Purpose of the Study The survival rate of central nervous system (CNS) tumors is increasing, but more side effects are recognized in survivors, as a result of tumor, chemo-, and radiotherapy given as treatment. We performed a retrospective analysis of cases identified as having brain tumors with survival for at least 5 years. We analyzed the charts to determine the frequency of late effects in those children who had survived their initial disease. Methods Used 296 children, diagnosed with CNS tumors from 1986 to the present, were identified; 225 patients were eligible for inclusion in the analysis. Patients with spinal cord tumors, lymphomas, and germinomas were excluded. There were 69 patients with 5+ years survival. Data were not available for 16 patients, leaving 53 patients for analysis. Cases were then restricted to those with astrocytoma, medulloblastoma, and ependymoma, leaving 42 patients for final analysis. Summary of Results There were 21 astrocytoma, 16 medulloblastoma, and 5 ependymoma patients. Among our patients, 71%. The problems identified included brain necrosis (5%), atrophy (12%), encephalopathy (5%), seizures (4%), hearing loss (16%), visual defect (9%), linear growth defect (1%), growth hormone deficiency (5%), sexual maturational delay (8%), intellectual/motor problems (33%), and behavioral problems (2%). The majority of side effects were seen in those individuals who received a combination of chemotherapy and radiation therapy; side effects were also more common after medulloblastoma. Among individuals receiving radiation only, necrosis was a more common effect, as was cerebral atrophy. In those having chemotherapy only, encephalopathy was more commonly seen than in those receiving radiation alone. Patients undergoing only surgery had a tendency to develop visual defects, and seizures were present in these individuals to the same extent as those receiving combination therapy. Among those with combination treatment, hearing loss was significant, as was atrophy and necrosis of the brain, and visual defect. Intellectual impairment was seen in all treatment groups but especially in those receiving chemotherapy and radiation combined. Combination therapy also resulted in the greatest degree of hormonal defects. Conclusion Late effects can be associated with increased morbidity and impaired quality of life. Combination therapy, although improving survival, can be associated with significant long-term complications.

Occhipinti, Elise MD*; Correa, Hernan MD*; Yu, Lolie MD†; Craver, Randall MD* Author Information

Background Disseminated intravascular coagulation (DIC) is a pathological disturbance of the complex balance between coagulation and anticoagulation that is precipitated by vascular injury, acidosis, endotoxin release and/or sepsis and characterized by severe bleeding and excessive clotting. The innately low levels of coagulation factors found in newborn infants place them at extremely high risk for DIC. Anecdotal reports suggest that either anticoagulant or fibrinolytic therapy may alleviate some of the manifestations of DIC. To test the hypothesis that replacement of both anticoagulants and fibrinolytics may improve survival and outcome better than either single agent or supportive care alone, we utilized a neonatal piglet model of endotoxin-induced DIC. Methods DIC was induced in twenty-seven neonatal pigs (7 to 14 days of age) by intravenous administration of E. coli endotoxin (800 μg/kg over 30 min). The piglets were divided into 4 groups on the basis of treatment protocol [A: supportive care alone; B: Antithrombin III (AT, 50 μg/kg bolus, 25 μg/kg per hr continuous infusion) and supportive care; C: Recombinant Tissue Plasminogen Activator (R-TPA, 25 μg/kg per hr continuous infusion) and supportive care; D: AT, R-TPA and supportive care] and monitored for 3 primary outcome parameters (survival time, macroscopic and microscopic organ involvement) and 4 secondary outcome parameters (hematocrit; platelet count; fibrinogen level; and antithrombin III level). Results Compared with supportive care alone, combination therapy with AT and R-TPA resulted in a significant improvement of survival time, hematocrit, AT level, macroscopic and microscopic organ involvement, p < 0.05. Compared with supportive care alone, R-TPA alone significantly reduced macroscopic organ involvement and AT alone increased AT levels. Conclusion The findings suggest that combining AT, R-TPA and supportive care may prove more advantageous in treating the clinical manifestations of DIC in this neonatal pig model than either single modality or supportive care alone.

Background : The development of a vaccine against Helicobacter pylori has become a priority to prevent major morbidity and mortality associated with this infection. Our goal was to prepare and evaluate a DNA vaccine based on the urease B gene (ureB).Methods : The ureB gene of H. pylori was amplified and cloned into the eukaryotic expression vector pcDNA3.1/TOPO. Plasmid DNA was purified from transformed Escherichia coli cells and used to immunize mice by the intragastric, intramuscular, intrarectal (40 mu g each) and intranasal (16 mu g) route, three doses every 2 weeks, with CpG oligodeoxynucleotide (ODN) as adjuvant. Four weeks after the third dose, animals were orally challenged with Helicobacter felis and were sacrificed 6 weeks later. The stomach was stained to detect the presence of infection.Results : Despite in vitro confirmation of successful cloning and functionality of the ureB gene with expression of a protein morphologically and antigenically identical to urease B, the DNA vaccine did not perform well in vivo. Immunization of mice produced a weak immune response. Overall, intrarectal and intranasal administration seemed more immunogenic than other routes. Protection against challenge was modest and nonsignificant, and slightly better on animals immunized by the intramuscular and intranasal route.Conclusion : A DNA vaccine based on H. pylori urease B was poorly immunogenic and nonprotective at the conditions evaluated. Higher doses, better adjuvants or a prime-boost approach may circumvent these limitations.

