Liver transplant for metastatic pancreatoblastoma: 7-year event-free survival after chemotherapy, pancreatectomy, complete hepatectomy, and liver transplant.

Pancreatoblastoma is a rare malignant tumor in children. Surgical resection of the tumor is necessary for cure; however, due to its aggressive nature, it is often unresectable at presentation due to tumor size, local invasion, and/or metastasis. Because it is a rare tumor, there is currently no standard treatment regimen. We report a case of a 4-year-old boy who presented with metastatic pancreatoblastoma with multiple large metastases involving all four sectors of the liver. We began treatment with chemotherapy (cisplatin, 5FU, vincristine, and doxorubicin), which significantly reduced the tumor burden in both the pancreas and liver. We then performed a staged subtotal pancreatectomy, complete hepatectomy, and living donor left lateral segment liver transplant. This was followed by postoperative adjuvant chemotherapy. Our patient is alive and healthy and has now been tumor-free for 7 years with no tumor relapse.

Non-operative treatment versus percutaneous drainage of pancreatic pseudocysts in children.

PURPOSE: The objective of this study was to characterize the clinical course and outcomes of children with pancreatic pseudocysts that were initially treated non-operatively or with percutaneous drainage. METHODS: A retrospective review of children with pancreatic pseudocysts over a 12-year period was completed. Categorical variables were compared using Fischer's exact method and the Student's t test was used to compare continuous variables. Analysis was done using logistic and linear regression models. RESULTS: Thirty-six children met the criteria for pancreatic pseudocyst and 33 children were treated either non-operatively or with percutaneous drainage. Of the 22 children managed non-operatively, 17 required no additional intervention (77 %) and five required surgery. Operative procedures were: Frey procedure (3), distal pancreatectomy (1), and cystgastrostomy (1). Eight of the 11 children treated with initial percutaneous drainage required no additional treatment (72 %). The other three children underwent distal pancreatectomy. Success of non-operative management or percutaneous drainage was not dependent on size or complexity of the pseudocyst Logistic regression did not identify any patient demographic (gender, age, and weight), etiologic (trauma, non-traumatic pancreatitis) or pseudocyst characteristic (size, septations) that predicted failure of non-operative therapy. CONCLUSIONS: In children, pancreatic pseudocysts can frequently be managed without surgery regardless of size or complexity of the pseudocyst. When an intervention is needed, percutaneous drainage can be performed successfully, avoiding the need for major surgical intervention in the majority of patients.

Immunology of herpesvirus infection: immunity to herpes simplex virus in eye infections.

A gereral, overall pattern of the temporal relationship and interaction between cell and antibody-mediated immune responses following herpes simplex virus infection of the rabbit cornea can be synthesized from our studies. Cell-mediated immunity (CMI) appears early following infection, at a time when mononuclear and lymphocytic cellular proliferation occur at the limbus. Interaction between specifically immune lymphocytes with virus antigens are detected by lymphocyte blastogenesis and migration inhabiting factor. During stromal keratitis, a second phase of CMI involves transient virus-specific cytotoxic lymphocytes, which destroy cells that display viral-induced antigens on their surface. Chemotatic factors generated by viral antigens alone or with antiviral antibody or by virus-sensitized lymphocytes play a role in attracting polymorphonuclear leukocytes to the cornea during stromal keratitis. Soluble mediators of CMI secreated by activated lymphocytes act both specifically and nonspecifically on virus-infected cells, allowing cell destruction and making intracellular virus available for neutralization by antiviral antibody. Cell-mediated immunity in the acute infection, diminishes with the appearance of significant antiviral antibody titers. The late phase of the corneal immune response results from a local antigen-antibody interaction and is characterized by cells predominantly of the plasmacytic type. The presence of complement-dependent cytotoxic antibodies capable of destroying virus-infected cells provide an additional factor in restriction of infection.

Relative phosphocreatine and nucleoside triphosphate concentrations in cerebral gray and white matter measured in vivo by 31P nuclear magnetic resonance.

