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CpG oligodeoxynucleotides (ODNs) are synthetic DNA sequences containing unmethylated cytosine-guanine motifs with potent immunomodulatory effects. Via Toll-like receptor 9 agonism of dendritic cells and B cells, CpG ODNs induce cytokines, activate natural killer cells, and elicit vigorous T-cell responses that lead to significant antitumor effects, including improved efficacy of chemotherapeutic agents. On the basis of these properties of CpG ODNs, we tested whether they also could enhance tumor response to radiotherapy. Using an immunogenic mouse tumor, designated FSa, the response to radiotherapy was assayed by tumor growth delay and tumor cure rate (TCD 50 , radiation dose yielding 50% tumor cure rate). Treatments were initiated when established tumors were either 6 or 8 mm in diameter. CpG ODN as a single agent given s.c. peritumorally had little effect on tumor growth; however, it dramatically enhanced tumor growth delay in response to single-dose radiation by a factor of 2.58 -2.65. CpG ODN also dramatically improved tumor radiocurability, reducing the TCD 50 by a factor of 1.

We observed persistent ECHOvirus infection of the central nervous system, as defined by continued presence of isolatable virus in cerebrospinal fluid, in five patients with agammaglobulinemia. The immunologic deficit in each was characterized by absence of surface-immunoglobulin-bearing B lymphocytes and of lymph-node cortical follicles, but normal T-cell function. ECHOviruses 30, 19, 9 and 33 were recovered from cerebrospinal fluid for periods varying from two months to three years. The patients had few signs of acute central-nervous-system infection. Three of the five patients had a dermatomyositis-like syndrome, with peripheral lymphocytes that reacted with anti-human leukemia-specific primate and rabbit serums in a cytotoxicity assay. These data suggest that intact B-cell function is essential for eradication of ECHOvirus infection of the central nervous system.

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The immunomodulator AS I0 I has been demonstrated to exhibit radioprotective and chemoprotective effects in mice. Following phase-I studies, preliminary resulk from phase-ll clinical trials on non-small-cell-lung-cancer patients showed a reduction in the severity of alopecia in patients treated with A S l O l in combination with chemotherapy. To further substantiate these findings, the present study was extended to include 58 patienk treated either with the optimal dose of 3 mg/rn2 AS I0 I combined with carboplatin and VP-16, or with chemotherapy alone. As compared with patienk treated with chemotherapy alone, there was a significant decrease in the level of alopecia in patients receiving the combined therapy. The newly developed rat model was used to elucidate the protective mechanism involved in this effect. We show that significant prevention of chemotherapy-induced alopecia is obtained in rats treated with Ara-C combined with AS 10 I, administered i.p. or S. C. or applied topically to the dorsal skin. We show that this protection by AS I0 I is mediated by macrophage-derived factors induced by AS I0 I. Protection by AS I0 I can be ascribed, at least in part, to IL-I, since treatment of rats with IL-IRA largely abrogated the protective effect of AS I0 I. Moreover, we demonstrate that in humans there is an inverse correlation between the grade of alopecia and the increase in IL-la. In addition, protection by A S l O l could be related to PGE2 secretion, since injection of indomethacin before treatment with AS I0 I and Ara-C partly abrogated the protective effect of AS 10 I. To assess the ability of AS 10 I to protect against chemotherapy-induced alopecia, phase-ll clinical trials have been initiated with cancer patienk suffering from various malignancies.o 1996 Wiley-Liss, Inc.The psychological impact of chemotherapy-induced alopecia represents one of the more devastating side effects of cancer chemotherapy and, in some instances, leads patients to refuse potentially curative chemotherapy (Hood, 1986). Although this complication has been known for many decades, little progress has been made in its prevention or treatment (Wood, 1985), in part because of lack of a suitable, reproducible experimental model. A new model has now been developed in which chemotherapy induces total alopecia in 8-dayold rats (Hussein et al., 1990). This model enables the investigation of agents that might protect against chemotherapyinduced alopecia, and the elucidation of their mechanism of action.The immunomodulator ASlOl [ammonium trichloro (dioxyethylene-0,O') tellurate] has been shown by us to exhibit radioprotective properties when injected into mice prior to sub-lethal and lethal doses of irradiation (Kalechman et al., 1990). In addition, AS101 was found to protect mice from hemopoietic damage caused by sub-lethal doses of various chemotherapeutic drugs, and to increase the rate of survival of mice treated with lethal doses of these agents. These include cyclophosphamide (Kalechman et al., 1991a), 5-FU (Kalechman et al., 1991b)...

The incidence, trend over a 41-year period, prevalence, familial aggregation, and survivorship of Crohn's disease in the population of Olmsted County, Minnesota, are described. During the period 1935-1975, there were 103 incidence cases; the age-adjusted incidence rate per 100,000 rose from 1.9 (1935-1954) to 4.0 (1955-1964) and to 6.6 in the most recent period (1965-1975). The increase of the rate over the last 11 years is due largely to the increase among persons 20 to 29 years old. No difference in the rates by sex was found. The urban rates were higher than the rural for both sexes and in each interval of the study. The prevalence of Crohn's disease among the residents of Olmsted County on Jan. 1, 1976, was found to be 105.7 per 100,000 population. The relatively high prevalence rate reflects the chronic nature of the disease, the recent increase of incidence, the completeness of case ascertainment, and the high survival rate among these patients.

\s=b\ Sixty-six patients with recurrent respiratory papillomatosis of juvenile onset were treated for six months with interferon alfa-n1 (Wellferon) in a randomized crossover trial. Half received interferon alfa-n1 intramuscularly at a dosage of 5 megaunits per square meter daily for 28 days and then thrice weekly for five months, followed by six months of observation. The other half were observed for six months and then treated. Operations were performed every two months to assess disease extent by a scale developed for this purpose. The score for the patients during the first observation period was stable. There was a statistically significant lowering of score in patients receiving interferon alfa-n1 during both periods of drug administration. Eight of 57 patients with assessable airway disease achieved complete remission, as did one additional patient with disease limited to the nasopharynx. No patients achieved complete remission during six months of observation alone. This difference was statistically significant. Patients without tracheostomy were significantly more likely to achieve remission than those with a tracheostomy. The patients who were observed after discontinuation of the drug therapy showed a significant rise in score within four months. Symptoms of toxicity included transient fever, fatigue, nausea, and headache. Elevations in serum aspartate aminotransferase levels occurred in 64% of the patients. There was an inverse correlation between age and the ability to tolerate the medication. The dose studied may be close to the maximum tolerated dose. It appears that interferon alfa-n1 as an adjuvant to routine surgical management is effective in slowing the growth of respiratory papillomas.(Arch Otolaryngol Head Neck Surg

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