Background and Aims: Interferon regulatory factor‐1 (IRF‐1) is a transcription factor with antiviral, proinflammatory and tumor suppressor properties. We examined the role of IRF‐1 in dextran sulfate sodium colitis, a murine model of inflammatory bowel disease, to determine if absence of the gene would protect against colitis.

Background. We previously reported that mice with diabetes and short-term Helicobacter felis infection had an increase in glycated hemoglobin (HbA(1c)). Here we report the effect of long-term infection.Materials and Methods. Six-week-old C57BL/6 mice were injected with streptozotocin to induce diabetes and started on daily insulin. Following streptozotocin injection, animals were paired according to their HbA(1c) values and randomized to orally receive either H. felis or culture medium alone. Weight and HbA(1c) were monitored monthly for 6 months.Results. Thirty animals corresponding to 15 pairs were included in the study. H. felis-infected diabetic mice developed significantly more gastritis than uninfected animals. Sixteen mice died during the observation period. As compared to uninfected animals, infected mice died more frequently (40% versus 67%, p = .14) and earlier (160 versus 61 days, p = .20); both variables combined showed that H. felis infection significantly decreased the chances of survival during the study period (p = .045). In addition, infected mice showed a trend for higher increase in their HbA(1c) (0.97 +/- 2.5% versus - 0.22 +/- 3.0%; p = .21) and lower weight gain (2.0 +/- 3.4 g versus 2.9 +/- 2.0 g; p = .15) than uninfected mice.Conclusion. Long-term H. felis infection had a deleterious effect in mice with streptozotocin-induced diabetes resulting in increased mortality. If the same phenomenon occurs in humans this could lead to interventions to improve the long-term outcome of patients with diabetes.

Background. The category, cytology, cytogenetics (CCC) system for myelodysplastic syndrome (MDS) and the pediatric WHO system for MDS/myeloproliferative disorder (MPD) have recently been proposed to characterize these diseases in pediatrics. Objective. We compare the CCC and pediatric WHO systems against each other and against the French, American, British (FAB) and adult WHO classifications in order to determine which more accurately classifies these diseases and predicts Outcome. Methods. An 18-year retrospective review identified patients less than 18 years of age meeting CCC and/or pediatric WHO criteria for the diagnosis of MDS or MPD. Resolution, stability, progression, and death in the subcategories of each system were compared. Results. Twenty-eight patients were included in the study. Pediatric WHO: 17 patients met criteria, 10 died. Eight developed acute myelogenous leukemia (AML) (seven died), one juvenile myelomonocytic leukemia (JMML) (died), one Chronic myelomonocytic leukemia (CMML) (Currently in relapse), two died of complications, two responded to BMT, three have stable disease, one resolved. Eleven patients were not classifiable by the pediatric WHO system, one of which progressed to AML and died. CCC: 26 patients met criteria, 9 died. Nine developed AML (8 died), I died of complications, 10 responded to treatment (BMT and/or chemotherapy). Four are stable without treatment, two resolved. Two patients with MPD were not classifiable by the CCC system. Conclusions. Both the pediatric WHO and CCC systems are better able to classify MDS in children than the adult WHO and FAB classifications. The pediatric WHO system is more exclusive. Children meeting these criteria are more likely to progress to AML or death. The restrictive nature of the pediatric WHO system was unable to classify one case of fatal MDS. The CCC system is more inclusive and can stratify patients into a neutral or poor prognosis based upon outcome. However, the CCC system ignores those diseases with a myeloprolifferative component. This resulted in two cases of MPD that were unclassifiable by the CCC system. One of these patients died, the other is currently in relapse. (C) 2004 Wiley-Liss, Inc.

BACKGROUND: Polymorphisms in several genes (NOD2, MDR1, SLC22A4) have been associated with susceptibility to Crohn's disease. Identification of the remaining Crohn's susceptibility genes is essential for the development of disease-specific targets for immunotherapy. Using gene expression analysis, we identified a differentially expressed gene on 5q33, the colony stimulating factor 1 receptor (CSF1R) gene, and hypothesized that it is a Crohn's susceptibility gene. The CSF1R gene is involved in monocyte to macrophage differentiation and in innate immunity. METHODS: Patients provided informed consent prior to entry into the study as approved by the Institutional Review Board at LSU Health Sciences Center. We performed forward and reverse sequencing of genomic DNA from 111 unrelated patients with Crohn's disease and 108 controls. We also stained paraffin-embedded, ileal and colonic tissue sections from patients with Crohn's disease and controls with a polyclonal antibody raised against the human CSF1R protein. RESULTS: A single nucleotide polymorphism (A2033T) near a Runx1 binding site in the eleventh intron of the colony stimulating factor 1 receptor was identified. The T allele of this single nucleotide polymorphism occurred in 27% of patients with Crohn's disease but in only 13% of controls (X2 = 6.74, p < 0.01, odds ratio (O.R.) = 2.49, 1.23 < O.R. < 5.01). Using immunohistochemistry, positive staining with a polyclonal antibody to CSF1R was observed in the superficial epithelium of ileal and colonic tissue sections. CONCLUSIONS: We conclude that the colony stimulating factor receptor 1 gene may be a susceptibility gene for Crohn's disease.

