Citations

Objective. Primary hyperparathyroidism (HPT) is unusual in children. We reviewed our experience with HPT to better characterize these children. Methods. The retrospective review of patients <19 years old who underwent parathyroid resection for primary HPT from 1970 to 2000 was performed at a single institution.. Results. Fifty-two patients were identified. Median age was 16.8 years (range: 4–18.9) with a female-to-male ratio of 3:2. Eighty-five percent had an elevated parathyroid hormone (PTH) level, and 15% had an inappropriately normal PTH level during hypercalcemia. Serum calcium was elevated in all patients except for 2 with multiple endocrine neoplasma (MEN)-IIA and 1 with familial non-MEN HPT, but both had elevated PTH levels. Alkaline phosphatase levels were significantly higher in children with documented bone involvement. At presentation 41 patients (79%) were symptomatic and end-organ damage (nephrocalcinosis, nephrolithiasis, acute pancreatitis, or bone involvement) occurred in 23 patients (44%). Thirty-four patients (65%) had a single adenoma; hyperplasia was identified in 16 patients (27%), and of these cases, 57% occurred in patients diagnosed with MEN-I. Short-term complications included transient hypocalcemia in 29 patients (56%) and transient vocal cord paralysis in 2 patients (4%). Long-term complications were significant for permanent hypocalcemia in 2 patients (4%) and no recurrent laryngeal nerve injuries. No parathyroid abnormalities were identified during exploration in 4 (8%) children. Long-term follow-up was achieved in 98% of patients for a mean and median of 13 years. Resolution of hypercalcemia was achieved in 94% of cases. Conclusion. The diagnosis of primary HPT in pediatric patients is frequently delayed, is commonly symptomatic, and has significant morbidity. For children in whom HPT is suspected, evaluation of serum calcium and PTH levels is diagnostic in 100% of children. Parathyroid resection is effective at restoring normal serum calcium, has few complications, and is the treatment of choice for children with primary hyperparathyroidism.

Previous studies demonstrated that ataxia telangiectasia mutated– and Rad3-related (ATR) kinase and its downstream target checkpoint kinase 1 (Chk1) facilitate survival of cells treated with nucleoside analogs and other replication inhibitors. Recent results also demonstrated that Chk1 is depleted when cells are treated with heat shock protein 90 (Hsp90) inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG). The present study examined the effects of 17-AAG and its major metabolite, 17-aminogeldanamycin (17-AG), on Chk1 levels and cellular responses to cytarabine in human acute myelogenous leukemia (AML) cell lines and clinical isolates. Cytarabine, at concentrations as low as 30 nM, caused activating phosphorylation of Chk1, loss of the phosphatase Cdc25A, and S-phase slowing. Conversely, treatment with 100 to 300 nM 17-AAG for 24 hours caused Chk1 depletion that was accompanied by diminished cytarabine-induced S-phase accumulation, decreased Cdc25A degradation, and enhanced cytotoxicity as measured by inhibition of colony formation and induction of apoptosis. Additional studies demonstrated that small inhibitory RNA (siRNA) depletion of Chk1 also sensitized cells to cytarabine, whereas disruption of the phosphatidylinositol 3-kinase (PI3k) signaling pathway, which is also blocked by Hsp90 inhibition, did not. Collectively, these results suggest that treatment with 17-AAG might represent a means of reversing checkpoint-mediated cytarabine resistance in AML.

ABSTRACTStaphylococcal enterotoxins (SEs) belong to a large group of bacterial exotoxins that cause severe immunopathologies, especially when delivered as an aerosol. SEs elicit the release of lethal amounts of cytokines by binding to major histocompatibility complex (MHC) class II and cross-linking susceptible T-cell receptors. Efforts to develop effective therapeutic strategies to protect against SEs delivered as an aerosol have been hampered by the lack of small animal models that consistently emulate human responses to these toxins. Here, we report that human leukocyte antigen-DQ8 (HLA-DQ8) transgenic (Tg) mice, but not littermate controls, succumbed to lethal shock induced by SEB aerosols without potentiation. Substantial amounts of perivascular edema and inflammatory infiltrates were noted in the lungs of Tg mice, similar to the pathology observed in nonhuman primates exposed by aerosol to SEB. Furthermore, the observed pathologies and lethal shock correlated with an upsurge in proinflammatory cytokine mRNA gene expression in the lungs and spleens, as well as with marked increases in the levels of proinflammatory circulating cytokines in the Tg mice. Unlike the case for littermate controls, telemetric evaluation showed significant hypothermia in Tg mice exposed to lethal doses of SEB. Taken together, these results show that this murine model will allow for the examination of therapeutics and vaccines developed specifically against SEB aerosol exposure and possibly other bacterial superantigens in the context of human MHC class II receptors.

