Richard A. Drachtman

Fanconi anemia: myelodysplasia as a predictor of outcome.

The adverse potential of the development of myelodysplastic syndrome (MDS) in Fanconi anemia (FA) was examined in a retrospective study of 41 FA patients who had bone marrow morphology and chromosomes reviewed by a single group. Thirty-three patients had adequate cytogenetic studies, and 16 (48%) had one or more abnormal studies: nine initially, and seven more on follow-up. Cytogenetic clonal variation was frequent, including disappearance of clones, clonal evolution, and appearance of new clones. The estimated five-year survival with a cytogenetic clone is 0.40, compared to 0.94 without a clone. Morphologic myelodysplasia (MDS), independent of a cytogenetic clone, was found in 13/41 patients (32%). The estimated five-year survival with MDS is 0.09, versus 0.92 without MDS. Leukemia developed in three patients whose initial cytogenetic clones prior to leukemia were t(1;18), t(5;22) and monosomy 7; the one with t(1;18) also had MDS. Our results focus on marrow morphology, and suggest that morphologic MDS may be more important than classical cytogenetics in prediction of an adverse outcome.

Dextromethorphan is effective in the treatment of subacute methotrexate neurotoxicity

Methotrexate-induced neurotoxicity (MTX-Ntox) is a frequent complication of methotrexate (MTX) therapy for patients with both malignant and inflammatory diseases. MTX-Ntox can occur after intrathecal MTX or afterlow-, intermediate-, or high-dose systemic administration. Symptoms can present in the acute, subacute, or late setting form, and can range from affective disorders, malaise, and headaches, to somnolence, focal neurologic deficits, and seizures. While the pathogenesis of MTX-Ntox is likely multifactorial, one potential biochemical pathway leading from MTX to neurotoxicity involves the folate dependent remethylation of homocysteine (Hcy). MTX therapy is known to cause elevations of both plasma and CSF Hcy. Hcy is directly toxic to vascular endothelium and it and its metabolites are excitatory agonists of the N -methyl-D-aspartate (NMDA) receptor. Competitive or noncompetitive antagonists might afford protection from or reversal of MTX-Ntox. Using high-performance liquid chromatography (HPLC) with coulometric electrochemical detection, the authors measured CSF Hcy in sequential patients with severe subacute MTX-Ntox. CSF Hcy was higher in these patients ( n = 9, median = 0.93 w M) than in asymptomatic patients ( n = 11, median 0.2 w M, p < .01). Five patients with severe subacute MTX-Ntox (most with dysarthria and/or hemiplegia) were treated with 1-2 mg/kg oral dextromethorphan (DM), a noncompetitive antagonist of the N -methyl-D-aspartate (NMDA) receptor. All five had resolution of symptoms. These data provide additional clinical support for elevated CSF Hcy in the induction of MTX-Ntox through activation of the NMDA-receptor. These data provide support for a placebo-controlled clinical trial to examine the ability of DM to prevent or alleviate MTX-Ntox.

Low Molecular Weight Heparin in the Treatment of Venous and Arterial Thromboses in the Premature Infant

