A Phase 3 Trial of Luspatercept in Patients with Transfusion-Dependent ß-Thalassemia.

BACKGROUND: Patients with transfusion-dependent ß-thalassemia need regular red-cell transfusions. Luspatercept, a recombinant fusion protein that binds to select transforming growth factor ß superfamily ligands, may enhance erythroid maturation and reduce the transfusion burden (the total number of red-cell units transfused) in such patients. METHODS: In this randomized, double-blind, phase 3 trial, we assigned, in a 2:1 ratio, adults with transfusion-dependent ß-thalassemia to receive best supportive care plus luspatercept (at a dose of 1.00 to 1.25 mg per kilogram of body weight) or placebo for at least 48 weeks. The primary end point was the percentage of patients who had a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24 plus a reduction of at least 2 red-cell units over this 12-week interval. Other efficacy end points included reductions in the transfusion burden during any 12-week interval and results of iron studies. RESULTS: A total of 224 patients were assigned to the luspatercept group and 112 to the placebo group. Luspatercept or placebo was administered for a median of approximately 64 weeks in both groups. The percentage of patients who had a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24 plus a reduction of at least 2 red-cell units over this 12-week interval was significantly greater in the luspatercept group than in the placebo group (21.4% vs. 4.5%, P<0.001). During any 12-week interval, the percentage of patients who had a reduction in transfusion burden of at least 33% was greater in the luspatercept group than in the placebo group (70.5% vs. 29.5%), as was the percentage of those who had a reduction of at least 50% (40.2% vs. 6.3%). The least-squares mean difference between the groups in serum ferritin levels at week 48 was -348 µg per liter (95% confidence interval, -517 to -179) in favor of luspatercept. Adverse events of transient bone pain, arthralgia, dizziness, hypertension, and hyperuricemia were more common with luspatercept than placebo. CONCLUSIONS: The percentage of patients with transfusion-dependent ß-thalassemia who had a reduction in transfusion burden was significantly greater in the luspatercept group than in the placebo group, and few adverse events led to the discontinuation of treatment. (Funded by Celgene and Acceleron Pharma; BELIEVE ClinicalTrials.gov number, NCT02604433; EudraCT number, 2015-003224-31.).

Little red riding hood in the social forest. Online grooming as a public health issue: a narrative review.

INTRODUCTION: Online grooming is a manipulative process through which an adult attempts to arrange a sexual interaction with a minor using internet. Children are constantly exposed to the online world, posing online grooming as a public health issue. OBJECTIVES: The aim of this narrative review is to describe the state of online grooming preventive strategies in recent literature through an overview of online grooming phenomenon. METHODS: Our literature review included research articles and reviews published between January 2014 and March 2019, as well as reference lists of included studies. RESULTS: The analysis provides a picture of online grooming phenomenon, identify recurrent features of perpetrators and victims. Several preventive strategies have been implemented, but they lack any kind of efficacy evaluation and miss a theory driven approach. Fragmentation of preventive initiatives is a critical issue, in contrast with the need of an institutional public health strategy. CONCLUSIONS: While the attention around online grooming is growing, there is still the need of further sensitizing the involved stakeholders and developing evidence based preventive strategies under an institutional guidance.

Measurement of liver iron overload: noninvasive calibration of MRI-R2* by magnetic iron detector susceptometer.

An accurate assessment of body iron accumulation is essential for the diagnosis and therapy of iron overload in diseases such as thalassemia or hemochromatosis. Magnetic iron detector susceptometry and MRI are noninvasive techniques capable of detecting iron overload in the liver. Although the transverse relaxation rate measured by MRI can be correlated with the presence of iron, a calibration step is needed to obtain the liver iron concentration. Magnetic iron detector provides an evaluation of the iron overload in the whole liver. In this article, we describe a retrospective observational study comparing magnetic iron detector and MRI examinations performed on the same group of 97 patients with transfusional or congenital iron overload. A biopsy-free linear calibration to convert the average transverse relaxation rate in iron overload (R(2) = 0.72), or in liver iron concentration evaluated in wet tissue (R(2) = 0.68), is presented. This article also compares liver iron concentrations calculated in dry tissue using MRI and the existing biopsy calibration with liver iron concentrations evaluated in wet tissue by magnetic iron detector to obtain an estimate of the wet-to-dry conversion factor of 6.7 ± 0.8 (95% confidence level).

Mutant lines of guinea pig L2C leukemia. I. Deletion of Ia alloantigens is associated with a loss in immunogenicity of tumor-associated transplantation antigens.

