Similar efficacy of 6 and 18 months of therapy with four drugs (COMP) for localized non-Hodgkin's lymphoma of children: a report from the Childrens Cancer Study Group.

Successful treatment of localized non-Hodgkin's lymphoma (NHL) in childhood with 18 months of cyclophosphamide, vincristine, methotrexate (MTX), and prednisone (COMP) prompted a randomized clinical trial to determine whether a 6-month course of the same therapy was as effective as an 18-month course when combined with local irradiation. Two successive Childrens Cancer Study Group (CCSG) protocols (CCG 551 and CCG 501) entered 232 eligible patients from October 1979 until April 1986. Initially, all children with localized disease were considered eligible, but by a subsequent amendment, those with lymphoblastic (LB) histology were excluded. Hence, the study population consisted of 211 patients with nonlymphoblastic (NLB) and 21 with LB disease. Early relapses (before 6 months) occurred in 13 patients with NLB histology. Late relapses were seen in seven patients, three with LB histology. Among the 104 randomized patients who followed the prescribed therapy, there were four recurrences and no differences between 6-month and 18-month therapy. The overall survival for NLB disease was 91% on CCG 551 and 98% on CCG 501. We conclude that 6 months of COMP is excellent therapy for children with localized NLB NHL.

Immature teratomas in children: pathologic considerations: a report from the combined Pediatric Oncology Group/Children's Cancer Group.

Pediatric germ cell tumors (n = 135) with a major component of immature teratoma (IT) registered on Pediatric Oncology Group/Children's Cancer Group treatment protocols from 1990 to 1995 were reviewed. Sixty cases were pure IT with no malignant component and 75 were mixed tumors with a major component of IT. Foci of yolk sac tumor (YST) were present in all 75 mixed tumors; additional malignant components were present in 15. The IT component was as follows: 47% grade 3, 29% grade 2, 24% grade 1. There were no significant correlations between tumor grade and patient age by specific subsets or overall (all p > 0.10). Significant correlations were detected between stage and the presence of foci of YST (p = 0.0145) and grade and the presence of foci of YST (p < 0.001). Serum alpha-fetoprotein concentrations were elevated at diagnosis in 96% of ovarian tumors with foci of YST and were mildly elevated (< 60 ng/dL) in only 16% of tumors without YST. Overall 2- to 6-year survival rate was 96% and was related to the presence of YST. Central pathologic review revealed aspects of morphologic diagnosis that were most frequently misinterpreted by contributing pathologists. These included the classification of differentiating tissues as immature and the failure to recognize two well-differentiated patterns of YST (the hepatoid pattern resembling fetal liver and the well-differentiated glandular pattern resembling fetal lung or intestine). Such foci were often overlooked. The authors conclude that the presence of microscopic foci of YST, rather than the grade of IT, per se, is the only valid predictor of recurrence in pediatric IT at any site.

Extracorporeal membrane oxygenation for perioperative support in pediatric heart transplantation.

Extracorporeal membrane oxygenation has demonstrated effectiveness for cardiopulmonary support in a variety of clinical situations. This article reviews the cases in which extracorporeal membrane oxygenation was used as an adjunct to pediatric cardiac transplantation. Twenty children, aged 7 days to 17 years, with cardiac failure refractory to conventional therapy received extracorporeal membrane oxygenation for 6 to 192 hours. In 4 cases it was used as a bridge to transplantation; in 10 cases it facilitated resuscitation of the cardiac allograft in the immediate postoperative period; and in 6 cases it complemented therapy for severe rejection in the late postoperative period. Twelve patients survived extracorporeal membrane oxygenation, 7 of whom lived more than 8 months. One long-term survivor was in the bridge-to-transplant group, 4 in the immediate postoperative group, and 2 in the rejection group. All survivors have normal cardiac allograft function. These data suggest that extracorporeal membrane oxygenation can be used to support profound cardiac failure in the pediatric heart transplant patient as a bridge to transplantation, in the resuscitation of the cardiac allograft, or to supplement a rejecting allograft.

