Studies of iodixanol in the rabbit lung and peritoneum.

OBJECTIVE: To evaluate a new water-soluble contrast agent, iodixanol. The study evaluates absorption from the peritoneal cavity and toxicity in the lung. MATERIALS AND METHODS: Thirty New Zealand white rabbits were given the study agent and comparative agents into an endotracheal tube. Serial chest radiographs were evaluated for development of pulmonary edema. All lungs were evaluated histopathologically for toxic inflammatory response. Fifteen different rabbits were given intraperitoneal injection of the study and comparative contrast agents. Serial abdomen radiographs, taken up to 24 h after injection, were evaluated for contrast absorption from the peritoneal cavity. RESULTS: Evaluation of indicators of pulmonary edema demonstrated that iodixanol caused the same or less pulmonary edema than comparative agents. Histopathologic analysis showed that iodixanol caused less macrophage response than saline (P = 0.010), the same lymphocyte infiltration as saline (P = 0.472), the same neutrophil response as saline (P = 0.297), and the same vasculitic reaction as saline (P = 0.128). Compared to iohexol 270, iodixanol caused the same macrophage infiltrate (P = 0.924), the same lymphocyte infiltration (P = 0.523), more neutrophil reaction (P = 0.007), and less vasculitic reaction (P = 0.042). Iodixanol was rapidly absorbed from the peritoneal cavity. CONCLUSION: Iodixanol is a new contrast agent that is isotonic at all clinically useful iodine concentrations. It appears safe in the lung and is absorbed from the peritoneal cavity.

Surgical resection alone is effective treatment for ovarian immature teratoma in children and adolescents: a report of the pediatric oncology group and the children's cancer group.

OBJECTIVE: In both adult women and children the potential for malignant recurrence from ovarian immature teratoma has prompted the standard use of chemotherapy after complete resection of the primary tumor. The efficacy of postoperative chemotherapy in children and adolescents with ovarian immature teratoma, however, has not been established. A pediatric intergroup trial (INT 0106) was designed to determine the need for postoperative chemotherapy in patients with ovarian immature teratoma after management with surgical resection only. STUDY DESIGN: Between 1990 and 1995, 44 patients with completely resected ovarian immature tumor and without postoperative chemotherapy, who were able to undergo assessment, were accrued. Tumor tissue was evaluated by central pathology review to confirm diagnosis and determine tumor grading of immature neural elements. Patients were followed carefully for recurrence of disease with appropriate diagnostic imaging and serum marker studies. RESULTS: Thirty-one patients had pure ovarian immature teratoma with a tumor grade of 1 (n = 17), 2 (n = 12), or 3 (n = 2). Age at diagnosis ranged between 1.5 and 15 years (median, 10). Of the 29 patients studied, the serum alpha-fetoprotein level was elevated in 10 (34%); the median level was 25 ng/ml. Thirteen patients had ovarian immature teratoma plus microscopic foci of yolk sac tumor. Tumor grade was 1, 2, or 3 in 1, 6, and 6 patients, respectively. Age ranged between 6 and 20 years (median, 12). In the 12 patients evaluated for serum alpha-fetoprotein, 10 (83%) had elevated levels; the median level was 262 ng/ml. The 4-year event-free and overall survival for the ovarian immature teratoma group and for the ovarian immature teratoma plus yolk sac tumor group was 97.7% (95% confidence interval, 84.9%-99.7%) and 100%, respectively. The only yolk sac tumor relapse occurred in a child with ovarian immature teratoma and yolk sac tumor who was then treated with chemotherapy and is alive and free of disease 57 months after recurrence. CONCLUSION: The results of this study suggest that surgery alone is curative for most children and adolescents with resected ovarian immature teratoma of any grade, even when elevated levels of serum alpha-fetoprotein or microscopic foci of yolk sac tumor are present. This experience strongly supports avoiding the long-term effects of chemotherapy in most children with ovarian immature teratoma by reserving postoperative therapy for cases with relapse.

