Showing papers by "Leslie N. Sutton published in 2003"

The Effect of Intrauterine Myelomeningocele Repair on the Incidence of Shunt-Dependent Hydrocephalus

Abstract: Background: Intrauterine myelomeningocele repair (IUMR) was first successfully performed in 1997. Preliminary reports suggest that this procedure reduces the incidence of shunt-depe

All-trans-Retinoic Acid-induced Apoptosis in Human Medulloblastoma: Activation of Caspase-3/Poly(ADP-ribose) Polymerase 1 Pathway

Abstract: Current treatments for childhood brain tumor medulloblastoma (MB), radiation and chemotherapy, lead to undesirable side effects. Identification of antitumor agents that reduce the toxicity will thus have significant therapeutic value. In this study, we investigated all-trans-retinoic acid (ATRA) as an antitumor agent. Although high concentrations (1-10 microM) of retinoic acid derivatives are generally needed for significant antitumor effects in many cancer cells, we observed that pharmacologically relevant concentrations of ATRA were effective in inducing cell death in human MB cells. Using 10-fold lower concentrations (100-500 nM), we found that ATRA inhibits MB (DAOY, D283, D425, and D458) cell proliferation as determined by cell viability [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] and bromodeoxyuridine incorporation assays. Furthermore, 100 nM ATRA was potent in inhibiting the anchorage-independent growth of the sensitive cell lines (D283, D425, and D458) in soft agar assays. We also demonstrate that the ATRA-induced decrease in cell viability was due to increased cell death by apoptosis, which was accompanied by a 20-fold induction of caspase-3 activity in the most sensitive cell line, D458. By contrast, induction of caspase-3 was only 2-fold in the relatively insensitive DAOY cells. Furthermore, ATRA-induced cell death in D283, D425, and D458 cells was accompanied by activation of caspase-3, a key executioner of apoptosis. We also demonstrate that activated caspase-3 resulted in cleavage of 116-kDa poly(ADP-ribose) polymerase 1 to its signature fragments (85 and 29 kDa). Pretreatment with a specific caspase-3 inhibitor, DEVD-CHO, significantly reduced ATRA-induced apoptotic cell death. Thus, we demonstrate for the first time that low concentrations of ATRA inhibit MB cell proliferation and induce apoptotic cell death in part by activating caspase-3/poly(ADP-ribose) polymerase 1 effector pathway, and we show that retinoic acids and novel retinoids are potential antitumor agents in MB therapy.

In utero surgery for hydrocephalus

Abstract: Neonatal hydrocephalus is one of the most common congenital anomalies affecting the nervous system. Currently, ultrasonography allows for early detection of fetal ventriculomegaly and presents the family with several treatment options: termination of pregnancy, early delivery and neonatal shunting, and delivery at term followed by shunting. Despite ventricular decompression after birth, the cognitive outcome is variable as prolonged in utero hydrocephalus has a detrimental effect. In the early 1980s, fetal intervention was explored with the intention of improving outcome. However, patient selection was poor. Fetal ventriculomegaly from other conditions was not adequately distinguished from fetal hydrocephalus. In addition, fetal surgical techniques were not advanced. Consequently, the results were poor and a de facto moratorium on fetal shunting was imposed. However, recent improvements in fetal imaging, such as magnetic resonance imaging, and advances in fetal surgical techniques offer the possibility that properly selected fetuses with hydrocephalus can benefit from an in utero intervention.

Fetal surgery for myelomeningocele.

Abstract: Although in utero treatment of myelomeningocele shows promise in decreasing the morbidity of this disease, the risks to the fetus are significant, and the benefits are unproven. The upcoming trial represents one of the few times that the pediatric neurosurgical community has come together to test a new procedure.

Ventriculosagittal Sinus Shunt Placement: Technical Case Report

Abstract: Objective and importance Determining an appropriate site for distal catheter placement for ventricular shunting for some hydrocephalic patients can be difficult. We describe a simplification of the technique for sagittal sinus shunt placement using a guidewire. Clinical presentation A 20-month-old infant with hydrocephalus secondary to Alexander's disease developed erosion of her parieto-occipital ventriculoperitoneal shunt reservoir through an occipital decubitus scalp ulceration. Her hydrocephalus was temporarily treated with a ventriculostomy; however, she developed pneumatosis intestinalis while in the hospital. Technique The patient underwent placement of a ventriculosagittal sinus shunt. The ventricular catheter and shunt valve were placed through a burr hole at Kocher's point, and the distal end of the catheter was placed in the superior sagittal sinus by using the Seldinger technique. Conclusion Ventriculosagittal sinus shunting may be used as an alternative to traditional methods for patients for whom distal shunt placement is problematic. Our technique has the theoretical advantage of reducing the risks of blood loss or air embolism by not requiring a scalpel incision into the sinus.

Fetal Neurosurgery for Myelomeningocele

Abstract: The increasing use of screening ultrasonography and amniocentesis has resulted in early detection of neural tube defects (NTDs). The neurosurgeon often is consulted to discuss the results of these tests with the prospective parents, to educate them as to the prognosis for their child, and to discuss the mode of delivery and the likely postnatal care that will be required. Until recently, three options were available to the parents of a fetus diagnosed with myelomeningocele: termination of the pregnancy; continuation of the pregnancy until term with cesarean or vaginal delivery; or early delivery by induced labor or planned cesarean section. Developments in diagnostic imaging, surgical techniques applicable to the fetus, and drugs for the prevention of premature labor over the past 10 years have provided a fourth option: in utero correction of the abnormality. Open fetal procedures for myelomeningocele are now being performed at three institutions—the Children’s Hospital of Philadelphia (CHOP), Vanderbilt University, and the University of California at San Francisco (UCSF)—under the auspices of a randomized clinical trial sponsored by the National Institutes of Health. Myelomeningocele remains a major source of morbidity and mortality. Although strides have been made in preventing these defects with folic acid supplementation, many women still are unaware of the relation between folic acid and NTDs, and nearly 1 in 2000 liveborn children still are affected with spina bifida. It is estimated that 23% of pregnancies in which the fetus is diagnosed with a NTD end in elective termination, but the remainder ultimately are delivered. Despite aggressive postnatal intervention, nearly 14% of children with NTD do not survive past 5 years of age, with the mortality rising to 35% among those with symptoms of brainstem dysfunction secondary to the Chiari II malformation. Although 68% of affected individuals have an IQ above 80, only half are able to live independently as adults. The cost of care exceeds $500 million per year (in 1992 dollars) in the United States alone. In addition to sphincter dysfunction and lower extremity paralysis, 85% of affected children have hydrocephalus, exposing them to all of the problems associated with shunts. Almost all patients with myelomeningocele have radiographic evidence of the Chiari II malformation, and the presence of this malformation may be detected as early as the second trimester of pregnancy using ultrafast fetal MRI.