Rates of ATP metabolism generally are higher in cerebral gray matter compared to white matter. In order to study the physiology of this regional difference in vivo, the 1-dimensional chemical shift imaging technique (1D-CSI) was used to acquire 31P nuclear magnetic resonance spectra from 2.5 mm slices of 4-week old piglet brains. Spectra from predominantly gray matter slices (estimated 76% gray matter, 7 mm below the scalp) were compared to predominantly white matter slices (56% estimated white matter, 13 mm below the scalp) as assessed by magnetic resonance images. The 1D-CSI technique introduced no systematic changes in the ratio of signals from a single chamber phantom containing a phosphocreatine (PCr) and ATP solution. Gray matter slices showed a PCr/NTP ratio of 0.93 +/- 0.11 (mean +/- S.D.) using a 2 s interpulse interval, a value very close to the ratio in surface coil localized spectra. The predominantly white matter slices showed a PCr/NTP ratio of 1.32 +/- 0.18 (P < 0.02 for gray versus white matter). Using the estimated percentages of gray and white matter in the two slices and calculated concentrations from fully relaxed spectra, the gray matter PCr/NTP ratio is approximately 0.77, while the ratio in white matter is approximately 2.18. The difference in PCr/NTP measured in vivo suggests that either the total NTP concentration is higher or the steady state PCr concentration is lower in gray matter than in white matter in the piglet brain.

Benign liver and biliary tract masses in infants and toddlers.

There is a remarkable diversity of conditions encompassed by benign liver masses in infants and toddlers. The most common benign hepatic tumor in this age group is infantile hepatic hemangioendothelioma. Other commonly seen benign tumors are mesenchymal hamartoma and focal nodular hyperplasia. Hepatic adenoma is almost exclusively a disease of older children; primary hepatic teratoma is exceedingly rare. There are several distinguishing characteristics of these benign tumors on radiographic evaluation; however, imaging techniques such as ultrasound scan, computed tomography, and angiography are not always reliable in differentiating benign from malignant tumors. The differential diagnosis of benign hepatic tumors includes nonneoplastic cystic masses including biliary and simple hepatic cysts, hematoma, parasitic cysts, and pyogenic and amebic liver abscess. Choledochal cyst presents with a classic triad of abdominal pain, cholestatic jaundice, and a palpable abdominal mass. They are classified anatomically into 5 subtypes with the most popular types being type I and type IV. Treatment is with complete cyst excision with hepaticojejunostomy reconstruction.

Inherited thrombophilia: a possible cause of in utero vascular thrombosis in children with intestinal atresia.

BACKGROUND: Congenital atresia of the small and large intestine is thought to evolve from in utero mesenteric vascular occlusion of the corresponding intestinal segment. Because spontaneous thrombosis recently has been described in association with inherited thrombophilia, the authors wondered if inherited thrombophilia also might be found in babies with intestinal atresia. METHODS: Genetic analysis was done on 28 children treated for congenital intestinal atresia. DNA was analyzed for point mutations to detect the 2 most common types of inherited thrombophilia, the G1691A mutation in the factor V gene (factor V Leiden) and the G20210A mutation in the prothrombin gene. In addition, other genetic risk factors for thrombosis were analyzed including the C677T mutation in the methylenetetrahydrofolate reductase gene (MTHFR) and 2 polymorphisms of the factor VII gene (the R353Q and the hypervariable region 4 polymorphisms). RESULTS: The factor V Leiden mutation was present in 5 of 28 (18%) children treated for congenital intestinal atresia. This is increased significantly when compared with the reported carrier frequency of 3% to 7% in the general population and a reported carrier rate of 4.2% in the local population (P <.005). The R353Q polymorphism of the factor VII gene, specifically the RR genotype, was noted in 85% of patients with atresia with an expected frequency of 64% (P <.008). There were no significant associations noted between mutations in the prothrombin gene, the MTHFR gene, or the hypervariable region of the factor VII gene. CONCLUSIONS: The factor V Leiden mutation and the RR subtype of the R353Q polymorphism of the factor VII gene are seen at an increased frequency in children with congenital intestinal atresia. This suggests that inherited thrombophilia may play a role in the etiology of these in utero mesenteric thrombotic events.

Bilateral laparoscopic adrenalectomy: a new treatment for difficult cases of congenital adrenal hyperplasia.