Candida funisitis: A clinicopathologic study of 32 cases.

We report on 32 cases of Candida funisitis and describe the associated clinicopathologic features. The Candida funisitis was characterized grossly by small, circumscribed, yellow-white nodules on the umbilical cord surface and, microscopically, by subamnionic microabscesses in which fungal organisms were demonstrable. Chorioamnionitis was present in all cases. Twenty-four (75%) of the 32 infants were premature. There were 7 perinatal deaths, all in immature fetuses. Five (16%) of the 32 fetuses had congenital candidiasis. Five (16%) of the mothers had a history of intrauterine foreign body, including intrauterine contraceptive device in three and cervical cerclage in two. The diagnosis of Candida funisitis should prompt a careful examination for fetal infection, even though it is associated with congenital candidiasis in only a minority of the cases.

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.

The detection of pulmonary metastases by helical CT: a clinicopathologic study in dogs.

PURPOSE: We sought to determine the accuracy of helical CT in the detection of pulmonary metastases. METHOD: Four anesthetized dogs with metastatic osteosarcoma underwent helical CT with a collimation of 5 mm, a pitch of 2, and a reconstruction interval of 5 mm. All macroscopically evident metastases were recorded at autopsy. CT images were independently reviewed by 10 radiologists and compared with pathologic results. Alternate slices in the dog with the most metastases were microscopically examined in their entirety. RESULTS: Pathologic examination of the lungs revealed 132 macroscopically evident pulmonary metastases, of which 74 (56%) were detected by at least one reader. Forty-four of the 99 (44%) metastases of < or = 5 mm in diameter were detected by at least one reader compared with 30 of 33 (91%) metastases of > 5 mm in diameter (p < 0.0001). The 10 readers reported a total of 107 false positives. Complete microscopy of alternate slices in the dog with the most metastases (n = 68) revealed an additional 38 micrometastases of < or = 3 mm in diameter. None of the 32 micrometastases of < or = 1 mm were detected by CT. CONCLUSION: Helical CT has some limitations in the detection of pulmonary metastases.

Hepatoblastoma: the Indiana experience with preoperative chemotherapy for inoperable tumors; clinicopathological considerations.

Analysis of the prognostic importance of various clinicopathological parameters in 17 hepatoblastomas (HBs) confirmed the utility of preoperative chemotherapy to convert inoperable to resectable tumors. There was no significant survival advantage for patients who underwent initial tumor resection compared with those resected following chemotherapy, although complete resection, with or without prior chemotherapy, was critical for cure. Young age was associated with better survival but did not correlate with histologic subtype or clinical stage. A relationship between low initial alpha-fetoprotein (AFP) level and tumor resectability was noted, perhaps related to tumor size, but tumor location was of greater importance than size in determining resectability. Neither the mean proportions of fetal and embryonal epithelium, nor their mitotic activity, nor the presence of vascular invasion in the prechemotherapy biopsy specimens was predictive of outcome, but the low mitotic activity of the fetal component correlated with ultimate resectability. On the other hand, although complete resection was necessary for survival, histologic examination of postchemotherapy specimens had additional predictive value; the presence of vascular invasion, the amount of viable mesenchyme, the extent of tumor necrosis, the proportion of embryonal epithelium, and the mitotic activity of the epithelial component in postchemotherapy resection specimens were each predictive of outcome. Although the presence of osteoid was not predictive, both the proportion of HBs that contained osteoid and the extent of mature mesenchymal tissues within individual HBs were increased by chemotherapy, suggesting that maturation of previously immature clones had been induced. We conclude that although complete resectability remains the fundamental goal of therapy, evaluation of the clinicopathologic characteristics that we have found to be predictive of outcome may permit tailoring of therapeutic regimens to individual patients; those whose tumors are deemed likely to respond well may require less toxic preoperative chemotherapy, and those deemed likely to progress in spite of complete resection may be considered for more aggressive postoperative regimens.

