Childhood Malignant Thymoma: Clinical, Therapeutic, and Immunohistochemical Considerations

Malignant thymomas are among the least common mediastinal tumors in the pediatric age group. Thymomas are considered malignant on the basis of macroscopic and microscopic invasiveness. As only 20 well-documented cases involving children have been reported in the literature, the pattern of responsiveness to therapy and the value of prognostic signs is obscure. Two cases of malignant pediatric thymomas are reported with pathognomonic histoimmunological features of aggressive thymoma. One was cured, with a follow-up of 70 months, and one died while on therapy. Analysis of the histological features and the immunoperoxidase staining displays the complexity of pediatric thymomas and the inability to prognosticate the outcome, respectively.     

Purification and characterization of placental heparanase and its expression by cultured cytotrophoblasts

The role of different extracellular matrix (ECM)-degrading enzymesin the normal functioning of the placenta is well documented.Heparan sulphate proteoglycan (HSPG) is an integral constituentof the placental and decidual ECM. Because this proteoglycanspecifically interacts with various macromolecules in the ECM,its degradation may disassemble the matrix. Hence, in the caseof the placenta, this may facilitate normal placentation andtrophoblast invasion. Crude placental specimens were collectedfrom first and third trimester placentas. Heparanase (endo-P-glucuronidase)was isolated and purified by ammonium sulphate precipitationfollowed by sequential chromatographies on carboxymethyl-, heparin-and ConA-Sepharose columns. The placental enzyme was furthercharacterized for its molecular weight and specific inhibitionby heparin, and was shown to resemble heparanase expressed byhighly metastatic tumour cells and activated cells of the immunesystem. In order to locate the source of heparanase activityin the placenta, primary cytotrophoblast cultures were established.Intact cells, as well as conditioned medium and cell lysates,were analysed for heparanase activity using metabolically sulphate-labelledECM as a natural substrate. Heparanase was highly active inlysates of cytotrophoblasts. This activity was also expressedby intact cytotrophoblasts seeded on ECM, but no activity couldbe detected in the culture medium. Incubation of the cytotrophoblastsin contact with ECM resulted in release of ECM-bound basic fibroblastgrowth factor (bFGF). We propose that the cytotrophoblasticheparanase facilitates placentation, through cytotrophoblastextravasation and localized neovascularization. cytotrophoblast/extracellular matrix/heparanase/heparan sulphate proteoglycan/placenta     

Antinuclear and related autoantibodies in sera of healthy subjects with IgA deficiency

The sera of 49 healthy IgA-deficient (SIgAD) subjects were evaluated for the presence of autoantibodies directed against 10 different nuclear and cytoskeletal antigens, as well as for the presence of the common lupus anti-DNA idiotype (16/6 Id). Twenty-nine sera were from IgG subclass-deficient subjects (4 = IgG2, 25 = IgG3), and 25 from normal healthy subjects, used as controls. The incidence of antinuclear but not anti-cytoskeletal antibodies were found to be significantly greater in the SIgAD group, as compared to the IgG-deficient subjects and the normal controls. Overall, 39% of SIgAD sera demonstrated polyreactivity, namely reactivity against more than one nuclear antigen. The incidence of specific antibody detection ranged from 37% against cardiolipin to 12% against RNP in the IgA-deficient group, albeit not with statistical significance in all cases when compared to the control group. Isotype evaluation of the antinuclear and related antibodies in the SIgAD group showed a greater tendency towards IgG. This increased incidence of autoantibody production in SIgAD may preceed the development of an overt autoimmune disease in the future.     