Incidence and outcome of primary Epstein-Barr virus infection and lymphoproliferative disease in pediatric heart transplant recipients.

BACKGROUND: The objective of this study was to assess the relationship between Epstein-Barr virus (EBV) infection and posttransplantation lymphoproliferative disease (PTLD) in pediatric heart transplant recipients. EBV is implicated in the development of PTLD. However, the relationship between primary EBV infection and PTLD is not well understood. METHODS: Serial EBV titers were determined prospectively in 50 children before and after heart transplantation. Results were correlated with the development of PTLD. The clinical presentation, management, and outcome of PTLD were characterized. RESULTS: Before transplantation, EBV titers were positive in 19 and negative in 31 patients. After transplantation, all EBV-positive patients remained positive; 1 developed PTLD. Among EBV-negative patients, 12 of 31 remained negative; none developed PTLD. Nineteen patients demonstrated serologic evidence of primary EBV infection after heart transplantation; 12 developed PTLD. Mean follow-up after heart transplantation was 3.3 years (range 0.4 to 8.4 years). Mean time from heart transplantation to histologic confirmation of PTLD was 29 months (range 3 to 72 months). Survival with PTLD was 92%. CONCLUSIONS: Twelve of 13 pediatric heart transplant recipients who developed PTLD had evidence of primary EBV infection. Serial monitoring of EBV titers may lead to earlier identification and improved treatment of PTLD.

Congenital diaphragmatic hernia survival and use of extracorporeal life support at selected level III nurseries with multimodality support.

BACKGROUND: Congenital diaphragmatic hernia (CDH) has been cited to have a mortality rate of 50%. There have been multiple studies at individual institutions demonstrating potential benefits from various strategies including extracorporeal life support (ECLS), delayed repair, and lower levels of ventilator support. There has been no multicenter survey of institutions offering these modalities to describe the current use of ECLS and survival of these infants. In addition, the relationship between the number of patients with CDH managed at an individual institution and outcome has not been evaluated. METHODS: We queried 16 level III neonatal intensive care centers on the use of ECLS and survival of infants with CDH who were treated during 2 consecutive years (1993 to 1995). Data are presented as mean +/- SEM, median, and range. RESULTS: Data were collected on 411 patients. Of these, 71% +/- 8% were outborn and 8% +/- 3% were considered nonviable. Overall survival of CDH infants was 69% +/- 4% (range, 39% to 95%). The survival rate of infants on ECLS was 55% +/- 4%, whereas survival of infants not requiring ECLS was significantly increased at 81% +/- 5% (p = 0.005). The mean rate of ECLS use was 46% +/- 2%. There was no correlation between the number of cases per year at an individual institution and overall survival, ECLS survival, or ECLS use (r = 0.341, 0.305, and 0.287, respectively). There was also no correlation between case volume at an individual institution and ECLS survival (r = 0.271). CONCLUSIONS: The current survival rate and rate of ECLS use in infants with CDH at level III neonatal intensive care units in the United States are 69% +/- 4% and 46% +/- 2%, respectively. There is no correlation between the yearly individual center experience with managing CDH and rate of ECLS use or outcome.

Diaphragmatic activity is a determinant of postnatal lung growth.