Feasibility of sequential high-dose chemotherapy and peripheral blood stem cell support for pediatric central nervous system malignancies.

BACKGROUND: The outlook for many brain tumors remains poor. Increased dose intensity has been correlated with response rate and survival in many solid tumors. PATIENTS AND METHODS: Ten children with recurrent or newly diagnosed brain tumors were treated with four sequential courses of high-dose single agent chemotherapy with peripheral blood stem cell (PBSC) support. PBSC harvesting was undertaken prior to chemotherapy and following the first course of chemotherapy (3.6 g/m2 etoposide). Each course of chemotherapy consisted of a single drug followed 48 hours later by PBSC reinfusion. Three patients were treated on Regimen A: etoposide, carboplatinum 1.95 g/m2, cyclophosphamide 5 g/m2, and thiotepa 300 mg/m2; three patients were treated on Regimen A' with carmustine 600 mg/m2 replacing cyclophosphamide; four patients received Regimen B: etoposide, carboplatinum 1.95g/m2, cyclophosphamide 7 g/m2, and thiotepa 900 mg/m2. RESULTS: No course of chemotherapy was complicated by >14 days of neutropenia. Platelet recovery was more prolonged, particularly in patients who had previously received craniospinal irradiation. Non-hematologic toxicity was severe with three toxic deaths including two patients who developed hemolytic-uremic syndrome and respiratory failure. Two of three patients with primitive neuroectodermal tumors had a partial response; no responses were observed in patients with high-grade gliomas. CONCLUSIONS: Administration of multiple courses of high-dose chemotherapy with PBSC support is feasible in this patient population and successfully mitigates hematologic toxicity. Non-hematologic toxicity becomes prohibitive as chemotherapy doses are escalated.

The prepubertal testis (prenatal and postnatal): its relationship to intratubular germ cell neoplasia: a combined Pediatric Oncology Group and Children's Cancer Study Group.

Seminiferous tubules adjacent to germ cell tumors (GCT) in prepubertal boys frequently contain increased germ cells with abundant, clear cytoplasm. These cells are placental alkaline phosphatase (PLAP) negative and are usually not considered to represent intratubular germ cell neoplasia (ITGCN). A recent case report found p53 and proliferating cell nuclear antigen (PCNA) positivity in such cells and equated these PLAP-negative cells with ITGCN. Because the proto-oncogene c-kit is also a marker of ITGCN, immunohistochemical tests for c-kit and PLAP were performed on 28 testes adjacent to prepubertal GCT in children aged 2 to 45 months. Additional slides from testes not associated with GCT from 18 preterm infants and children ages 19 weeks to 7 years were also tested. An adult testis with seminoma and ITGCN served as a positive control. PCNA, PLAP, and p53 were tested on available slides. No intratubular germ cells adjacent to GCT in prepubertal children were positive for PLAP or c-kit; five of seven were positive for PCNA; p53 was present in the two examined. These results indicate that germ cells adjacent to infantile GCT are proliferative but not neoplastic and offer additional evidence that intratubular germ cells and GCT in prepubertal boys are different from those of adolescents and adults.

Anterior pericardial tracheoplasty for congenital tracheal stenosis: intermediate to long-term outcomes.

BACKGROUND: Although several techniques for the treatment of long-segment stenosis of the trachea have been reported, including slide tracheoplasty, rib grafting, and use of a pericardial patch, the optimal repair remains controversial because of a lack of midterm to long-term follow-up data. METHODS: To assess the intermediate and long-term outcomes of patients having repair with anterior pericardial tracheoplasty, we reviewed case histories of 12 patients (1984 to present). The median age was 6.7 months (range, 1 to 98 months), and the median weight was 6.0 kg (range, 0.97 to 42 kg). All patients underwent anterior pericardial tracheoplasty through a median sternotomy during partial normothermic cardiopulmonary bypass. An average of 13 tracheal rings (range, five to 23) were divided anteriorly, and a patch of fresh autologous pericardium was used to enlarge the trachea by 1.5 times the predicted diameter for patient age and weight. RESULTS: There was one hospital death, and all but 2 patients are long-term survivors. All but 1 current survivor remain asymptomatic, with no bronchoscopic evidence of airway obstruction or granulation on the pericardial patch. All survivors examined have normal tracheal growth and development, with a median follow-up of 5.5 years (range, 1 to 11 years). CONCLUSIONS: Anterior pericardial tracheoplasty for congenital tracheal stenosis provides excellent results at intermediate to long-term follow-up.