Klippel-Trenaunay syndrome (KTS) is a rare disorder that consists of a triad of capillary vascular malformation, venous malformations and/or varicose veins, and soft tissue and/or bony hypertrophy. Pain is a real and debilitating problem in these patients. We have observed 9 common causes of pain in KTS: (1) chronic venous insufficiency, (2) cellulitis, (3) superficial thrombophlebitis, (4) deep vein thrombosis, (5) calcification of vascular malformations, (6) growing pains, (7) intraosseous vascular malformation, (8) arthritis, and (9) neuropathic pain. The management of pain in patients with KTS depends on its cause. These patients are best evaluated initially in a center with an experienced multidisciplinary team that includes a primary health care provider, surgeons, and ancillary staff. The ongoing care of a patient with KTS often depends on a local provider who is more readily accessible to the patient but may not have the expertise of a large center to manage the complications of KTS. The purpose of this communication is to review the common causes of pain in these patients to provide local health care providers and patients and their families with appropriate management strategies.

Purpose Preclinical studies of mafosfamide, a preactivated cyclophosphamide analog, were performed to define a tolerable and potentially active target concentration for intrathecal (IT) administration. A phase I and pharmacokinetic study of IT mafosfamide was performed to determine a dose for subsequent phase II trials. Patients and Methods In vitro cytotoxicity studies were performed in MCF-7, Molt-4, and rhabdomyosarcoma cell lines. Feasibility and pharmacokinetic studies were performed in nonhuman primates. These preclinical studies were followed by a phase I trial in patients with neoplastic meningitis. There were five dose levels ranging from 1 mg to 6.5 mg. Serial CSF samples were obtained for pharmacokinetic studies in a subset of patients with Ommaya reservoirs. Results The cytotoxic target exposure for mafosfamide was 10 μmol/L. Preclinical studies demonstrated that this concentration could be easily achieved in ventricular CSF after intraventricular dosing. In the phase I clinical trial, headache was the dose-limiting toxicity. Headache was ameliorated at 5 mg by prolonging the infusion rate to 20 minutes, but dose-limiting headache occurred at 6.5 mg dose with prolonged infusion. Ventricular CSF mafosfamide concentrations at 5 mg exceeded target cytotoxic concentrations after an intraventricular dose, but lumbar CSF concentrations 2 hours after the dose were less than 10 μmol/L. Therefore, a strategy to alternate dosing between the intralumbar and intraventricular routes was tested. Seven of 30 registrants who were assessable for response had a partial response, and six had stable disease. Conclusion The recommended phase II dose for IT mafosfamide, administered without concomitant analgesia, is 5 mg over 20 minutes.

Purpose We determined the maximum-tolerated dose (MTD) and the dose-limiting toxicities (DLT) of 17-allylamino-17-demethoxygeldanamycin (17-AAG) when infused on days 1, 8, and 15 of a 28-day cycle in advanced solid tumor patients. We also characterized the pharmacokinetics of 17-AAG, its effect on chaperone and client proteins, and whether cytochrome P450 (CYP) 3A5 and NAD(P)H:quinone oxidoreductase 1 (NQO1) polymorphisms affected 17-AAG disposition or toxicity. Patients and Methods An accelerated titration design was used. Biomarkers were measured in peripheral-blood mononuclear cells (PBMCs) at baseline and on days 1 and 15, and pharmacokinetic analysis was performed on day 1 of cycle 1. CYP3A5*3 and NQO1*2 genotypes were determined and correlated with pharmacokinetics and toxicity. Results Twenty-one patients received 52 courses at 11 dose levels. DLTs at 431 mg/m2 were grade 3 bilirubin (n = 1), AST (n = 1), anemia (n = 1), nausea (n = 1), vomiting (n = 1), and myalgias (n = 1). No tumor responses were seen. 17-AAG consistently increased heat shock protein (Hsp) 70 levels in PBMCs. At the MTD, the clearance and half-life (t1/2) of 17-AAG were 11.6 L/h/m2 and 4.15 hours, respectively; whereas the active metabolite 17-aminogeldanamycin had a t1/2 of 7.63 hours. The CYP3A5*3 and NQO1*2 polymorphisms were not associated with 17-AAG toxicity. The CYP3A5*3 polymorphism was associated with higher 17-AAG clearance. Conclusion The MTD of weekly 17-AAG is 308 mg/m2. 17-AAG induced Hsp70 in PBMCs, indicating that Hsp90 has been affected. Further evaluation of 17-AAG is ongoing using a twice-weekly regimen, and this schedule of 17-AAG is being tested in combination with chemotherapy.