To test the hypothesis that activity of respiratory muscles determines regional growth of lung parenchyma, we studied the effects of unilateral diaphragmatic paralysis on contralateral/ipsilateral lung growth in cats and piglets. Five 10- to 12-wk-old cats and five 8-wk-old piglets underwent unilateral diaphragmatic paralysis by thoracic and cervical phrenectomy, respectively. Five to seven weeks after surgery, when the cats were killed for studies of lung growth, gain in body weight was the same as in five sham-operated controls. At this time, mean pleural pressure ipsilateral to the paralyzed hemidiaphragm was the same as contralateral mean pleural pressure during tidal breathing, and values did not differ from controls. However overall functional residual capacity was lower in the phrenectomized cats (35 +/- 4 ml) than in the controls (55 +/- 11 ml, P less than 0.01). Growth of contralateral lungs relative to ipsilateral lungs was greater in the phrenectomized cats than in the controls, as shown by ratios of contralateral/ipsilateral wet lung weight (1.44 vs. 1.34, P less than 0.01), maximum inflation volume (1.53 vs. 1.33, P less than 0.05), and total protein content (1.45 vs. 1.26, P less than 0.05). Ratios of total protein to DNA and RNA to DNA were unchanged. One week after surgery in the piglets, the ratio of contralateral/ipsilateral wet lung weight was increased (1.61 vs. 1.29, P less than 0.01) and total weight of both lungs was reduced. We conclude that regional growth of lung parenchyma by cell proliferation depends in part on regional distribution of respiratory muscle activity.

Aortic thrombosis after umbilical artery catheterization.

Neonatal arterial thrombosis has become more common with the use of umbilical artery catheters; however, catheter-induced aortic thrombosis is rare. A review of the literature disclosed a 100% mortality from medically managed neonatal aortic thrombosis. Two cases of umbilical artery catheterinduced acute neonatal thrombosis were managed successfully by surgical thrombectomy. Severe lower extremity ischemia and hypertension with aortic occlusion developed in two neonates, and intractable congestive heart failure developed in one of the neonates. This seems to be the first documented report of successful surgical treatment of umbilical artery catheter-induced aortic thrombosis. Acute neonatal aortic occlusion should be considered a surgical emergency.

Anatomic and functional abnormalities of the esophagus in infants surviving congenital diaphragmatic hernia.

As more infants with congenital diaphragmatic hernia (CDH) survive by means of extracorporeal membrane oxygenation (ECMO), new clinical observations are being made. We report anatomic and functional abnormalities of the esophagus in these infants. Twenty-two of 30 infants with CDH survived. Three of 7 non-ECMO-treated infants and 14 of 17 ECMO-treated infants had an air- or fluid-filled mediastinal mass that was confirmed by an upper gastrointestinal series as ectatic esophagus. Contrast studies demonstrated severe gastroesophageal reflux. Intra-esophageal pH monitoring confirmed significant reflux (Euler scores greater than 50) in 69% of tested patients. Prolonged acid clearance in most patients implied abnormal peristalsis. Hydramnios was correlated to the observed esophageal abnormalities, being present in 13 of 16 infants with an available amniotic history. All patients had symptomatic gastroesophageal reflux managed without antireflux surgery and were discharged 36 +/- 2 days after initiation of feeding. Follow-up (range: 7 to 56 months; mean: 32 months) showed that weight gain in affected children was slower than in those not affected. All but one are asymptomatic. Repeat upper gastrointestinal series shows persistent ectasia but less gastro-esophageal reflux. Gastroesophageal reflux/ectasia is a new observation with CDH. The associated hydramnios may result from proximal foregut obstruction by kinking the gastroesophageal junction with CDH. The radiographic appearance can be quite unusual. Clinical manifestations of gastro-esophageal reflux are manageable without surgery but may account for the observed compromised growth.

Pediatric hepatobiliary disease.

The surgical aspects of pediatric hepatobiliary disease concern a unique set of diagnoses, disease processes, diagnostic issues, and treatment problems. In this context, this article discusses features of biliary atresia, choledochal cyst, gallbladder disease, and liver abscess in the infant, child, and adolescent.

What do survivors of congenital diaphragmatic hernia look like when they grow up?

An important consequence of the extracorporeal membrane oxygenation (ECMO) era is a renewed interest by pediatric surgeons in the infant with congenital diaphragmatic hernia (CDH). As increasing numbers of the infants survive, previously unappreciated aspects of the problem are being unmasked, provoking important questions as to their etiology. Importantly, as these children grow and develop, we must ask ourselves if their various problems are specific to CDH or are they consequences of our treatment strategies. This article considers pulmonary, cardiac, gastrointestinal, and neurocognitive markers of outcome.