Objective. Thrombosis in the preterm newborn is a growing problem, a result of improved survival of the smallest and sickest infants. Treatment with low molecular weight heparin (LMWH) has potential advantages, including predictable pharmacokinetics, subcutaneous administration, and minimal monitoring. However, studies with LMWH in term infants demonstrate the need for higher doses as compared with older children and adults. Physiologic differences suggest the need for gestational age–appropriate treatment strategies. Because of the relatively small numbers of infants affected each year, large-scale prospective studies have not been feasible. With the goal of establishing treatment guidelines within our own institution, we reviewed retrospectively our experience with LMWH for the treatment of thrombosis in the preterm infant. Methods. Medical and pharmacy records of the intensive care nursery were used to identify preterm infants with venous and arterial thrombosis. Chart documentation, orders, pharmacy records, and radiologic studies were used to develop a retrospective database to assess efficacy and safety of the treatment. Main outcome measures were the dose of LMWH required for therapeutic levels, anti-factor Xa levels achieved, bleeding complications, resolution of thrombosis, additional thromboembolic events, and death from all causes. Results. Ten preterm infants (mean gestational age: 26 weeks) who were treated with LMWH were identified. Mean patient weight at diagnosis of thrombosis was 1215 g (range: 565–1950 g). All 10 patients had either a current or recent history of a central venous or arterial catheter. Mean starting dose of enoxaparin was 1.25 mg/kg per 12 hours (range: 0.8–2 mg/kg). Therapeutic anti-factor Xa levels were achieved in only 5 patients. Mean time to therapeutic range was 33 days (range: 14–63 days). The mean dose of enoxaparin required to achieve therapeutic levels was 2.27 mg/kg per 12 hours (dose range: 2.0–3.5 mg/kg per 12 hours). Clot resolution was observed in all but 2 patients, both of whom died of complications of their thromboembolic events. No bleeding events that necessitated a change in treatment strategy occurred. Conclusions. Higher doses of LMWH are required in the preterm infant as compared with the healthy term neonate. Once therapeutic levels are achieved, continued regular monitoring and dose adjustments are required to maintain anticoagulation in therapeutic range.

Dyskeratosis congenita : clinical and genetic heterogeneity : report of a new case and review of the literature

Dyskeratosis congenita (DC) is a rare form of ectodermal dysplasia consisting of dystrophic nails, hyperpigmentation, and leukoplakia often associated with aplastic anemia. DC is considered to be an X-linked recessive trait, but affected females suggest genetic heterogeneity. We report an additional female with DC and review the world literature, indicating transmission in X-linked recessive, autosomal recessive, and autosomal dominant manners. The clinical and genetic aspects of DC are heterogeneous, and different patterns of inheritance are associated with distinct clinical manifestations. DC should be considered in the diagnosis of a patient with any features of the syndrome regardless of gender. Conversely, DC should be considered in patients with aplastic anemia at any age.

Phase II Study of Weekly Gemcitabine and Vinorelbine for Children With Recurrent or Refractory Hodgkin's Disease: A Children's Oncology Group Report

PURPOSE The Childrens Oncology Group conducted this phase II study to assess the efficacy and toxicity of gemcitabine and vinorelbine (GV) in pediatric patients with heavily pretreated relapsed/refractory Hodgkins disease. Both agents have significant single-agent response rates in this setting. METHODS GV was given on days 1 and 8 of each 21-day treatment cycle: vinorelbine 25 mg/m(2)/dose administered via intravenous (IV) push before gemcitabine 1,000 mg/m(2)/dose IV over 100 minutes. Any patients who demonstrated a measurable response (complete response [CR], very good partial response [VGPR], or partial response [PR]) were considered to have experienced a response to GV. Response was evaluated after every two cycles. A two-stage minimax rule was used to test the null hypothesis that the response rate is <or= 40% against an alternative hypothesis of a response rate more than 65%. RESULTS Thirty eligible patients with a median age of 17.7 years (range, 10.7 to 29.4 years) were enrolled. All patients had received at least two prior chemotherapy regimens, and 17 patients had undergone prior autologous stem-cell transplantation. Hematologic toxicity was predominant in all treatment cycles. Nonhematologic grade 3 to 4 toxicity, including elevated hepatic enzymes and hyperbilirubinemia, was less common. Pericardial and pleural effusions developed in one patient after cycles 4 and 5 of GV, consistent with gemcitabine-induced radiation recall. There were no toxic deaths. Measurable responses were seen in 19 (76%) of 25 assessable patients (95% exact binomial CI, 55% to 91%), including six CRs, 11 VGPRs, and two PRs. CONCLUSION GV is an effective and well-tolerated reinduction regimen for children with relapsed or refractory Hodgkins disease.

