Synergistic activation of innate immunity by double-stranded RNA and CpG DNA promotes enhanced antitumor activity

Double-stranded RNA (dsRNA) and unmethylated CpG sequences in DNA are pathogen-associated molecular patterns of viruses and bacteria that activate innate immunity. To examine whether dsRNA and CpG DNA could combine to provide enhanced stimulation of innate immune cells, murine macrophages were stimulated with poly-rI:rC (pIC), a dsRNA analog, and CpG-containing oligodeoxynucleotides (CpG-ODN). Combined treatments demonstrated synergy in nitric oxide, interleukin (IL)-12, tumor necrosis factor alpha, and IL-6 production. Studies using neutralizing antibodies for type I interferons (IFNs), IFN-alpha and IFN-beta, indicated that nitric oxide synthase synergism is mediated by paracrine/autocrine effects of IFN-beta. In contrast, enhanced cytokine production occurred independent of type I IFN and was maintained in macrophages from IFN-alpha/beta receptor knockout mice. Cotransfection of human Toll-like receptors 3 and 9 (receptors for dsRNA and CpG DNA, respectively) into 293T cells supported synergistic activation of an IL-8 promoter reporter construct by pIC, indicating interaction of the signaling pathways in driving the synergy response. In vivo stimulation of mice with pIC and CpG-ODN demonstrated synergy for serum IL-6 and IL-12p40 levels that correlated with an enhanced antitumor effect against established B16-F10 experimental pulmonary metastases. Treatment of tumor-bearing mice with pIC and CpG-ODN in combination resulted in enhanced nitric oxide synthase expression in lung tissue and enhanced up-regulation of class I major histocompatibility complex on splenic dendritic cells relative to treatments with either agent alone. In conclusion, the combined detection of viral pathogen-associated molecular patterns, i.e., dsRNA and CpG DNA, may mimic definitive viral recognition, resulting in an enhanced innate immune response that could be used for tumor vaccination or immunotherapy.     

Phase 2 trial of interferon-beta as second-line treatment of ovarian cancer, fallopian tube cancer, or primary carcinoma of the peritoneum

OBJECTIVE: The protocol was designed to examine the biological effects and clinical activity of interferon-beta in patients with platinum/taxane-resistant ovarian cancer. METHODS: Patients with resistant ovarian and fallopian tube cancers and primary peritoneal carcinoma were treated with recombinant human interferon-beta (Rebif, Serono International) at doses ranging from 6 to 24 million international units (MIU)/day, based on their tolerance to therapy. Levels of IP-10, an interferon-inducible protein, were measured in the serum to evaluate the biological effects of the drug. Also, the peripheral blood mononuclear cells and serum were examined for the induction of previously described novel regulators of interferon-induced death. RESULTS: Eighteen patients were treated, of whom 9 (50%) could be treated at the highest dose level (24 MIU). The major toxicities were fever, chills and fatigue. The median duration of therapy was 6 weeks (range 1-22). No objective responses were observed. IP-10 levels were significantly increased, compared with baseline, at 2, 4, and 6 weeks after initiation of therapy (p < 0.01). CONCLUSIONS: Recombinant human interferon-beta produced a definite biological effect in the serum of treated patients, but this outcome was not translated into any clinically observable or meaningful impact on the disease process.     

Medical aspects of the squint operation as day surgery - a contribution to quality control

BACKGROUND: The strained situation in the financing of our health system makes it necessary that we reassess therapeutic procedures and their management. Since the squinting operation is mainly performed in the form of day surgery in the English-language area, we followed this example and treated 112 patients in this way. Afterwards we examined their acceptance in cooperation with the Department for Interdisciplinary Quality Management. PATIENTS AND METHOD: 112 patients in whom a squinting operation had been performed in the form of day surgery, received a comprehensive questionnaire with 24 questions, which had been compiled together with the Institute for Psychology, the Institut for Social Medicine and the University Clinic for anaesthesiology. RESULTS: There was a very high acceptance and a positive feedback so that for 3 years now we reserve one day per week for squinting operations in the form of day surgical performance.     

Chromosomal alterations in osteosarcoma cell lines revealed by comparative genomic hybridization and multicolor karyotyping

We characterized the chromosomal alterations in eight osteosarcoma cell lines (OST, HOS, U-2 OS, ZK-58, MG-63, SJSA-1, Saos-2, and MNNG) by comparative genomic hybridization (CGH); gains and losses of DNA sequences were defined as chromosomal regions with a fluorescence ratio, wherein all of the 95% confidence interval was above 1.25 and below 0.75, respectively. In four of 8 cell lines, multicolor karyotyping (MK) was added. CGH revealed the average number of aberrations per cell line was 20.8 (range: 10–31); the average numbers of gains and losses were 11.1 and 9.6, respectively. The frequent gains were identified on 1p21q24, 1q25q31, 7p21, 7q31, 8q23q24, and 14q21; frequent losses were at 18q21q22, 18q12, 19p, and 3p12p14. High-level gains were observed on 8q23q24, 5p, and 1p21p22. MK revealed the most common translocations in the four cell lines were t(8;9), t(1;3), t(3;5), t(1;13), t(2;6), t(3;17), t(1;15), t(10;20), and t(6;20). Chromosomes 1, 3, 8, 9, and 20 were most frequently involved in translocation events. The concordance rate of aberrations in CGH and translocations in MK was 76%. MK was useful to identify the chromosomal alterations and as a supplement to the CGH results in three of four chromosomes.     

Cutaneous melanoma during pregnancy at the Cancer Center-Institute in Warsaw

Malignant melanoma is a neoplasm which frequency has been increasing rapidly in Poland. The paper describes five cases of patients with cutaneous melanoma coexisting with pregnancy, who have been recently treated in the Department of Soft Tissue/Bone Tumors of M. Sklodowska-Curie Memorial Cancer--Institute of Oncology, Warsaw. All patients presented clinically advanced primary lesions with poor prognosis. In paper recommendations for treatment of women with suspicious cutaneous lesions before or during pregnancy and patients with melanoma planning a pregnancy are presented. The suspicion of melanoma is indication for immediate excisional biopsy by local anesthesia. Further treatment should be performed in tertiary oncological centres. There is no evident clinical data that pregnancy has a significant impact on progression of melanoma. The most important factor influencing prognosis of melanoma is the stage of the disease at the diagnosis. There are no grounds for abortion in pregnant women with melanoma in I/II/III stages.     

Evaluation and management of the sexually assaulted woman

The evaluation and management of the sexually assaulted woman is a challenging task that emergency physicians frequently face. The physician must assume dual roles as advocate for the patient and as an agent of the government. While caring for the immediate physical and emotional well being of the victim, the physician also must be diligent in the forensic evaluation and evidence collection. To receive quality care, the victim should receive a thorough history and physical examination with appropriate diagnosis and treatment of injuries, a thorough evidentiary examination, counseling and treatment for prevention of pregnancy and STDs, provisions for initial and ongoing mental health evaluation, and appropriate follow-up. To provide this high quality care, the physician must be familiar with the process of the evidentiary examination, have knowledge of the current recommendations for pregnancy and STD prophylaxis. and have thorough knowledge of the community resources that are available.