Acute neurologic dysfunction associated with high-dose chemotherapy and autologous bone marrow rescue for primary malignant brain tumors

Acute neurologic complications occurred 103 times in 50 (54%) of 92 patients (primarily children) treated with high-dose chemotherapy and autologous bone marrow rescue for primary central nervous tumors. Different types of neurologic compromise occurred during the chemotherapy infusion as compared to the first 100 days after the chemotherapy and the greater-than-100-day time period. The causes of the neurologic compromise were also time sensitive. BACKGROUND: Results of treatment for children with primary brain tumors using high-dose chemotherapy with autologous marrow rescue (ABMR) have been encouraging. However, the neurotoxicity associated with this technique remains a major concern. We reviewed the records of 92 patients who underwent ABMR for malignant brain tumors between 1986 and 1992 for the occurrence and timing of acute neurologic dysfunction (AND). METHODS: Individual investigators at the participating institutions retrospectively completed standardized forms on each patient. The manner in which the distribution of AND versus time of treatment emerged led to the establishment of distinct time periods for data analysis and discussion. The pre-ABMR period included those events that occurred during the chemotherapy infusion, the early posttreatment period included the first 100 days following bone marrow rescue, and the late posttreatment period was greater than 100 days following bone marrow rescue. RESULTS: Fifty patients (54%) had 103 episodes of AND. AND included encephalopathies with or without hallucinations or coma (32), seizures (23), headaches (9), ataxia-tremor-dysarthria syndrome (7), anorexia and nausea syndrome (7) and others (25). During the chemotherapy infusion, encephalopathies and seizures were most common. Hallucinations occurred primarily related to drug infusion, while encephalopathies without hallucinations were usually due to demonstrable dysmetabolic states. In the 100 days following ABMR, dysmetabolic states and iatrogenic factors caused 45% and progressive disease caused 33% of AND. Greater than 100 days from ABMR, progressive disease caused 55% of AND; 7 patients were noted to develop chronic anorexia and nausea of unclear etiology. The occurrence of neurologic compromise was not related to the chemotherapy regimens, tumor histology, tumor location, patient age, prior treatment, or the amount of tumor at time of treatment. Dexamethasone use was the only clinical factor associated with AND (p < 0.004). CONCLUSIONS: The cause of AND was definable for 95% of instances that occurred within 100 days of ABMR. Early AND was often iatrogenic and reversible. The greater the time from ABMR the more likely AND was due to progressive disease. Clinical factors could not predict the occurrence of AND as only the concurrent use of dexamethasone at the time of treatment proved significant. Although frequent, AND should not be considered a limiting toxicity of this approach or preclude the use of this technique.     

Visceral varicella-zoster after bone marrow transplantation: report of a case series and review of the literature

OBJECTIVE: To compare the efficacy and vaginal birth intervals after intravaginal or oral misoprostol for labor induction. METHODS: One hundred seventy-eight women were randomized to one of two double-blind groups: 1) oral misoprostol 200 microg and one-half tablet placebo intravaginal or 2) oral placebo tablet and one-half tablet of a 100-microg misoprostol intravaginal (dose 50 microg). Doses were repeated every 6 hours until labor was established (maximum of three doses). RESULTS: Ninety-three subjects were assigned to oral misoprostol and 85 to intravaginal administration. Oral administration was accompanied by significantly shorter intervals to the onset of uterine contractility (133+/-78 minutes versus 168+/-93, P < .01) but a higher incidence of abnormal uterine contractile activity (tachysystole 38.7% versus 20.0%, P < .01; hyperstimulation syndrome 44.1% versus 21.2%, P < .01). No adverse maternal or neonatal outcomes were noted, nor were there differences in cesarean delivery rates or total lengths of labor. CONCLUSION: Oral administration of 200 microg misoprostol has similar efficacy to intravaginal administration of 50 microg but is associated with more frequent abnormal uterine contractility.     