PURPOSE: In difficult cases of congenital adrenal hyperplasia (CAH), often the child may have normal cortisol levels and elevated androgen levels, or normal androgen levels and elevated cortisol levels, but not normal levels of both. Because bilateral adrenalectomy removes the source of the abnormal androgen production, the authors felt that in some cases it might be more efficacious than conventional medical therapy. METHODS: Three children with CAH and suboptimal response to medical management underwent bilateral laparoscopic adrenalectomy. Parents were counseled extensively regarding the experimental nature of this treatment and the potential long-term complications. RESULTS: All children recovered quickly after a mean hospital stay of 1.8 days. Pathologic examination of the removed adrenal glands showed persistent cortical hyperplasia. Follow-up at 6 months indicated marked reduction in abnormal androgen production, which allowed lowering of the steroid dosing to physiologic levels. CONCLUSION: In children with CAH refractory to medical management, bilateral laparoscopic adrenalectomy can be performed safely with almost trivial morbidity. Although early results are very encouraging, the anticipated long-term beneficial effects on growth, short stature, and adult infertility will require years to assess.

Tracheobronchial injuries after blunt chest trauma in children--hidden pathology.

BACKGROUND: Blunt thoracic injuries in children are unique because the pliability of the chest wall allows transmission of massive external force directly into the mediastinum. Children presenting after blunt chest trauma may have complete disruption of the airway with little external sign of injury. Without prompt diagnosis and appropriate treatment, the risk for progressive respiratory failure is high. METHODS: Four children with tracheobronchial injuries were referred to a pediatric trauma center from 1994 to 1997. All children, age 18 months to 13 years, suffered unusual crush injuries. All diagnoses were based on unresolved pneumothorax or pneumomediastinum. RESULTS: Bronchoscopy identified the location of injury as posterior trachea (n = 1) and right mainstem bronchus (n = 2). A tertiary bronchial injury (n = 1) was missed by initial tracheogram and subsequent bronchoscopy but identified during surgical exploration. All children survived after thoracotomy and primary repair of the injury. CONCLUSIONS: Tracheobronchial disruption is a rare, life-threatening injury. Suspicion should be high when pneumomediastinum and pneumothorax are refractory to adequate pleural drainage. Flexible bronchoscopy with intubation distal to the injury may be necessary to prevent loss of the airway. Advance preparation should include setups for bronchoscopy, thoracotomy, and cardiopulmonary bypass. Patient survival depends on preparation and prompt surgical intervention.

Are scintiscans accurate in the selection of reflux patients for pyloroplasty?

BACKGROUND: Gastric emptying scintiscans are currently used to select reflux patients for added pyloroplasty at the time of fundoplication. The accuracy of this scan selection approach has been assumed. If preoperative scintiscans do not reliably predict postfundoplication gastric emptying, however, the decision to add pyloroplasty to the fundoplication operation may be inappropriate and even harmful. METHODS: The authors studied 27 children prospectively before and after gastric fundoplication. Gastric emptying at 60 minutes was measured by double isotopic labeling of liquid (111In) and solid (99mTc) phases of a test meal specifically designed for label fixation. The authors' question involved the accuracy of preoperative gastric scintiscans in predicting postfundoplication delay of gastric emptying (DGE). An evaluation of pyloroplasty as an effective treatment for DGE was not part of the study design. Pyloroplasty was performed as a secondary operation in three of the study children, however, because they persisted with unrelieved symptoms of retching, fullness, and abdominal discomfort. Scintiscan-documented postfundoplication delay in gastric emptying was present in all three patients at 18, 58, and 12 weeks, respectively. Additional scintiscans were performed in these patients after pyloroplasty. RESULTS: Gastric emptying of solids at 60 minutes did not show a significant change after a gastric fundoplication operation, although the trend was in the direction of a decrease (paired t test, P= .13). Liquid emptying at 60 minutes, however, was significantly increased (paired t test, P = .01). The variation in values between patients was wide, and the correlation between pre- and postoperative study results in the same patient was poor (r2 = 0.337 for solids and r2 = 0.116 for liquids). Most unexpectedly, scintiscans after postfundoplication pyloroplasty in the three patients with persistent symptoms showed no improvement in delayed gastric emptying on repeat scintiscan 42 to 117 weeks later. CONCLUSIONS: The data suggest that preoperative scintiscan evidence for postfundoplication DGE is probably accurate for solid emptying but not for liquids, at least as measured by the double isotope methodology of our study. Preoperative scintiscans that use a liquid phase label only may be highly misleading for the prediction of postfundoplication DGE. Furthermore, pyloroplasty may not be useful as treatment even when postfundoplication delay in gastric emptying can be accurately anticipated or confirmed. A fundamental motility disorder of the gastric body seems to be more important than muscular resistance at the gastric outlet as a cause for postfundoplication DGE, and the most effective treatment approach remains unclear.

