Currently, there is no long-term effective treatment for unresectable hepatic malignancies. Salmonella sp. are known to naturally track to the liver during active infection. To develop a biological vector for delivery of Interleukin-2 (IL-2) to the liver for anti-tumor purposes, the avirulent and highly immunogenic chi 4550 strain of Salmonella typhimurium was used as a vector for IL-2. The gene for human IL-2 was cloned into plasmid pYA292 (renamed pIL-2) and inserted into the attenuated Salmonella typhimurium and renamed [chi 4550 (pIL-2)]. This transformant was found to produced biologically active IL-2 demonstrated by NK cell activation in a 4 hour chromium release cytotoxicity assay. To determine anti-tumor potential, MCA-38 murine adenocarcinoma cells were injected intrasplenically into C57BL/6 mice to produce hepatic metastases and metastases were subsequently enumerated after 12 days. Statistical significance was determined by ANOVA with Fisher's test for significance. Hepatic metastases enumerated by blinded observers revealed that the mean number of metastases was 106.4 in control mice, 103.7 in mice gavage fed attenuated salmonella without IL-2 [chi 4550(pYA292)], and 44.3 in mice fed the chi 4550(pIL2); (ANOVA: p < 0.01). Culture of livers and spleens in mice administered a single gavage dose of salmonella demonstrated persistent colonization for up to 4 weeks. No observable toxicity was seen to either IL-2 or salmonella. These studies demonstrate that the chi 4550(pIL2) is a novel form of in vivo biotherapy which produces biologically active IL-2 and employs the oral route of administration to stimulate an immune response against malignancy in the liver.

The melanotic neuroectodermal tumor of infancy is an uncommon neoplasm typically of early childhood which has a predilection for the head and neck region, particularly the maxilla. Except for one previous example in the literature, this tumor has consistently behaved in a benign fashion. This study documents the clinical course and pathologic findings of a tumor which began in the maxilla of a 4-month-old boy, followed by a local recurrence, metastasis to a cervical lymph node and finally, widespread dissemination and death at 18 months, 24 months and 38 months, respectively. The tumor was initially composed of nests consisting of melanin-containing cells and small dark cells. An elevated vanillylmandelic acid level was recorded during the course of the disease. At autopsy, the tumor in lymph nodes, liver, bone and soft tissues had a monotonous pattern of small dark cells similar to a conventional neuroblastoma. Previous ultrastructural studies indicate that the melanotic neuroectodermal tumor of infancy is composed of melanocytes and neuroblast-like cells. Our case provided the unique opportunity to examine in sequence the ultrastructural and in vitro characteristics of a recurring and eventually metastasizing melanotic neuroectodermal tumor. Although the neuroblast-like cells were initially difficult to identify by electron microscopy, a melanin-producing cell line and a separate nonpigmented cell line were successfully isolated from various tumor explants. Various stages of melanosome development were identified in the pigmented cells froni the local recurrences and in vitro. Dibutyryl CAMP accentuated the formation of pigment and dendritic development in the melanocytes and dendrites only in the small nonpigmented cells. Electron dense granules were observed in the cultured smaller cells and also in the lymph node and soft tissue metastases. Tyrosine hydroxylase activity was demonstrated in the neuroblast-like cells. In the final biopsy and autopsy material, only the neuroblast-like cells remained and the tumor resembled a conventional neuroblastoma.

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Postsplenectomy vulnerability to infection is not limited to age or disease process. Postsplenectomy infection is an emergency problem that requires immediate and accurate treatment because death is potential within a few hours of onset. Although the pathogenesis of overwhelming postsplenectomy sepsis is not completely understood, experimental evidence suggests that loss of mechanical filtration is more important than immunologic deficiences resulting from splenectomy. Certainly, a combination of both may be present. While no single measure seems to completely protect against overwhelming postsplenectomy sepsis, experimental evidence suggests that by reducing or minimizing the amount of spleen removed by newer surgical techniques, and by the addition of pneumococcal vaccine and prophylactic penicillin, the incidence of overwhelming sepsis can be reduced. Further evaluation of splenic function is necessary to assess the role of autotransplantation in the prevention of postsplenectomy sepsis (Fig. 1).Patients splenectomized at any age, for a variety of conditions including abdominal trauma, are susceptible to overwhelming bacterial sepsis [1-9]. As early as 1919, Morris and Bullock [10] suggested that removal of the spleen would increase susceptibility to infection, and this association between splenectomy and increased susceptibility to overwhelming sepsis was first documented in 1952 when King and Shumacker [11] reported 5 splenectomized infants with fulminant sepsis. The data of Smith et al. [12] regarding infection in postsplenectomy patients with thalassemia were corroborated by our own review at the University of Minnesota [ 1].

Central venous catheterization in children is relatively safe, with only a 3.2% complication rate and no mortality in our series.

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