Elevated serum cytokines are associated with cytomegalovirus infection and disease in bone marrow transplant recipients

To assess the relationship between serum cytokines and cytomegalovirus (CMV) reactivation, 75 allogeneic bone marrow transplant patients underwent weekly measurements of interleukin (IL)-6, IL-8, and tumor necrosis factor (TNF)-alpha, CMV blood cultures, and antigenemia tests. Of the patients, 44 (58.7%) developed CMV infection, and 19 (25.3%) developed clinical CMV disease. The mean maximum levels of all three cytokines were significantly increased in patients with CMV infection compared with levels in those without. Maximum levels of IL-6 were significantly higher in patients with active CMV disease than in those who did not develop CMV disease (281.2+/-85.5 vs. 95.7+/-15.0 pg/mL; P=.034). Levels of IL-8 and TNF-alpha were also elevated in patients who developed active disease. In a multivariate logistic regression model, IL-6 levels were independently associated with CMV disease (odds ratio=1.70 per 100-pg/mL increase in IL-6; P=.009). Cytokines may play an important role in the pathogenesis of CMV after bone marrow transplantation and may be a useful predictor for CMV.     

Effective treatment of mice with type II collagen induced arthritis with lethal irradiation and bone marrow transplantation

Ricin A-chain is delivered into macrophages via receptor-mediated endocytosis. We have found that following uptake via the mannose receptor, ricin A-chain is rapidly cleaved by endosomal proteases. Inhibition of endosomal proteases such as cathepsin D and B leads to the accumulation of toxin inside the cell. Inhibition of cathepsin D reduces ricin A-chain cytotoxicity, while blocking cathepsin B enhances cytotoxicity. Similar results were obtained using fibroblasts transfected with the mannose receptor. Our data strongly suggest that the activation or membrane translocation of ricin A-chain is dependent upon the action of specific proteases.     

Pancytopenia in children with brucellosis: clinical manifestations and bone marrow findings

Among 276 paediatric cases of brucellosis seen over a 7-year period, 16 patients (5.8%) with pancytopenia were identified. The most frequent presentations were fever, malaise, anorexia, weight loss, arthralgia, and hepatosplenomegaly. Fourteen patients (87.5%) had positive blood and/or bone marrow cultures for Brucella melitensis. Bone marrow aspiration specimens showed hypercellularity in 14 patients and normocellularity in 2. Histiocytes, eosinophils and plasma cells were increased in every marrow aspirate, and haemophagocytosis was observed in 14 patients (87.5%). Non-caseating granulomas were present in the bone marrow biopsy of 11 patients (68.8%). The pancytopenia was transient, and resolved on treatment of the Brucella infection.     

Visceral fit: While in a visceral state, associated states of the world seem more likely.

We propose that visceral states can influence beliefs through “visceral fit”: People will judge states of the world associated with their current visceral experience as more likely. We found that warmth influenced belief in global warming (Studies 1–3) and that thirst impacted forecasts of drought and desertification (Study 5). These effects emerged in a naturalistic setting (Study 1) and in experimental lab settings (Studies 2, 3, and 5). Studies 2–6 distinguished between 3 mechanistic accounts: temperature as information (Studies 2 and 3), conceptual accessibility (Studies 4 and 5), and fluency of simulation (Studies 6a and 6b). Studies 2 and 3 ruled out the temperature as information account. Feeling warm enhanced belief in global warming even when temperature was manipulated in an uninformative indoor setting, when participants' attention was first directed to the indoor temperature, and when participants' belief about the current outdoor temperature was statistically controlled. Studies 4 and 5 ruled out conceptual accessibility as the key mediator: Priming the corresponding concepts did not produce analogous effects on judgment. Studies 6a and 6b used a causal chain design and found support for a “simulational fluency” account. Participants experiencing the visceral state of warmth constructed more fluent mental representations of hot (vs. cold) outdoor images, and those who were led to construe the same hot outdoor images more fluently believed more in global warming. Together, the results suggest that visceral states can influence one's beliefs by making matching states of the world easier to simulate and therefore seem more likely. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Psychiatric disturbances associated with Erhard Seminars Training: II. additional cases and theoretical considerations

In a previous article, the authors reported on 5 individuals who developed psychoses after participation in Erhard Seminars Training (est). Two additional cases are reported, and the combined case material is discussed in terms of group and psychodynamic theories. The authoritarian est leadership style may mobilize in trainees an overdetermined and pathological reliance on identification with the aggressor. Such a mechanism may be central to the production of psychiatric casualties, particularly in individuals with defective ego boundaries. Future controlled research is necessary to ascertain the rate of occurrence of psychiatric disturbances associated with est and to test the authors' hypotheses.     