TREATMENT OF ALPHA-FETOPROTEIN SECRETING HEPATOBLASTOMA BY RESPONSE OF SERUM ALPHA-FETOPROTEIN LEVELS: A New Concept

Hepatoblastoma, thecommonest primary malignant livertumorin infants and children, is usually associated with elevated serum alpha-fetoprotein (AFP) levels. The authors sought to determine if AFP levels can be used to modify treatment, thereby avoiding the wait for formal imaging studies and prolonged suboptimal treatment and limiting the use of effective but toxic chemotherapy. From April 1984 to December 1997, 8 children were diagnosed with AFP-secreting hepatoblastoma. Serum AFP levels were measured weekly. If AFP levels failed to improve, or increased on at least 2 successive examinations, the chemotherapy protocol was changed. When an excellent response was achieved, less toxic chemotherapy was substituted. Six patients (75%) were disease-free for at least 2 years, some with high-risk or metastatic disease. Two patients died. Six of the 7 nonmetastatic patients (86%) remain disease-free (only one had a resectable tumor). Chemotherapy changes resulted in reduced AFP levels in 7 patients. This study supports the use of AFP monitoring to modify treatment in hepatoblastoma responding to therapy with less toxic drugs and the use of nonstandard therapy when suboptimal responses are obtained.     

T-cell acute lymphoblastic leukemia following therapy of rhabdomyosarcoma.

Multiple studies have documented an increased risk of secondary malignancies in patients receiving alkylating agents. Secondary leukemia following chemotherapy accounts for about 20% of all secondary neoplasms; most are acute nonlymphocytic. Secondary acute lymphoblastic leukemia has rarely been reported in either adult or childhood cancer. We report the development of acute T-cell lymphoblastic leukemia in a child following successful treatment of a paravertebral embryonal rhabdomyosarcoma (ERS). Southern blot analysis of DNA extracted from the T-cell lymphoblasts, using probes homologous to loci on the short arm of chromosome 11; P-calcitonin, P40.1 and H-ras, did not demonstrate the chromosomal loss of heterozygosity (LOH), a common feature of embryonal rhabdomyosarcoma. The data presented support the assumption that de novo leukemia emerged following treatment of the primary malignancy.     

Methotrexate treatment protocols and the central nervous system: significant cure with significant neurotoxicity

Methotrexate can influence the central nervous system through several metabolic toxic pathways. These effects can be categorized as immediate, acute to subacute, or chronic neurologic syndromes. The acute to subacute syndrome occurs frequently in acute lymphoblastic leukemia treatment protocols, generally manifesting with focal neurologic signs and changes seen on magnetic resonance imaging and single photon emission computed tomography. While in some patients the neurotoxicity is transient and benign and allows for continuation of chemotherapy, in others it can be quite severe and debilitating, leading to permanent neurologic deficits. The need to modify the treatment protocols when neurotoxicity appears is not fully established. It is also unknown whether the use of sufficient amounts of leucovorin can overcome the toxic effects of the drug.     

Role of the central amygdala in modulating the pituitary-adrenocortical and clinical responses in experimental herpes simplex virus-1 encephalitis

The amygdala is known to regulate neuroendocrine and behavioral responses to a variety of stimuli. Herpes simplex virus-1 (HSV-1) is the common cause of viral encephalitis, manifested by hypothalamic-pituitary-adrenal (HPA) axis activation, fever, hypermotor activity and aggression. We examined here the role of the central amygdala (cAMG) in regulating the HPA axis function, febrile and behavioral responses to HSV-1 infection in rats. Bilateral electrolytic lesions were performed in the cAMG. HSV-1 encephalitis was induced by intracerebroventricular (ICV) inoculation of purified virions. Motor activity and body temperature were examined by a biotelemetric system. ICV inoculation of HSV-1 caused a marked time-dependent increase in serum corticotropin (ACTH) and corticosterone at 4 and 24 h post-infection. These responses were attenuated in rats with bilateral lesions of the cAMG. HSV-1 infection induced fever, motor hyperactivity and aggressive behavior. These responses were also attenuated in rats with cAMG lesions. The cAMG plays an important role in mediating the neuroendocrine, febrile and behavioral responses to HSV-1 infection.