Fetal tissue derived from spontaneous pregnancy losses is insufficient for human transplantation.

OBJECTIVE: To determine if sufficient fetal tissue with desirable transplant characteristics can be obtained from spontaneous abortions. METHODS: A survey of fetal tissues collected from newly diagnosed spontaneous pregnancy losses from three Indianapolis hospitals was conducted from December 1992 to September 1993. Forty-nine of 356 mothers (13.8%) with spontaneous abortions or ectopic pregnancies consented to the evaluation of their products of conception by gross and microscopic pathologic examination, bacterial culture, cytogenetic analysis, cell culture, and maternal serologic tests. RESULTS: Forty-nine pregnancies (gestational age range 5-30 weeks) provided four identifiable embryos, 12 second-trimester fetuses, and one third-trimester fetus. Nine samples (18.4%) were of excellent or good quality on pathologic grading. Twenty-five of 38 samples tested (66%) grew pathogenic bacteria. Maternal serologic tests were negative for antibodies to human immunodeficiency virus, human T-cell lymphotropic virus, syphilis, and hepatitis B in all cases. One of 43 sera was reactive for hepatitis C, and 33 (77%) were positive for cytomegalovirus. Cytogenetic abnormalities were found in 25% of cultured samples. Five fetal brain samples had cell viabilities of 50% or more. Few viable fetal hepatocytes were found. Only two fetal brain samples (4.1%) were potential candidates for human transplantation. CONCLUSION: Spontaneous pregnancy losses yield minimal usable tissue for human transplantation because of a lack of embryonic or fetal tissues, delayed collection, decomposition, genetic abnormality, and bacterial contamination.

Necrotizing funisitis associated with Actinomyces meyeri infection: a case report.

Necrotizing funisitis is associated with an increased rate of stillbirth, perinatal infection, and preterm delivery. No one organism has been associated with necrotizing funisitis, although this condition has been linked with congenital syphilis in some studies. We report a case of necrotizing funisitis in a 24-year-old G2P0A2 woman who experienced preterm labor at 31 weeks of gestation. Examination of the placenta revealed severe chorioamnionitis and necrotizing funisitis; large numbers of gram-positive filamentous branching organisms could be seen on the surface of the cord and within Wharton jelly. Initial cultures of the placenta, which had not been maintained under anaerobic conditions after delivery, were negative. A fragment of the cord was then homogenized; anaerobic culture on brain-heart infusion agar yielded Actinomyces meyeri. This organism usually resides in the periodontal sulcus and has not been previously reported in the female genital tract. The mother gave a history of a dental abscess that flared up and drained with each of her three pregnancies; the pain was particularly severe during the last 2 months of this pregnancy, so she had the tooth removed after delivery. The infant was treated for prematurity and presumed sepsis and did well.

Necrotizing funisitis and herpes simplex infection of placental and decidual tissues: study of four cases.