Corticosteroids as adjunctive therapy for diffuse alveolar hemorrhage associated with bone marrow transplantation. University of Nebraska Medical Center Bone Marrow Transplant Group

BACKGROUND: Diffuse alveolar hemorrhage is a frequent complication of treating malignancies with high-dose chemotherapy and bone marrow transplantation and is associated with very high mortality. This disorder's association with pulmonary inflammation, its coincidence with marrow recovery, and the usefulness of corticosteroids for treating other pulmonary hemorrhage syndromes provided the rationale for this study. METHODS: We retrospectively studied 65 episodes of diffuse alveolar hemorrhage that has occurred in 63 of 603 consecutively treated patients who had undergone high-dose chemotherapy with bone marrow transplantation. Patients were divided into three groups according to the therapy they had received for diffuse alveolar hemorrhage: supportive therapy alone (n = 12); low-dose corticosteroids (30 mg or less of methylprednisolone or its equivalent; n = 10); and high-dose corticosteroids (more than 30 mg methylprednisolone or its equivalent; n = 43). The primary outcome measures were overall survival and survival to hospital discharge, occurrence of respiratory failure requiring intubation, and development of infections subsequent to the diagnosis of diffuse alveolar hemorrhage. RESULTS: Overall survival at the end of the follow-up period was significantly higher for the high-dose corticosteroid group compared with the supportive therapy group (P = 0.005); however, treatment with low-dose steroids did not increase survival over supportive therapy alone (P = 0.198). In addition, survival to discharge was significantly increased for the high-dose group compared with the other two groups combined (33% versus 9.1%, P = 0.038). Respiratory failure after the diagnosis of diffuse alveolar hemorrhage developed in only 12 of the 22 unintubated patients in the high-dose group compared with 9 of the 10 initially unintubated patients in the other two groups (P = 0.056). Although the incidence of infections was high (40%) subsequent to diffuse alveolar hemorrhage, neither high-dose nor low-dose corticosteroid treatment significantly increased the risk of infections (P > 0.4, all comparisons). CONCLUSIONS: In this study, high-dose corticosteroid therapy for diffuse alveolar hemorrhage related to bone marrow transplantation was associated with improved total survival and survival to hospital discharge, and decreased development of respiratory failure in these patients. These results suggest the therapy is beneficial, and further prospective studies are warranted to verify the effectiveness of the treatment.     

ER-MP12 antigen, a new cell surface marker on mouse bone marrow cells with thymus-repopulating ability: I. Intrathymic repopulating ability of ER-MP12-positive bone marrow cells

We searched for new cell surface markers that allow a positive identification of thymus-repopulating cells in the bone marrow (BM) of the mouse. Recently we raised two rat monoclonal antibodies (ER-MP12 and ER-MP20) that recognize cell surface antigens expressed by mouse haematopoietic progenitor cells, among which are progenitor cells of the macrophage lineage. Here we show that the ER-MP12 antigen, but not the ER-MP20 antigen, is also expressed by BM cells with thymus-repopulating ability. Using ER-MP12 and ER-MP20 in two-colour immunofluorescence analysis six subpopulations of BM cells can be identified. The thymus-repopulating ability of each BM subpopulation was assessed after fluorescence-activated cell sorting and subsequent intrathymic injection into sublethally irradiated Thy-1 congenic recipient mice. Thymus-repopulating activity appeared to be exclusively confined to two subsets of BM cells expressing either high or intermediate levels of the ER-MP12 antigen, but lacking ER-MP20 antigen expression. These BM subsets comprised 1-2% and 30% of total nucleated BM cells respectively. The frequency of thymus-repopulating cells was maximal in the minor BM subpopulation with the highest level of ER-MP12 antigen expression. We conclude that ER-MP12 detects a hitherto unknown cell surface marker expressed by BM cells with thymus-repopulating ability.     

