Dendritic cells as potential adjuvant for immunotherapy in adrenocortical carcinoma

Objective Adrenocortical carcinoma (ACC) is a rare malignancy associated with a dismal prognosis. Dendritic cells (DCs) are professional antigen‐presenting cells leading to an antitumour immune response. The aim of this study was to elaborate two methods of antigen delivery to DCs and to evaluate an immunotherapy protocol in ACC patients. Design/patients Autologous DCs were pulsed with autologous tumour lysate (TL). Fusion of DCs with tumour cells was based on a polyethylene glycol method. Two patients with metastasized hypersecretory ACC were vaccinated twice. Measurements In vitro data were quantified by measurement of PBMC (peripheral blood mononuclear cell) responses and cytokine secretion and by flow cytometry analyses. Clinical response was monitored by CT scan of tumour mass and measurement of angiogenic factors. Results The maximum loading of TL was obtained at 24 h as 48·2% (± 26·8%) of DCs were TL‐positive. The DC/tumour cell fusion efficacy was ～45% as shown by double positive staining for ACTH receptor and DC‐specific CD83. In vivo DC vaccination resulted in positive delayed‐type hypersensitivity skin reactions reflecting specific memory T‐lymphocyte reaction. In vitro analyses revealed specific T‐cell proliferation in patient 1 (stimulation index: 5·7 compared to pretreatment) and induction of cytotoxic granzyme B secreting T cells in patient 2 (0·41% CD8 + cells vs. 0·06% pretreatment) as indicators of specific cytotoxic T cells. Although angiogenic serum markers could be stabilized, no impact on tumour growth could be observed. Conclusion Our data demonstrate that autologous dendritic cells induce antigen‐specific Th1 immunity in adrenocortical carcinoma. The clinical outcome, however, was not improved in the patients studied here.     

A single dose of 6 or 12 mg of pegfilgrastim for peripheral blood progenitor cell mobilization results in similar yields of CD34+ progenitors in patients with multiple myeloma

BACKGROUND: Current regimens for peripheral blood progenitor cell (PBPC) mobilization in patients with multiple myeloma are based on daily subcutaneous injections of granulocyte-colony-stimulating factor (G-CSF) starting shortly after cytotoxic therapy. Recently a polyethylene glycol-conjugated G-CSF (pegfilgrastim) was introduced that has a substantially longer t(1/2) than the original formula. STUDY DESIGN AND METHODS: The use of pegfilgrastim was examined at two dose levels for PBPC mobilization in patients with Stage II or III multiple myeloma. Four days after cytotoxic therapy with cyclophosphamide (4 g/m(2)), a single dose of either 6 mg pegfilgrastim (n = 15) or 12 mg pegfilgrastim (n = 15) or daily doses of 8 microg per kg unconjugated G-CSF (n = 15) were administered. The number of circulating CD34+ cells was determined during white blood cell (WBC) recovery, and PBPC harvesting was performed by large-volume apheresis. RESULTS: Pegfilgrastim was equally potent at 6 and 12 mg with regard to mobilization and yield of CD34+ cells. No dose dependence was observed because CD34+ cell concentration peaks were 131 and 85 per microL, respectively, and CD34+ cell yield was 10.2 x 10(6) and 7.4 x 10(6) per kg of body weight, respectively. Pegfilgrastim in either dose was associated with a more rapid WBC recovery (p = 0.03) and an earlier performance of the first apheresis procedure (p < 0.05) in comparison to unconjugated G-CSF. No difference regarding CD34+ cell maximum and yield could be observed. CONCLUSION: A single dose of 6 mg pegfilgrastim is equally potent as 12 mg for mobilization and harvest of PBPCs in patients with multiple myeloma. Because no dose dependency was seen at these dose levels, this might be also true for even smaller doses.     