Necrotizing funisitis (NF) is a macroscopically and microscopically distinctive pattern of umbilical cord inflammation recently heralded as presumptive of congenital syphilis. Four nonsyphilitic cases are presented in which herpes simplex virus (HSV) 2 antigen was demonstrated in the placenta by immunohistochemistry. The clinicopathologic findings in one case, including HSV 2 antigen in amniotic epithelium, subamniotic chorion, and Wharton jelly, indicate that NF was caused by chronic ascending primary HSV 2 infection, whereas those of the other three cases with HSV 2 Ag confined to decidual cell clusters suggest that NF was caused by chronic ascending bacterial infection and that latent endometrial HSV 2 infection was fortuitous. We conclude that (1) NF is caused by protracted inflammation of a structure whose normal anatomy precludes removal of inflammatory debris; (2) no single pathogen causes NF; and (3) NF is strongly associated with latent endometrial HSV 2 infection, which should be sought in all instances. Although latent HSV 2 endometrial infection may be more prevalent than currently recognized, we speculate that its strong association with NF may be more than causal; whereas the usual ascending bacterial infection leads to labor before NF has had sufficient time to develop, latent endometrial HSV 2 infection may alter local paracrine factors and delay parturition for the time sufficient to permit NF, a morphological hallmark of chronicity, to become apparent.

Gastrointestinal abnormalities: a significant cause of feeding difficulties and failure to thrive in Brachmann-de Lange syndrome.

Gastroesophageal abnormalities occur with increased frequency in patients with Brachmann-de Lange syndrome (BDLS) and contribute to problems with feeding, emesis and failure to thrive. Comprehensive evaluation including longitudinal assessment of growth and development of 8 patients with BDLS was performed. Clinically significant feeding problems occurred in 6 of the 8 patients and the affected children were subsequently evaluated for gastrointestinal abnormalities. Findings in these patients included tracheal aspiration, esophageal dysmotility, gastroesophageal reflux, hiatal hernia, and esophagitis. Medical treatment was instituted where appropriate, and surgical treatment was performed if the problems did not resolve with medical treatment. Improvement in weight centiles occurred in all patients fed by nasogastric or feeding gastrostomy tube but only one patient appeared to experience increase in rate of linear growth. Careful monitoring of symptoms and growth parameters, and prompt institution of appropriate medical and surgical measures can improve the health and physical outcome of many patients with BDLS.

Ovarian neoplasms in children.

OBJECTIVE: To review the clinical presentation, treatment, and outcome in a series of children with ovarian neoplasms. DESIGN: A retrospective review of the medical records in a case series of 29 girls with ovarian neoplasms. The length of follow-up ranged from 6 months to 7 1/2 years and averaged 3.0 years in the girls with malignant tumors. SETTING: The patients were treated at a large referral children's hospital. PATIENTS: Twenty-nine girls with ovarian neoplasms were treated from 1976 to 1992. The average age of the patients was 10 years and ranged from 2 to 16 years. MAIN OUTCOME MEASURES: The principal outcomes examined were mortality and surgical morbidity. RESULTS: The most common presenting symptoms for these ovarian tumors in pediatric patients included chronic abdominal pain, an abdominal mass, or distention. Three girls presented with precocious puberty or hirsutism. In 27 cases, the tumor was a primary ovarian lesion. In two patients, the ovarian mass was the presenting finding for a stage IV non-Hodgkin's lymphoma. Seventeen tumors were benign and 12 were malignant. Tumors originating from the germ-cell line predominated (n = 17). Seven of the 10 ovarian malignant neoplasms were stage I at the time of diagnosis. All but one of the girls with malignant tumors received either adjunctive radiation therapy or multiple-agent chemotherapy. Two girls with sex cord/stromal cell tumors who presented with stage I disease ultimately developed widespread metastases. Both girls with large epithelial tumors survived. All of the girls with benign tumors and seven (70%) of 10 with malignant lesions survived. CONCLUSION: Ovarian tumors are unusual lesions in the pediatric population. Unlike in adults, such neoplasms generally originate from the germ-cell line. Whereas most ovarian tumors in girls are benign, some children have malignant tumors that are very aggressive and do not respond well to adjuvant therapy. In particular, malignant sex cord/stromal cell tumors, even when they present at an early stage, may behave unpredictably.

Urethral polyp presenting as interlabial mass in young girls.

We describe two young girls who presented with an interlabial mass. Histologic examination of each excised mass revealed a benign urethral polyp covered with transitional and squamous epithelium. Urethral polyps should be included in the differential diagnosis of an interlabial mass in young female patients.