinal radiation and a radiosurgical boost, followed by temozolomide (200 mg/m2 × 5 days/month). Three patients achieved a partial response during treatment, with two of these patients dying of progressive disease after treatment. One patient has no evidence of disease. Three patients achieved stable disease, with one of these patients dying of progressive disease after treatment. Toxicities observed included low-grade neutropenia, thrombocytopenia, and lymphopenia. The combination of temozolomide and radiotherapy appears to be well tolerated in a variety of treatment schemas for aggressive pediatric central nervous system malignancies. This information is of particular use in designing future studies, given the recent positive results in a randomized study examining the use of temozolomide concomitant with radiation in the treatment of adult glioblastoma.

Insulin infusion to treat severe hypertriglyceridemia associated with pegaspargase therapy: a case report.

We describe a pediatric patient with acute leukemia who developed an uncommon but significant metabolic consequence of pegaspargase therapy—severe hypertriglyceridemia (hyperTG). We also relate our experience with continuous insulin infusion treatment for pegaspargase-induced hyperTG. This treatment approach led to a decrease in triglycerides from 4640 mg/dL on admission to 522 mg/dL at discharge 9 days later. Genetic testing revealed that our patient was an apolipoprotein E 3/4 heterozygote. Our review of the literature suggests that apolipoprotein E polymorphism may influence the development of hyperlipidemia in acute lymphoblastic leukemia patients receiving asparaginase therapy and may identify patients at high risk for developing asparaginase-induced hyperTG.

Palliative Ventriculoperitoneal Shunt in a Pediatric Patient with Recurrent Metastatic Medulloblastoma

The authors present a case report of a pediatric patient with recurrent metastatic medulloblastoma who demonstrated significant clinical improvement after placement of a palliative ventriculoperitoneal (VP) shunt. They also review the medical literature that supports palliative surgical management of hydrocephalus and intracranial hypertension (ICH) caused by leptomeningeal (LM) spread of malignancy. The burdens and benefits of an invasive surgical procedure must always be weighed carefully, especially at end-of-life. Yet for some patients with LM spread and ICH, VP shunting may improve their quality of life, although their prognosis remains poor.

Feasibility of Pegylated Interferon in Children and Young Adults With Resected High-Risk Melanoma.

Pegylated interferon α‐2b (IFN α‐2b) improves disease‐free survival in adults with resected stage III melanoma. We conducted a study to determine the feasibility and safety of incorporating pegylated IFN α‐2b as adjuvant therapy in the treatment of children and adolescents with high‐risk melanoma. Pharmacokinetic studies of IFN α‐2b and neuropsychological and quality of life (OL) assessments were performed.

Effects of a unique pediatric hematology–oncology palliative care program on medical decision-making and communication between healthcare providers and families: Results of a supportive care survey

Abstract Purpose The purpose of this study was to evaluate family satisfaction with an embedded pediatric hematology–oncology (Hem-Onc) palliative care program and its decision-making tool (DMT). A secondary aim was to identify factors that play an important role in family medical decision-making. Methods Families were asked to complete a self-administered questionnaire within 4 weeks of participating in a Supportive Care Team (SCT) conference and receiving a DMT. Results Twenty parents or guardians of pediatric Hem-Onc patients participated in the study. All of the patients had approached a major treatment-related change; all of the study participants had attended a SCT medical decision-making conference and received a DMT. The most important considerations to the study participants regarding treatment decisions were their childs quality of life, their childs chance of improving, perception of their childs wishes, and the hospital staffs advice. Of the people and services that were most useful in guiding medical decision-making, 100% reported that nurses, 95% reported physicians, and 90% reported the SCT helped guide treatment decisions. Ninety percent of those surveyed remembered receiving the DMT, found it to be clear and straightforward, and thought that it improved communication between the family and the healthcare providers. Conclusions These findings suggest an embedded pediatric Hem-Onc supportive care program (SCP) and use of a DMT facilitate effective communication between families and healthcare providers, and provide families with adequate decision-making support.

Hereditary Intrinsic Factor Deficiency in Chaldeans

Juvenile vitamin B(12) or cobalamin (Cbl) deficiency is notoriously difficult to explain due to numerous acquired and inherited causes. The consequences of insufficient Cbl are megaloblastic anemia, nutrient malabsorption, and neurological problems. The treatment is straightforward with parenteral Cbl supplementation that resolves most health issues without an urgent need to clarify their cause. Aside from being clinically unsatisfying, failing to elucidate the basis of Cbl deficiency means important information regarding recurrence risk is not available to the individual if the cause is contagious or inherited. Acquired causes have largely disappeared in the Modern World because they were mostly due to parasites or malnutrition. Today, perhaps the most common causes of juvenile Cbl deficiency are Imerslund-Gräsbeck syndrome and inherited intrinsic factor deficiency (IFD). Three genes are involved and genetic testing is complicated and not widely available. We used self-identified ancestry to accelerate and confirm the genetic diagnosis of IFD in three families of Chaldean origin. A founder mutation limited to Chaldeans from Iraq in the intrinsic factor gene GIF was identified as the cause. World events reshape the genetic structure of populations and inherited diseases in many ways. In this case, all the patients were diagnosed in the USA among recent immigrants from a single region. While IFD itself is not restricted to one kind of people, certain mutations are limited in their range but migrations relocate them along with their host population. As a result, self-identified ancestry as a stratifying characteristic should perhaps be considered in diagnostic strategies for rare genetic disorders.