Immunology of herpes simplex virus in fection.

The accompanying inflammation seen in ocular HSV infection-the result of interactions between viruses and the immune response-can be both beneficial and potentially harmful to the host. An understanding of the interaction of virus-immune cells is just evolving from current advances in basic research. Based on our studies on HSV keratitis [11], the control of ocular HSV infection appears to involve an early inflammatory phase with macrophage reactivity and elaboration of MIF. Transient virus-specific lymphocytes with effector reactivity, as well as neutrophils with chemotactic activity, occur during the stromal keratitis. Finally, antibody-dependent complement-mediated lysis provides another phase of restriction of infection. Thus, a rationale for effective management and therapy of occular HSV disease must be based on an understanding of (1) the immunological and immunopathological mechanisms of corneal inflammatory disease initiated by the virus; (2) the immunological mechanisms in recovery from the disease; and (3) the host's humoral and cellular immune status during virus persistence (latency) and during recurrent episodes of infection. We hope that new information obtained from assessment of roles of the humoral and cellular immune responses in recovery from disease and in recurrent disease will provide new approaches to the management of ocular HSV infections.

Presumed chronic ocular histoplasmosis syndrome: a clinical-pathologic case report.

An eye of a patient with clinically typical presumed ocular histoplasmosis was studied by light microscopy, electron microscopy and immuno-fluorescence techniques. There was clinical and pathological evidence of anterior segment involvement. The posterior segment showed granulomatous and nongranulomatous chorioretinal lesions with and without subretinal neovascularization. Immunohistopathological staining for histoplasma antigens revealed positive staining at sites of lymphoid inflammation. Organisms were not identified.

Experimental allergic uveitis: induction by retinal rod outer segments and pigment epithelium.

EAU was produced in strain 13 guinea pigs after immunization with purified guinea pig retinal rod outer segments and with retinal pigment epithelium in mycobacterial adjuvant emulsion. The lesions of EAU appear as inflammatory infiltrates of the iris and ciliary body followed by choroidal inflammation, often with retinal photoreceptor degeneration. Specific antibodies are detected in the serum of a majority of the animals with clinical disease. Immunohistochemical staining of normal and inflamed eyes with serum from the immunized animals with uveitis demonstrates specific antigens localized in the outer segments. All immunized animals demonstrate delayed-type hypersensitivity characterized by skin reactions of mononuclear cells, by the in vitro inhibition of migration of peritoneal macrophages from the sensitized animals in the presence of specific antigen, and by antigen-specific lymphocyte stimulation. More pronounced delayed-type hypersensitivity reactions occurred during uveitis and indicated that cellular immunity correlates with clinical EAU, whereas no correlation was found with serum antibody. Successful experiments at transferring clinical disease passively with sensitized lymphocytes from animals with uveitis to normal recipients were conducted via the intravenous as well as intravitreal routes. No inflammatory reactions occurred after similar transfer of nonsensitized lymphocytes. The recipients of the passively transferred cells demonstrated both humoral and delayed type hypersensitivity to the retinal antigens. These findings suggest that the retinal rod outer segments and pigment epithelium are the sourve of significant antigens in autoimmune uveitis and retinitis.

Pathogenesis of experimental allergic uveitis induced by retinal rod outer segments and pigment epithelium.

Experimental allergic unveitis (EAU) was produced in strain 13 guinea pigs after immunization with purified guinea pig retinal rod outer segments and pigment epithelium (PE) in mycobacterial adjuvant emulsion. The lesions of EAU appear as inflammatory infiltrates of the iris, ciliary body, and choroid, often with photorecptor degeneration. Specific antibodies are frequently detected in the serum of some but not of all animals with clinical uveitis. Immunohistochemical staining of normal and inflamed eyes with serum from the immunized animals with clinical disease demonstrated specific antigens localized in the retinal photoreceptor layers, whether or not circulating precipitating antibodies were also present in the serum. All immunized animals demonstrated delayed-type hypersensitivity (DTH) characterized by skin reactions of mononuclear cells and by the vitro inhibition of migration of cells from the sensitized animals in the presence of specific antigen whether or not clinical uveitis occurred. However, stronger DTH reactions were observed during clinical uveitis. Cellular immunity appears to correlate with clinical EAU, whereas, no correlation was found with serum antibody. These findings suggest that the retinal photoreceptor cell and PE are the source of the significant antigens in autoimmune uveitis and retinitis.

