Variant on Manifestation of Duodenal Metastasis 26 Years after Initial Diagnosis of Primary Cutaneous Melanoma

Malignant duodenal neoplasms are relatively rare, and the diagnosis is often delayed because of their vague and nonspecific symptoms. We report the case of a 79-year-old female who had a medical history of malignant melanoma of the cheek that had initially been diagnosed at 53 years of age. Work-up revealed severe stenosis of the duodenum caused by a large mass with ulceration at the tip of its mucosal surface. Tumor biopsy led to a histological diagnosis of extremely poorly differentiated carcinoma, but it was impossible to determine whether the lesion was a primary neoplasm or represented secondary involvement. Pancreatoduodenectomy was performed, and the surgical specimen showed a protuberant tumor in the nonampullary region of the second portion of the duodenum. Final diagnosis of metastatic duodenal melanoma was made by immunohistological examination. She is currently alive without recurrence 28 months after the surgical treatment

Inhibitory Effect of TNF-α on Malaria Pre-Erythrocytic Stage Development: Influence of Host Hepatocyte/Parasite Combinations

BACKGROUND: The liver stages of malaria parasites are inhibited by cytokines such as interferon-gamma or Interleukin (IL)-6. Binding of these cytokines to their receptors at the surface of the infected hepatocytes leads to the production of nitric oxide (NO) and radical oxygen intermediates (ROI), which kill hepatic parasites. However, conflicting results were obtained with TNF-alpha possibly because of differences in the models used. We have reassessed the role of TNF-alpha in the different cellular systems used to study the Plasmodium pre-erythrocytic stages. METHODS AND FINDINGS: Human or mouse TNF-alpha were tested against human and rodent malaria parasites grown in vitro in human or rodent primary hepatocytes, or in hepatoma cell lines. Our data demonstrated that TNF-alpha treatment prevents the development of malaria pre-erythrocytic stages. This inhibitory effect however varies with the infecting parasite species and with the nature and origin of the cytokine and hepatocytes. Inhibition was only observed for all parasite species tested when hepatocytes were pre-incubated 24 or 48 hrs before infection and activity was directed only against early hepatic parasite. We further showed that TNF-alpha inhibition was mediated by a soluble factor present in the supernatant of TNF-alpha stimulated hepatocytes but it was not related to NO or ROI. Treatment TNF-alpha prevents the development of human and rodent malaria pre-erythrocytic stages through the activity of a mediator that remains to be identified. CONCLUSIONS: Treatment TNF-alpha prevents the development of human and rodent malaria pre-erythrocytic stages through the activity of a mediator that remains to be identified. However, the nature of the cytokine-host cell-parasite combination must be carefully considered for extrapolation to the human infection

Human TNF-α inhibits the pre-erythrocytic stage of <i>P. falciparum</i>.

<p>Primary human hepatocyte cell cultures were treated with various concentrations of recombinant human TNF-α, 24 h (A) or 48 h (B) before, at the time of sporozoite inoculation, and then every day for day 1 to day 5. Cultures were stopped 5 days later after sporozoite inoculation. The data presented are mean numbers (± SD) of 5 days <i>P. falciparum</i> liver stages from triplicate experimental wells and from 8 control wells. * <i>p</i><0.05 versus control non-treated cultures (Kruskal-Wallis test, followed by Dunn test). The rate of infection for <i>P. falciparum</i> sporozoites was 0.2–0.5% for primary human hepatocytes depending on the experiment. Data are representative of two independent experiments with similar results.</p

A soluble mediator but not NO or RO intermediates synthesized by human TNF-α-stimulated human hepatocytes inhibits <i>P. falciparum</i> development.