Evaluation and management of pediatric solid ovarian tumors.

Solid ovarian tumors are uncommon in the pediatric population, but when they occur, they are a major source of anxiety for the patient and her family. The pediatric surgeon will be relied on to diagnose these tumors because they usually present as abdominal pain with a mass. The diagnostic evaluation consists of a carefully obtained history and physical examination, ultrasound examination, serum assay for tumor markers, and further radiographic evaluation as indicated. Two thirds of malignant tumors in children are germ cell tumors, and most of these are dysgerminomas or endodermal sinus tumors. A multimodal, team-oriented approach to therapy is crucial. Reproductive organ-sparing surgery with salpingo-oophorectomy, ascites sampling, nodule biopsy, omentectomy, and contralateral ovarian biopsy as indicated, may be curative for stage I tumors; more advanced or highly aggressive tumors should be treated with cytoreduction surgery and will require platinum-based chemotherapy. Postinduction surgery is indicated for progressive or recurrent disease. One third of tumors are physiologically active stromal tumors that often become apparent because of hormonal effects. Epithelial tumors, common in the adult, are uncommon in children and are of mild to moderate malignant potential. Other miscellaneous tumors and benign lesions are less common.

Newborn surgical emergencies. Congenital diaphragmatic hernia and extracorporeal membrane oxygenation.

Bochdalek hernia is a posterolateral defect in the embryogenesis of the diaphragm. Abdominal contents enter the thorax during fetal development and result in pulmonary hypoplasia. A cause of respiratory distress in the newborn, the management of this disease has undergone dramatic changes. The defect requires surgical repair, but success depends more on preoperative and postoperative management of the associated physiologic derangements.

Evaluation of ischemic bowel viability with a fluorescent technique.

Clinical estimations of bowel viability after ischemic insult are unreliable. Accurate criteria are essential to avoid unnecessary resection. This study describes a safe technique using fluorescein that predicts bowel viability with increased accuracy.

Growth of mouse hepatoma following liver resection.

Liver regeneration occurs after resection. Hepatic tumors may be subject to the same factors which influence cell mass in regenerating liver. Partial hepatectomy is shown to cause a significant transient augmentation of tumor growth compared to non-operated and nephrectomized controls. Skin grafting studies indicate this phenomenon is probably not immunologically mediated.

Extracorporeal membrane oxygenation causes significant changes in intracranial pressure and carotid artery blood flow in newborn lambs.

The effects of ECMO on cerebral dynamics, particularly in the face of asphyxia, are largely unknown. We inquired as to whether carotid artery blood flow (CABF) and intracranial pressure (ICP) were affected by carotid artery/jugular vein ligation, asphyxia, ECMO, and ECMO with asphyxia. Lightly sedated newborn lambs (two to four days old, 3 to 4 kg) in four groups were monitored for mean ICP by an epidural sensor, mean CABF by a flow probe, and mean arterial pressure. Mean values were determined for the duration of each step of the experiment. ECMO was venoarterial at 100 to 120 mL/kg/min. CABF and ICP were measured in group 1 before and after CA/JV ligation; in group 2 during normoxia/normocapnia followed by hypoxia (30 to 40 torr)/hypercapnia (70 to 90 torr); in group 3 before, during, after ECMO while normoxic/normocapnic throughout; and in group 4 as ECMO was begun while hypoxic/hypercapnic. Vessel ligation alone caused no significant CABF/ICP changes. Asphyxia caused physiologic increases in CABF (P less than .03) and ICP (P less than .01). ECMO alone caused a significant decrease in ICP (P less than .003). ECMO with asphyxia caused an even more severe decrease in ICP (P less than .001) combined with augmented CABF (P less than .03). The ICP decrease was limited to the duration of ECMO. Possible explanations include loss of cerebral autoregulation induced by hypoxia/hypercarbia and alterations in cerebral venous drainage necessitated by this method of cardiopulmonary bypass.

Modification of cardiopulmonary hemodynamics and vasoactive mediators by extracorporeal membrane oxygenation in newborn lambs.