Infection with Helicobacter pylori has been recognized as a cause of gastric carcinoma. Although the neoplasia is always detected in adults, the infection starts in childhood. It has been reported that early age at first infection is a determinant of gastric cancer risk. In this study, we examined the histopathology of the gastric mucosa in infected children from a population at high risk for gastric cancer (Pasto, Colombia) and compared it with that of a lower-risk population (New Orleans, LA). Gastric biopsies obtained from antrum and corpus were stained with hematoxylin and eosin and Steiner's silver method. Immunohistochemical stains were used to identify B lymphocytes (CD20), T lymphocytes (CD3 and CD8), macrophages (CD68), and polymorphonuclear neutrophil myeloperoxidase. Morphometric techniques were used to evaluate the immunohistochemical stains. In both populations, the inflammatory lesions were seen predominantly in the antrum. Compared with children from the lower-risk populations, children from the higher-risk population exhibited more severe polymorphonuclear neutrophil infiltration, stromal and intraepithelial lymphocyte infiltration, mucus depletion, and H. pylori colonization density. Regenerative activity was significantly more marked in the lower-risk population. Morphometric analysis of immunohistochemical stains showed increased representation of T lymphocytes and macrophages in the higher-risk population. Most T lymphocytes stained positive for CD8, a marker of suppressor/cytotoxic cells. B lymphocytes were relatively more abundant in the lower-risk population. The possibility that the aforementioned characteristics of H. pylori infection in children are related to cancer risk in adults is discussed. Hum Pathol 34:206-213. Copyright 2003, Elsevier Inc. All rights reserved.

A 3-year-old boy had fever and bone pain. Magnetic resonance imaging of his femurs showed marrow replacement; iliac crest marrow biopsy revealed myelofibrosis. Although the pathologic criteria for Langerhans cell histiocytosis were not met, the clinical picture led to treatment with etoposide and methylprednisolone, without clinical improvement. One month after presentation, generalized tonic-clonic seizures occurred, and magnetic resonance imaging revealed parenchymal brain lesions. 2-chlorodeoxyadenosine was used. Because of the unexpected lack of response to etoposide and methylprednisolone, a second bone biopsy was performed. The diagnosis was revised to infantile myofibromatosis. After six courses of 2-chlorodeoxyadenosine, brain and bone lesions regressed, with resolution of the clinical symptoms.

Perinatal herpes simplex virus (HSV) is caused by HSV type 2 transmitted from the mother to the child during delivery when the infant has direct contact with infected maternal genital secretions. Manifestations of the disease occur between the First and second week of life. The hallmark of the infection is skin vesicles. However, 45% of infected newborns initially have no vesicles. Other signs of infection include temperature instability, lethargy, hypotonia, respiratory difficulty, convulsions, hepatitis, and disseminated intravascular coagulopathy (DIC). Newborns with disseminated disease and visceral organ involvement usually have hepatitis, pneumonitis, and/or DIC with or without encephalitis or skin disease, The diagnosis is frequently made at autopsy with immunohistochemical stains, especially if the mother has not had prenatal care.

Posttransplant lymphoproliferative disorders are often accompanied by >500 Epstein-Barr virus (EBV) genome copies/10(5) lymphocytes, and they occur shortly after transplantation. Hodgkin lymphoma occurs rarely after transplantation, appearing a mean of 4.2 years posttransplant, and although Hodgkin lymphoma has strong associations with EBV, no quantitative analysis of peripheral blood EBV genome copies has been reported. A mixed cellularity Hodgkin lymphoma developed in a 17-year-old boy 4 years after a renal transplant. Serial EBV genome copy numbers from blood by competitive polymerase chain reaction had been obtained to assess for lymphoproliferative disease. Epstein-Barr virus genome copy numbers peaked at 500 copies/10(5) lymphocytes 8 months prior to Hodgkin lymphoma diagnosis but fell to 8 copies/10(5) lymphocytes at diagnosis. Reliance on EBV levels greater than 500 copies may result in delay of biopsy and diagnosis of Hodgkin disease in the posttransplant setting.

We present a 10-day-old boy who developed fulminant urosepsis. At autopsy, he was found to have a prostatic abscess as his sole source of infection. We reviewed the 12 previous reported cases of prostatic abscess in newborns and present factors that may suggest the diagnosis. The treatment and outcome in each of the cases are also presented.

Pediatric Hematology/Oncology, Pathology, Surgery, LSU Health Sciences center/Children's Hospital, New Orleans, LA