Tumor angiogenesis and micrometastasis in bone marrow of patients with early gastric cancer

In a subset of patients with early gastric cancer, there were recurrences of the disease after a curative resection had been done. Direct evidence of tumor seeding in distant organs at the time of surgery for gastric cancer is not available. An immunocytochemical assay for epithelial cytokeratin protein may fill this gap because it is a feature of epithelial cells that would not normally be present in bone marrow. From 1994-1997, the bone marrow of 45 patients with early gastric cancer was examined for tumor cells, using immunocytochemical techniques and an antibody reacting with cytokeratin, a component of the intracytoplasmic network of intermediate filaments. Intratumoral microvessels were stained with anti-CD31 monoclonal antibody. Clinicopathological characteristics were determined for subjects with cytokeratin-positive cells in the bone marrow. Of these 45 patients, 9 (20.0%) had cytokeratin-positive cells in the bone marrow at the time of primary surgery. These positive findings were not related to tumor advance-related factors of lymph node metastasis and distinct lymphatic and vascular invasion. Microvessel density in the primary tumor exceeded 2-fold in cytokeratin-positive cells, compared with findings in negative cells (P < 0.05). Tumor cells in bone marrow are indicative of the general disseminative metastasis in patients with early gastric cancer, and the metastatic potential was closely related to angiogenesis in the primary tumor.     

Drug and environmental factors associated with adverse pregnancy outcomes. Part II: Improvement with folic acid

OBJECTIVE: To provide a comprehensive review of periconceptional folic acid supplementation and factors affecting folate supplementation trials. DATA SOURCES: A MEDLINE search was conducted through December 1997. Additional sources were obtained from Current Contents and citations from the references obtained. Search terms included folate, folic acid, neural tube defect, spina bifida, and anencephaly. STUDY SELECTION: Relevant animal and human studies examining the effects of folate were reviewed. DATA EXTRACTION: Data collected included: type of study, folate dosing, dietary folate intake, serum and red blood cell folate concentrations, type of defect(s) studied, vitamin usage, parental risk factors, factors affecting trial results. DATA SYNTHESIS: Nine key factors have been identified that affect outcomes of folic acid supplementation trials. Daily doses of 0.8 mg decreased the occurrence and doses of 4 mg decreased the recurrence of neural tube defects in randomized clinical trials. Since lower folic acid doses were effective in nonrandomized trials, research is needed to determine the lowest effective dosage. Other benefits involving pregnancy outcome are suggested. CONCLUSIONS: Women of childbearing age should take a daily folic acid supplement to reduce the risk of pregnancies resulting in infants with a neural tube defect and other potential adverse pregnancy outcomes. Further health benefits from folic acid supplementation are reviewed in Part III of this series.     

Interstitial pneumonitis in bone marrow transplant recipients is associated with local production of TH2-type cytokines and lack of T cell-mediated cytotoxicity