We asked if prolonged venoarterial extracorporeal membrane oxygenation (ECMO) causes alterations in cardiopulmonary hemodynamics that might be reflected in arbiters of vascular tone: thromboxane, prostacylin, norepinephrine, and epinephrine. Newborn lambs undergoing ECMO demonstrated significant augmentation of systemic and pulmonary arterial blood pressure that was temporally related to rises in all vasoactive mediators measured. Although the prostanoids returned to baseline within 30 minutes, the catecholamines remained elevated significantly throughout bypass. Long-term bypass, however, was not associated with sustained systemic hypertension. Pulmonary hypertension was achieved only after 6 hours of bypass. These acute and chronic changes may exacerbate a pathological state for which ECMO is indicated.

Vitamin A effect on tumor angiogenesis.

The inhibitory effect of vitamin A on tumor establishment and growth has been studied in two animal models. The C57L/J hepatoma, when placed in C57L/J mice receiving inoculations of vitamin A, showed slow growth and the hosts had significantly prolonged survival over untreated mice. The V-2 carcinoma, when implanted in the corneas of New Zealand white rabbits receiving injections of vitamin A, showed decreased vascular response in the limbic vessels. The absence of an induced vascular response prevents vascularization of the tumor and subsequent tumor growth. The evidence suggests that vitamin A may exert its inhibitory effect by modifying the normal vascular response to neoplastic tissue.

Differential effects of alveolar and arterial oxygen tension on pulmonary vasomotor tone in ECMO-perfused, isolated piglet lungs.

Hypoxia is a known stimulant of pulmonary hypertension. We hypothesized graded effects of alveolar (PAO2) and arterial (PaO2) oxygen tension on pulmonary vascular resistance (PVR). A standard in situ, isolated lung preparation was modified by adding an oxygenator to the perfusion circuit with cannulation of the unarrested heart, allowing control of PAO2 and PaO2 in lungs devoid of ischemic injury. Seven anesthetized piglets were prepared with occlusive tracheostomy, ductus arteriosus ligation, and cannulation of the left atrium and main pulmonary artery. Animals were exsanguinated while simultaneously perfusing the lungs with a donor-blood primed extracorporeal membrane oxygenation circuit. Flow, left atrial pressure, pH, and PCO2 were kept constant. PAO2 and PaO2 were altered to establish four different experimental conditions as described by a latin square. PVR was calculated from measurements of pulmonary artery pressure (PAP) before and after introducing an experimental condition. Results show that (1) alveolar hypoxia significantly increases PVR despite arterial hyperoxia; (2) alveolar hypoxia is a more potent stimulus of pulmonary vasoconstriction than arterial hypoxemia; (3) alveolar and arterial oxygen tension are independent, additive effectors of PVR; and (4) recovery from acute hypoxic pulmonary vasoconstriction may be more sensitive to alveolar oxygen tension.

Pressure- versus volume-cycled ventilation in liquid-ventilated neonatal piglet lungs.