In vivo bicarbonate secretion by human esophagus.

The capacity of the human esophagus to secrete bicarbonate was studied in vivo in 10 healthy subjects. A 10-cm segment of the lower esophagus was isolated between two balloons, and the segment was perfused with an unbuffered isotonic saline solution (pH 7) for 30 minutes. The perfusate was collected, pooled, and analyzed for bicarbonate using a sensitive back-titration method. Measurements of aspirate amylase and salivary amylase and bicarbonate permitted correction of perfusate bicarbonate values for contamination by swallowed saliva. The esophagus of all 10 subjects were found to secrete bicarbonate in amounts ranging from 10 to 274 microEq/30 min (average, 78 microEq/30 min); based on in vitro studies, these amounts of bicarbonate were shown to be capable of neutralizing enough residual acid from an episode of reflux to increase pH from 2.5 almost to neutrality (pH 6-7). These findings document the presence within the human esophagus of an additional mechanism for defense against (acid) reflux damage, namely, through enhanced luminal acid clearance by the secretion of bicarbonate ions.

Effect of prostaglandin on the blood aqueous barrier in the rabbit ciliary process.

Distinct structural changes occur in the rabbit ciliary epithelium following intravitreal injection of prostaglandin E-1 (PGE-1). Up to four hours after PGE-1 administration, alteration of the pigmented epithelium was characterized by dilated intercellular spaces and the disruption of many intercellular junctions. The nonpigmented epithelium demonstrates a spectrum of morphologic variation from only some thinning of cytoplasmic processes to area of severe distortion. In these regions, marked thinning of the nonpigmented cells occurs in association with an absence of apical tight junctions. This alteration of the nonpigmented epithelium and its tight junctions allows for the leakage of proteins into the posterior chamber which is consistent with the breakdown in the blood-aqueous barrier. The temporal sequence of these changes would suggest a differential susceptibility of the pigmented and nonpigmented layers with the pigmented layers being affected earliest and the nonpigmented epithelium altered subsequently. The recovery of this epithelial change was rapid and complete and demonstrated the transient effects of PG on the ciliary epithelium with recovery of the blood-aqueous function by 8 hours after injection.

Protection against alkali injury to rabbit esophagus by CO2 inhalation.

Lye ingestion, a poisoning with no known effective treatment, frequently results in esophageal ulceration and healing by stricture formation. Tissue injury by lye is due to its alkalinity, and so therapy is logically directed at neutralization by acid. Here we describe a novel method, the inhalation of CO2, for the rapid delivery of (carbonic) acid capable of neutralizing tissue and luminal alkalinity. We also show that CO2 inhalation in anesthetized rabbits provides protection to the lye-exposed esophagus against transepithelial necrosis. This method has the potential to protect the human esophagus against lye injury, because it is relatively safe, rapidly effective, and can be administered in the field under emergency circumstances.

Vascular responses of umbilical-placental circulation to vasodilators in fetal lambs.

It has been suggested that the umbilical-placental circulation is maximally vasodilated under normal conditions. To test this hypothesis, we investigated the effect of vasodilators on umbilical-placental vascular resistance. In nine chronically instrumented fetal lambs, catheters were placed in the descending aorta, umbilical artery, umbilical vein, and inferior vena cava. Umbilical-placental blood flow was measured by an electromagnetic flow probe placed around the common umbilical artery. Forskolin and nitroglycerin both dilated the umbilical-placental circulation, causing a dose-dependent decrease in umbilical-placental resistance to approximately 80% of baseline, indicating that the umbilical-placental circulation has some dilatory reserve. Both the adenosine 3',5'-cyclic monophosphate and the guanosine 3',5'-cyclic monophosphate mechanisms, which are directly stimulated by forskolin and nitroglycerin, respectively, are functional in the umbilical-placental circulation. However, the vasodilators prostacyclin and adenosine, which act through specific cell membrane receptors, have no effect on the umbilical-placental resistance. The inability of these agents to dilate the umbilical-placental circulation could be due to a lack of the appropriate receptors in the umbilical-placental vasculature.