BACKGROUND: Interstitial pneumonitis, especially associated with cytomegalovirus (CMV) infection, is a serious complication after bone marrow transplantation (BMT), with a high fatality rate despite adequate antiviral treatment. The aim of this study was to elucidate the local immunopathogenesis of interstitial pneumonitis caused by CMV or other agents in BMT recipients. METHODS: Cryopreserved lung tissue obtained from 12 patients with interstitial pneumonitis following BMT was analyzed for cytokine production at the single-cell level using a cytokine-specific monoclonal antibody and immunohistochemical technique. Cytokine production in individual cells was analyzed using monoclonal antibodies to 23 different human cytokines: interleukin (IL)-1 to IL-13, tumor necrosis factor (TNF)-alpha, TNF-beta, interferon-gamma (IFNgamma), granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, and transforming growth factor (TGF)-beta1 to 3. RESULTS: Marrow transplant patients with interstitial pneumonia had increased numbers of infiltrating alveolar macrophages, CD3+, CD4+ T cells, and CD40+ B cells and significantly increased numbers of IL-4-, IL-10-, IL-1-, TGF-beta1-, TGF-beta2-, and TGF-beta3-producing cells than controls. IL-2-, IFN-gamma-, and TNF-beta-producing cells were undetectable in most patients with CMV pneumonitis (n=7). Neither perforin-positive CD8+ T lymphocytes nor up-regulation of the apoptotic pathway was detected in lung tissue from patients with interstitial pneumonia. In contrast, extensive local production of IgA, IgG, and IgM was demonstrated in all patients. Intracellular and extensive extracellular deposition of CD68, the L-1 antigen synthesized in CD14+ macrophages, was found. CONCLUSIONS: The cytokine profile suggested that Th1-type cytokine production was absent, whereas production of Th2-type cytokines was significantly up-regulated. Interstitial pneumonitis in BMT recipients with fatal outcome (11/12 patients) was associated with dysregulation in the local cytokine network notable for a predominant Th2 immune response with minimal or absent T cell-mediated cytotoxicity.     

Comparative dynamics of elimination of potential chromosome damage in mouse bone marrow cells after low and moderate doses of radiation

Possible dynamics of the incidence, repair, and realization of potential chromosome aberrations (PAs) was examined by indirect methods based on cytogenetic analysis of radiation effects. PAs were characterized as chemical modifications of DNA responsible for the incidence of structural aberrations of chromosomes. We interpreted our data as providing evidence that two types of radiation-induced PAs, differing in repair rates, could occur in the exposed cells: quick- (short-term) and slow (long-term) repairing PAs. We showed that the PA spectrum gradually changed with an increase in radiation dose within the interval from 24 to 150 cGy. This process was paralleled by changes in the cell response and chromosome resistance to radiation. Short-term PAs were induced mainly by low radiation doses ranging from 24 to 75 cGy. Their incidence was associated with activation of the corresponding repair process. Further increase in radiation dose resulted in changes in the PA spectrum, and doses of 150 cGy induced predominantly long-term PAs with concomitant activation of the appropriate repair process. Induction of repair occurred in the dose intervals limited by lower and upper threshold doses, Dl and Du. In our experiments, short-term PAs were repaired when Dl < 24 cGy and 126 cGy < Du < < 150 cGy. Long-term PAs were repaired when 75 cGy < Dl < 99 cGy and Du > 150 cGy.     

Pilot neuropsychological findings from a treatment regimen consisting of intensive chemotherapy and bone marrow rescue for young children with newly diagnosed malignant brain tumors

Ten children (6 girls and 4 boys) who completed a protocol in which their localized brain tumors were successfully treated without cranial irradiation were referred for neuropsychological assessment. At the time of testing, they were disease free without any neuroaxis dissemination or leptomeningeal disease. Tumor types included pineoblastoma, glioblastoma, ependymoma, PNET and medulloblastoma. They had a mean age of 5 years and 8 months (SD = 1.86; range = 2.1-8.9 years) and were an average of 37.8 months post bone marrow transplant (SD = 16.42; range = 14-58 months). Neuropsychological data from this study reveal that the mean scores for this nonradiated group of children were within the average range for the following domains: academic achievement tests of reading, spelling and mathematics, verbal and visual memory, visual-motor integration, social-emotional and behavioral functioning. Furthermore, this group of children were performing within the low average range of overall Intelligence, as well as both verbal IQ/verbal reasoning and performance IQ/abstract visual reasoning. On tasks of fine motor dexterity, this group was within the low average range when using their dominant hand; however, they performed within the borderline range when using their non-dominant hand. Of note, this group of children demonstrated significant deficits within the borderline to impaired ranges on language tasks of expressive picture naming and receptive picture vocabulary.