Myeloid-derived suppressor cells have a central role in attenuated Listeria monocytogenes-based immunotherapy against metastatic breast cancer in young and old mice.

BACKGROUND: Myeloid-derived suppressor cells (MDSCs) are present in large numbers in blood of mice and humans with cancer, and they strongly inhibit T-cell and natural killer (NK) cell responses, at young and old age. We found that a highly attenuated bacterium Listeria monocytogenes (Listeria(at))-infected MDSC and altered the immune-suppressing function of MDSC. METHODS: Young (3 months) and old (18 months) BALB/cByJ mice with metastatic breast cancer (4T1 model) were immunised with Listeria(at) semi-therapeutically (once before and twice after tumour development), and analysed for growth of metastases and primary tumour, in relation to MDSC-, CD8 T-cell and NK cell responses. RESULTS: We found that Listeria(at)-infected MDSC, which delivered Listeria(at) predominantly to the microenvironment of metastases and primary tumours, where they spread from MDSC into tumour cells (infected tumour cells will ultimately become a target for Listeria-activated immune cells). Immunotherapy with Listeria(at) significantly reduced the population of MDSC in blood and primary tumours, and converted a remaining subpopulation of MDSC into an immune-stimulating phenotype producing IL-12, in correlation with significantly improved T-cell and NK cell responses to Listeria(at) at both ages. This was accompanied with a dramatic reduction in the number of metastases and tumour growth at young and old age. CONCLUSIONS: Although preclinical studies show that immunotherapy is less effective at old than at young age, our study demonstrates that Listeria(at)-based immunotherapy can be equally effective against metastatic breast cancer at both young and old age by targeting MDSC.

Ridaforolimus as a single agent in advanced endometrial cancer: results of a single-arm, phase 2 trial.

BACKGROUND: This open-label, multicentre, phase 2 trial evaluated the efficacy and tolerability of the mammalian target of rapamycin inhibitor ridaforolimus in women with advanced endometrial cancer. METHODS: Women with measurable recurrent or persistent endometrial cancer and documented disease progression were treated with ridaforolimus 12.5 mg intravenously once daily for 5 consecutive days every 2 weeks in a 4-week cycle. The primary end point was clinical benefit response, defined as an objective response or prolonged stable disease of 16 weeks or more. RESULTS: In all, 45 patients were treated with single-agent ridaforolimus. Clinical benefit was achieved by 13 patients (29%), including 5 (11%) with confirmed partial responses and 8 (18%) with prolonged stable disease. All patients with clinical benefit response received ridaforolimus for more than 4 months. In this heavily pretreated population, the 6-month progression-free survival was 18%. Ridaforolimus was generally well tolerated: adverse events were predictable and manageable, consistent with prior studies in other malignancies. Overall, the most common adverse events were diarrhoea (58%) and mouth sores (56%); most common grade 3 or higher adverse events were anaemia (27%) and hyperglycaemia (11%). CONCLUSION: Single-agent ridaforolimus has antitumor activity and acceptable tolerability in advanced endometrial cancer patients. Further clinical evaluation of ridaforolimus is warranted.

Management of uterine malignancy found incidentally after supracervical hysterectomy or uterine morcellation for presumed benign disease.

Patients who have undergone supracervical hysterectomy or uterine morcellation for presumed benign uterine disease and are found to have malignancy on final pathology represent a management dilemma. Our goal was to analyze our experience and make observations regarding staging, treatment, and outcomes. We performed a retrospective case series of patients referred to our institution with uterine malignancy who previously underwent supracervical hysterectomy or uterine morcellation at the time of original surgery for presumed benign uterine disease. Between January 2000 and March 2006, 17 patients with uterine malignancy were identified. Following initial surgery, 15 (88%) patients had presumed stage I disease and 2 (12%) patients had stage III disease. Two (15%) of 13 patients who underwent completion surgery were upstaged; both had leiomyosarcoma (LMS) originally resected with morcellation. Ten of 11 patients whose stage was confirmed with secondary surgery remain disease free. None of the patients who initially underwent supracervical hysterectomy without morcellation were upstaged by secondary surgery. The median follow-up interval was 30 months (range, 2-90 months). Reoperation for completion surgery and staging is important when uterine malignancy is found incidentally after morcellation or supracervical hysterectomy for presumed benign uterine disease. Approximately 15% of patients will be upstaged by reexploration, particularly those with LMS who underwent morcellation. Patients who undergo completion surgery with restaging and are not upstaged appear to have a good prognosis. Surgical staging is valuable for prognosis and may alter postoperative treatments.

Neonatal sepsis and death caused by resistant Escherichia coli: possible consequences of extended maternal ampicillin administration.

OBJECTIVE: Our goal was to evaluate the relationship between neonatal death caused by sepsis associated with ampicillin-resistant organisms and length of antibiotic exposure. STUDY DESIGN: All neonatal deaths from culture-positive sepsis over a 3-year period were examined. Infants who were delivered at either the University of Mississippi Medical Center or at Saint Barnabas Medical Center at >/=24 weeks' gestation and died within 7 days of life were included. Information on the organism causing sepsis and its sensitivities was collected, and the number of doses of ampicillin administered to the mother before delivery was determined. RESULTS: Of the 78 neonatal deaths, 35 met the inclusion criteria. There were 8 cases of sepsis from ampicillin-resistant Escherichia coli and 27 cases caused by other organisms. There was a statistically significant difference between the mean number of doses of ampicillin received by the ampicillin-resistant Escherichia coli group (17.6 +/- 5.5) compared with the other organisms group (4.9 +/- 3.6) (P <.001). CONCLUSION: A relationship exists between neonatal death caused by ampicillin-resistant Escherichia coli and prolonged antepartum exposure to ampicillin.

Antibody to HIV-1, HTLV-I, and HCV in three populations of rural Haitians.

The seroprevalence of antibodies to HIV-1, HTLV-I, and HCV was evaluated in three populations from northern rural Haiti: 1,727 patients attending the hospital for symptoms suggestive of HIV disease, 228 consecutive surgical patients, and 500 pregnant women were tested. HIV-1 seroprevalence was 6.1 and 4.0% in the last two groups, respectively, and 39.3% in the symptomatic population. Associated symptoms of wasting, cough, and diarrhea and a clinical diagnosis of AIDS were significantly predictive of HIV-1 seropositivity. Antibody to HTLV-I seroprevalence ranged from 2.2-5.3% in pregnant women, surgical patients, and HIV-seronegative symptomatic patients and was similar among the three groups when stratified by age. In contrast, HIV-1 seropositivity and HTLV-I seropositivity were significantly associated. The prevalence of confirmed antibody to HCV was low and not associated with either HIV-1 or HTLV-I seropositivity.

Monitoring of specific antibodies to human immunodeficiency virus structural proteins: clinical significance.

Levels of antibodies to six major structural proteins of human immunodeficiency virus type 1 (gp120, gp41, p66, p31, p24, and p17) were assessed in serial samples from 22 persons with severe hemophilia (16 asymptomatic and 6 who developed acquired immunodeficiency syndrome [AIDS] or AIDS-related complex) with an automated dot blot assay using purified recombinant antigens. High and sustained levels of antibody to gp120, gp41, and p31 were found in all patients irrespective of their clinical condition for 4 to 6 years after seroconversion. In contrast, immune response to p66 and p17 was significantly lower in symptomatic patients. Over time, the levels of these two antibodies, as well as anti-p24, decreased and tended to become undetectable. Abnormal immune response and low levels of antibody to p66 and p17 are early indications of rapid clinical progression.