<p>A. Primary human hepatocytes were treated or not with 100 ng/ml of human TNF-α together with or without SMT or NAC at 48 h before, at the time and every day for day 1 to day 5 after sporozoite inoculation. B. In the same experiment, supernatants from cells treated previously for 48 h with human TNF-α were added together with <i>P. falciparum</i> sporozoites to fresh human primary hepatocytes. Medium was changed after 3 hr and every day after sporozoite inoculation. In both experimental settings, cultures were stopped 5 days later. Data are presented are the mean (± SD) reduction in liver schizont numbers in triplicate wells to the mean number in 6 control wells and are derived from one of two experiments. The numbers of <i>P. falciparum</i> 5 day-liver schizonts in the 6 control wells were 179.2±26.1. * <i>p</i><0.05 versus control non-treated cultures (Kruskal-Wallis test, followed by Dunn test).</p

Human TNF-α inhibits the pre-erythrocytic stage of Pyy265BY.

<p>A. HepG2/CD81 hepatoma cell cultures were treated with various concentrations of recombinant human TNF-α, 48 h prior to, at the time of, and then 3 h and 24 h after sporozoite inoculation. Cultures were stopped 45 h after infection. Data are presented as the mean (± SD) reduction in Pyy265 liver schizonts numbers and represent data from two independent experiments (one represented by filled circles and the other by open circles). Parasite number reduction was calculated by enumerating 48 h liver schizonts in triplicate cultures exposed or not to TNF-α. Data are presented as the mean (± SD) reduction in liver schizont numbers in triplicate wells compared to the mean number in 6 control wells. The number of liver schizonts in control wells was 67±9.9. B. Timing of the antiparasitic effect of human TNF-α. HepG2/CD81 cells were incubated with 100 ng/ml of human TNF-α for different times. Cultures were stopped 48 h after sporozoite inoculation. Data are presented as the mean (± SD) numbers of liver schizonts in triplicate experimental wells and in six control wells. * <i>p</i><0.05 versus control non-treated cultures (Kruskal-Wallis test, followed by Dunn test). The rate of infection Pyy265 sporozoites for HepG2/CD81 hepatoma cell was between 0.5 to 2% depending on the experiment. Data are representative of three independent experiments with similar results.</p

Human TNF-α inhibits the pre-erythrocytic stage of PbA.

<p>HepG2/CD81 hepatoma cell cultures were treated with various concentrations of recombinant human TNF-α, 48 h prior to, at the time of, and then 3 h and 24 h after sporozoite inoculation. Cultures were stopped 48 h after sporozoite inoculation. Data are presented as the mean (± SD) reduction in 48 h PbA liver schizont numbers from triplicate experimental wells compared to those from 8 control wells. The number of liver schizonts in the control wells was 357±31. * <i>p</i><0.05 versus control non-treated cultures (Kruskal-Wallis test, followed by Dunn test). The rate of infection PbA sporozoites for HepG2/CD81 hepatoma cell was between 0.3 to 2% depending on the experiment. Data are representative of two independent experiments with similar results.</p

Effect of human or mouse TNF-α against the pre-erythrocytic stage of PbA and Pyy265BY grown in Hepa 1–6 hepatoma cells or primary hepatocytes cultures.

<p>(A) Hepa 1–6 cells and (B) primary hepatocyte cultures were treated with 100 ng/ml of recombinant human or mouse TNF-α, 48 h prior to, at the time of, and then 3 h and 24 h after sporozoite inoculation. Cultures were stopped 48 h later. Data are presented as the mean (± SD) reduction in PbA liver schizont numbers at 48 h in triplicate experimental wells as compared to those enumerated in 6 control wells. In the control wells, there were 110.3±13.1 liver schizonts in Hepa1-6 and 602±83.4 in the primary mouse hepatocytes infected with PbA, and 25.5±3.6 liver schizonts in Hepa1-6 and 443.5±133.5 in primary hepatocytes infected with Pyy265 BY. * <i>p</i><0.05 versus control non-treated cultures (Kruskal-Wallis test, followed by Dunn test). The rate of infection for Pyy265 sporozoites was 0.02-.004% for Hepa1.6 cells and 0.1–2% for primary mouse hepatocytes. For PbA sporozoites, it was of 0.1–0.5% for Hepa1.6 cells and 0.5–1% for primary mouse hepatocytes. Data are representative of two independent experiments with similar results. ND, not done.</p