Upfront window trial of topotecan in previously untreated children and adolescents with poor prognosis metastatic osteosarcoma children's cancer group (CCG) 7943

Patients with metastatic osteosarcoma have a poor prognosis. The objectives of the study were to determine the antitumor activity and toxicity of topotecan (daily ×5) in newly diagnosed patients with metastatic osteosarcoma followed by chemotherapy (ifosfamide, carboplatin, etoposide [ICE], alternating with cisplatin and doxorubicin [CD]).

Stratification of treatment intensity in relapsed pediatric Hodgkin lymphoma

Risk‐adapted, response‐based therapies for pediatric Hodgkin lymphoma have resulted in 5‐year survival exceeding 90%. Although high‐dose chemotherapy and autologous hematopoietic stem cell transplantation (AHSCT) are considered standard for most patients with relapsed or refractory Hodgkin lymphoma, a subset of children with low risk relapse do not require AHSCT for cure. Currently there are no widely accepted criteria defining who should receive standard dose chemotherapy and/or radiotherapy, nor is there a standardized treatment regimen. We propose a risk‐stratified, response‐based algorithm for children with relapsed or refractory Hodgkin lymphoma that is based on a critical appraisal of published outcomes and prognostic factors. Pediatr Blood Cancer 2014;61:579–586.

Radiologic Placement of a Low Profile Implantable Venous Access Port in a Pediatric Population

AbstractPurpose: To evaluate the feasibility and complications of placement of a low-profile venous access port in the chest in children requiring long-term venous access. Method: A low-profile peripheral arm port (PAS port; Sims Deltec, St. Paul, MN, USA) was implanted in the chest in 22 children over a 4-year period. The mean age of the study group was 6 years (range: 9 months to 20 years). Ports were placed for the administration of chemotherapy, hyperalimentation and frequent blood sampling. Sonographic guidance was used to access the internal jugular or subclavian vein in each case. A review of all inpatient and outpatient charts was undertaken to assess catheter performance and complications. Results: Access to the central venous circulation was successfully achieved in each case without complication. Ports remained implanted for 6579 catheter-days (mean: 299 days). Ten ports have been removed. Of three patients (13%) experiencing device-related infections (0.45 infections/1000 catheter days), two (9.1%) were unresponsive to antibiotics and removed (0.3 infections/1000 catheter days). One port was removed because of pain in the shoulder adjacent to the port implantation site. One port was removed because of difficult access. The final port was removed in order to place a dual-lumen catheter prior to bone marrow transplant. Twelve ports remain implanted. Aspiration occlusion occurred in four patients (18%). Deep venous thrombosis did not occur in any patient. Conclusion: Low-profile chest ports placed by interventional radiologists in the interventional radiology suite can be placed in children as safely as traditional chest ports placed in the operating room. The incidence of infection, venous thrombosis and aspiration occlusion is comparable to that of ports placed operatively.

Activity and Toxicity of Intravenous Erwinia Asparaginase Following Allergy to E. coli-Derived Asparaginase in Children and Adolescents With Acute Lymphoblastic Leukemia.

Erwinia asparaginase is antigenically distinct from E.coli‐derived asparaginase and may be used after E.coli‐derived asparaginase hypersensitivity. In a single‐arm, multicenter study, we evaluated nadir serum asparaginase activity (NSAA) and toxicity with intravenously administered asparaginase Erwinia chrysanthemi (IV‐Erwinia) in children and adolescents with acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma with hypersensitivity to E.coli‐derived asparaginase.

Successful treatment of a primary cardiac leiomyosarcoma with ifosfamide and etoposide.

Purpose: Primary cardiac leiomyosarcoma is a rare malignant tumor in childhood. Patients with unresectable or partially resected cardiac leiomyosarcoma typically have a poor prognosis. The role of chemotherapy in the treatment of these patients has not been well defined. Patient and Methods: A 6-week-old infant with an incompletely resected cardiac leiomyosarcoma was treated postoperatively with ifosfamide and etoposide. Results: The patient is disease-free and without apparent late effects 5 years following the completion of therapy. Conclusion: The combination of ifosfamide and etoposide warrants further evaluation in patients with leiomyosarcoma.