Effect of maternal oxygen administration on fetal oxygenation during graded reduction of umbilical or uterine blood flow in fetal sheep.

OBJECTIVE: Effects of maternal oxygen administration on fetal blood gases and on oxygen delivery and consumption during reduced uterine and reduced umbilical blood flows were examined. STUDY DESIGN: In eight pregnant sheep (gestational age 133 +/- 4 days) flow transducers were applied to a uterine and the common umbilical artery. Graded reductions in uterine and umbilical blood flows were achieved by a hypogastric artery snare and a balloon cuff encircling the umbilical cord. Fetal femoral arterial and umbilical venous oxygen contents and flows were measured at varying flow reductions with the ewe breathing air or oxygen. RESULTS: During 75% reduction in umbilical blood flow maternal oxygen administration significantly increased fetal oxygen delivery (6.4 +/- 2.5 to 7.7 +/- 2.3 ml/min/kg) and oxygen consumption (4.3 +/- 1.2 to 5.0 +/- 0.8 ml/min/kg). With similar reduction of uterine flow oxygen administration increased oxygen delivery from 8.3 +/- 2.4 to 12.3 +/- 3.6 and oxygen consumption from 3.3 +/- 0.8 to 4.7 +/- 1.6 ml/min/kg. CONCLUSION: Maternal oxygen inhalation improves fetal oxygenation during umbilical but especially during uterine blood flow reduction.

Cardiovascular responses to acute, severe haemorrhage in fetal sheep.

In adults, the responses to acute haemorrhage vary greatly depending on the amount of blood lost. While many studies have documented fetal responses to mild haemorrhage, fetal responses to severe haemorrhage are not known. In this study we examined the effect of acute, severe haemorrhage in fetal lambs. Despite the severity of haemorrhage, we found that mean arterial blood pressure was restored within 2 min, and heart rate was restored within 30 min. This restoration of blood pressure and heart rate was facilitated by an increase in peripheral vascular resistance mediated in part by secretion of catecholamines and plasma renin. In addition, about 40% of the shed blood volume was restored within 30 min by fluid from either the fetal interstitium or placenta. The PO2 of umbilical venous blood increased from 33 +/- 9 mmHg to 49 +/- 17 mmHg 2 min post-haemorrhage, and to 47 +/- 15 mmHg 30 min post-haemorrhage. However, this increase was not sufficient to offset the fall in both haemoglobin concentration and umbilical-placental blood flow, so that oxygen delivery decreased from 21.1 +/- 5.5 ml/min per kg to 9.1 +/- 5.2 ml/min per kg 2 min post-haemorrhage, and 14.1 +/- 9.2 ml/min per kg 30 min post-haemorrhage. Because of this decrease in oxygen delivery, oxygen consumption fell and a metabolic acidemia ensued. Nevertheless, oxygen delivery to the heart and brain was maintained because hepatic vasoconstriction diverted more of the well oxygenated umbilical venous return through the ductus venosus. Although the fetus was able to tolerate acute loss of 40% of blood volume, larger volumes of haemorrhage resulted in fetal death.

Umbilical and hepatic venous responses to circulating vasoconstrictive hormones in fetal lamb.

Acute fetal hypoxemia increases the vascular resistance of the umbilical veins as well as that of the liver. Because, at least in the human, the umbilical-placental circulation has no autonomic innervation, circulating hormones could well be responsible for this increase in umbilical-placental outflow resistance. In chronically instrumented fetal sheep, norepinephrine, epinephrine, vasopressin, and angiotensin II were infused in sequentially increasing doses into the descending aorta and vascular resistance to umbilical-placental blood flow was measured. Norepinephrine and epinephrine increased the vascular resistance of the umbilical veins in a dose-dependent manner. Both catecholamines also increased the vascular resistance of the liver, resulting in an increase in ductus venosus blood flow. In contrast, vasopressin and angiotensin II had no effect on umbilical-placental outflow resistance. Thus catecholamines may be responsible for the increase in the vascular resistance of the umbilical veins and liver in response to acute fetal hypoxemia.