BACKGROUND/PURPOSE: If the goal of partial liquid ventilation (PLV) with perfluorocarbons in the management of respiratory failure is to improve dynamic lung compliance (Cdyn) and pulmonary vascular resistance (PVR) while sustaining O2 delivery, the optimal ventilatory management is unclear. The authors asked if volume-cycled or pressure-limited ventilation had different effects on PVR, cardiac index (CI), and Cdyn in uninjured and injured neonatal piglet lungs. METHODS: Anesthetized piglets (6 to 8 kg) were ventilated after tracheostomy. Cdyn was measured by in-line Fleisch pneumotach/PC data acquisition terminal. Thermodilution instrumentation allowed determination of both CI and PVR. Volume-control or pressure-limited ventilation was established in uninjured or injured (surfactant deficiency induced by saline lavage at 18 mL/kg) animals. After a stable 30-minute baseline, animals were assigned randomly to one of four groups: group I (n = 9), uninjured animals plus volume-cycled ventilation (intermittent mandatory ventilation [IMV], 10 bpm; tidal volume [TV], 15 mL/kg, positive end-expiratory pressure [PEEP], 5 cm H2O; FIO2, 1.0; and PLV for 150 minutes); group II (n = 9), uninjured animals plus pressure-limited ventilation (IMV, 10 bpm; peak inspiratory pressure (PIP), 25 cm H2O, PEEP, 5 cm H2O, FIO2, 1.0; and PLV for 150 minutes); group III (n = 7), injured animals plus volume-cycled ventilation (IMV, 10 bpm; TV, 15 mL/kg; PEEP, 5 cm H2O; FIO2, 1.0 for 30 minutes, followed by saline injury for group IV (n = 7), injured animals plus pressure-limited ventilation (IMV, 10 bpm; PIP, 25 cm H2O; PEEP, 5 cm H2O; FIO2, 1.0 for 30 minutes, followed by saline injury, and PLV rescue). Comparison within and between groups was accomplished by repeated measures analysis of variance (ANOVA) with Tukey correction. RESULTS: There was no significant difference between volume-cycled or pressure-limited ventilation in healthy lungs; however, in the setting of lung injury, dynamic compliance was 1.44 +/- 0.15 after 180 minutes in the volume-cycled group and 0.91 +/- 0.10 in the pressure-limited group after the same interval (mL/cm H2O x kg +/- SEM). Similarly, PVR was 100 +/- 6 in the volume-cycled group and 145 +/- 12 in the pressure-limited group after 180 minutes of lung injury (mm Hg/L/kg x min +/- SEM). Cardiac index declined significantly in all groups independent of ventilatory mode. CONCLUSIONS: These results suggest that in the setting of lung injury, Cdyn and PVR improved significantly when volume-cycled, compared with pressure-limited ventilation was used. Although no difference existed between ventilatory modes in healthy lungs, pressure-limited ventilation, when combined with PLV in injured lungs, had adverse effects on lung compliance and pulmonary vascular resistance. Volume-cycled ventilation may optimize the ability of perfluorocarbon to recruit collapsed or atelectatic lung regions.

Extracorporeal membrane oxygenation and neonatal respiratory failure: experience from the extracorporeal life support organization.

Extracorporeal membrane oxygenation (ECMO) has rescued moribund infants with respiratory failure from a variety of causes. We report the experience from 58 United States and 7 overseas ECMO centers between 1980 and 1989. Voluntarily submitted data forms provided details of diagnosis, clinical condition, ECMO indications, morbidity, and mortality. Of 3,528 infants with a predicted mortality greater than 80% treated with ECMO, 83% survived. Entry diagnoses and aggregate survival were: meconium aspiration syndrome (MAS) 1,356 (93%), persistent pulmonary hypertension of the newborn (PPHN) 480 (83%); congenital diaphragmatic hernia (CDH) 585 (62%); hyaline membrane disease (HMD) 532 (84%); sepsis 416 (77%); and other 185 (77%). ECMO indications were a-AdO2 greater than 600 for 6 to 8 hours (22%), oxygenation index greater than 40 for 4 hours (18%), acute deterioration (14%), maximal therapy failure (34%), and barotrauma (1%). Annual survival improved over 9 years except for CDH, which decreased from 70% (1987) to 56% (1989) P less than .01). Survivors differed from non-survivors (P less than .05) by birth weight (greater than 2 kg), gestational age (greater than 37 weeks), entry diagnosis (MAS, PPHN, HMD, sepsis v CDH), inborn versus outborn, pre-ECMO pH, and ECMO duration. Technical complications in 25% of patients and medical complications in 75% adversely affected survival. Annual sepsis survival improved to 75% (1989) but had significantly greater complication rates (P less than .05) than other diagnoses. Multicenter data yield information not available from single institution experience. Although entry criteria and conventional therapy continue to evolve, ECMO currently improves survival from an estimated 20% to 83% overall. Individual prognosis depends on entry diagnosis, clinical condition, and complications.