Yersinia enterocolitica Infection with Multiple Liver Abscesses Uncovering a Primary Hemochromatosis

A 60-year-old man, although treated with antibiotics, suffered from a severe pyrexial illness of unknown origin, weight loss and intermittent abdominal pain. There was no history of diarrhea or common infections. Computed tomography and ultrasound imaging showed uncharacteristic multiple small lesions of the entire liver parenchyma. These lesions were histologically pyogenic abscesses. In addition, an unexpected, pronounced accumulation of iron pigment in hepatocytes and second degree fibrotic changes of the liver were detected. Serum iron and serum transferrin were low, but serum ferritin concentration and transferrin saturation were increased to the maximum. The demonstration of the cysteine-282-tyrosine mutation confirmed underlying primary hemochromatosis. Bacteriological cultures of the abscess material yielded Yersinia enterocolitica serotype O:3, while stool and blood cultures were negative. Antibiotic therapy with piperacillin/tazobactam and tobramycin was successful within a few days. A repeat CT scan and ultrasound imaging demonstrated complete regression of the pathologic liver morphology. The patient was discharged and treated with an orally administered fluoroquinolone for an additional 6 months. After this time the patient had no morphological residues of the infection except one enlarged lymph node near the portal vein but still was so weak that he was unable to work again. In conclusion, severe septic forms of yersiniosis are mainly found in patients with iron overload, due to a handicapped iron metabolism of the Yersinia bacteria. Mortality is high despite treatment.     

Parents', nurses', and educators' perceptions of risks and benefits of school attendance by children who are medically fragile/technology-dependent

Few studies have focused on school activities of children who are medically fragile/technology-dependent. This article reports on an exploratory, interpretive study that examined the perceptions of parents, nurses, and educators with regard to their school concerns and strategies for ensuring the safety and health of these students. Informants all believed that attending school provided benefits to most children who are medically fragile/technology-dependent, including opportunities for skill acquisition, socialization, and respite care for families. However, they also perceived that there were real risks involved, including obtaining appropriate care, exposure to infection, and social isolation or teasing.     

Achieving a cure for HIV infection: do we have reasons to be optimistic?

The introduction of highly active antiretroviral therapy (HAART) in 1996 has transformed a lethal disease to a chronic pathology with a dramatic decrease in mortality and morbidity of AIDS-related symptoms in infected patients. However, HAART has not allowed the cure of HIV infection, the main obstacle to HIV eradication being the existence of quiescent reservoirs. Several other problems have been encountered with HAART (such as side effects, adherence to medication, emergence of resistance and cost of treatment), and these motivate the search for new ways to treat these patients. Recent advances hold promise for the ultimate cure of HIV infection, which is the topic of this review. Besides these new strategies aiming to eliminate the virus, efforts must be made to improve current HAART. We believe that the cure of HIV infection will not be attained in the short term and that a strategy based on purging the reservoirs has to be associated with an aggressive HAART strategy.     

The fungicide chlorothalonil is nonlinearly associated with corticosterone levels, immunity, and mortality in amphibians

Background: Contaminants have been implicated in declines of amphibians, a taxon with vital systems similar to those of humans. However, many chemicals have not been thoroughly tested on amphibians or do not directly kill them.Objective: Our goal in this study was to quantify amphibian responses to chlorothalonil, the most commonly used synthetic fungicide in the United States.Methods: We reared Rana sphenocephala (southern leopard frog) and Osteopilus septentrionalis (Cuban treefrog) in outdoor mesocosms with or without 1 time (1×) and 2 times (2×) the expected environmental concentration (EEC) of chlorothalonil (~ 164 μg/L). We also conducted two dose–response experiments on O. septentrionalis, Hyla squirella (squirrel treefrog), Hyla cinerea (green treefrog), and R. sphenocephala and evaluated the effects of chlorothalonil on the stress hormone corticosterone.Results: For both species in the mesocosm experiment, the 1× and 2× EEC treatments were associated with > 87% and 100% mortality, respectively. In the laboratory experiments, the approximate EEC caused 100% mortality of all species within 24 hr; 82 μg/L killed 100% of R. sphenocephala, and 0.0164 μg/L caused significant tadpole mortality of R. sphenocephala and H. cinerea. Three species
showed a nonmonotonic dose response, with low and high concentrations causing significantly greater mortality than did intermediate concentrations or control treatments. For O. septentrionalis, corticosterone exhibited a similar nonmonotonic dose response and chlorothalonil concentration was inversely associated with liver tissue and immune cell densities (< 16.4 μg/L).Conclusions: Chlorothalonil killed nearly every amphibian at the approximate EEC; at concentrations to which humans are commonly exposed, it increased mortality and was associated with elevated corticosterone levels and changes in immune cells. Future studies should directly quantify the effects of chlorothalonil on amphibian populations and human health.