Five different lines of a strain 2 guinea pig leukemia (L2C) which had been carried in different laboratories share certain chromosomal markers and have a common surface immunoglobulin idiotypic determinant indicating that they have a common origin. All these leukemic lines have on their surface of the B alloantigen (equivalent of the murine H-2K and H-2D antigens) and four of these five lines have on their surface the Ia alloantigens normally present on the strain 2 lymphocytes. The result of a study of the growth and rejection patterns of these leukemias in inbred and random-bred guinea pigs of selected histocompatibility type indicates that both the B and Ia antigens can act as transplantation antigens in guinea pigs. Immunization protection tests in syngeneic animals demonstrated that the four Ia-positive leukemias possessed a tumor-associated transplantation antigen (TATA), while the one Ia-positive leukemias possessed a tumor-associated transplantation antigen (TATA), while the one Ia-negative leukemia by this criteria did not appear to have TATA. However, crisscross immunization protection tests demonstrated that preimmunization of syngeneic animals with an Ia-positive L2C line lead to a subsequent protection against challenge with the Ia-negative leukemia. Immunization with the Ia-negative line never protected against a subsequent challenge with any of the leukemic cells of L2C lines. These results strongly suggest that the Ia-negative leukemia possessed a TATA that can be recognized but is not itself immunogenic, and also indicate that Ia antigens on L2C cells are functionally associated with TATA and can act as immunological carries for tumor transplantation determinants.

Expression of an exogenous interleukin 6 gene in human Epstein Barr virus B cells confers growth advantage and in vivo tumorigenicity.

The biological role of interleukin 6 (IL-6) molecules in human B cell tumorigenesis was studied by using an episomal expression vector, pHEBoSV-IL6, to introduce stably the human IL-6 gene into human Epstein Barr virus (EBV)-transformed B lymphoblasts. The gene was present in the IL-6-transfected cells in a high copy number and was efficiently expressed, resulting in the secretion of consistent levels of IL-6 molecules. The constitutive expression of the IL-6 gene led to an altered pattern of growth and to a malignant phenotype, as shown by clonogenicity in to an altered pattern of growth and to a malignant phenotype, as shown by clonogenicity in soft agar cultures and tumorigenicity in nude mice. These data suggest that the combined action of EBV, which exerts an immortalizing function, and of the growth-promoting activity of IL-6 molecules, can give rise to fully transformed B cell tumors in immunodeficient subjects.

Combined allogeneic tumor cell vaccination and systemic interleukin 12 prevents mammary carcinogenesis in HER-2/neu transgenic mice.

Transgenic Balb/c mice expressing the transforming rat HER-2/neu oncogene develop early and multifocal mammary carcinomas. Within the first 5 months of life the tissue-specific expression of HER-2/neu causes a progression in all their 10 mammary glands from atypical hyperplasia to invasive carcinoma. It was previously observed that chronic administration of interleukin (IL)-12 increased tumor latency, but every mouse eventually succumbed to multiple carcinomas. A significant improvement in tumor prevention was sought by administering allogeneic mammary carcinoma cells expressing HER-2/neu combined with systemic IL-12. This treatment reduced tumor incidence by 90% and more than doubled mouse lifetime. For the maximum prevention p185(neu) antigen must be expressed by allogeneic cells. IL-12 treatment strongly increased the cell vaccine efficacy. The mammary glands of mice receiving the combined treatment displayed a markedly reduced epithelial cell proliferation, angiogenesis, and HER-2/neu expression, while the few hyperplastic foci were heavily infiltrated by granulocytes, macrophages, and CD8(+) lymphocytes. Specific anti-HER-2/neu antibodies were produced and a nonpolarized activation of CD4(+) and CD8(+) cells secreting IL-4 and interferon (IFN)-gamma were evident. A central role for IFN-gamma in the preventive effect was proven by the lack of efficacy of vaccination in IFN-gamma gene knockout HER-2/neu transgenic Balb/c mice. A possible requirement for IFN-gamma is related to its effect on antibody production, in particular on IgG2a and IgG2b subclasses, that were not induced in IFN-gamma knockout HER-2/neu mice. In conclusion, our data show that an allogeneic HER-2/neu-expressing cell vaccine combined with IL-12 systemic treatment can prevent the onset of genetically determined tumors.

Interleukin 12-mediated prevention of spontaneous mammary adenocarcinomas in two lines of Her-2/neu transgenic mice.

The ability of interleukin (IL)-12 to prevent tumors when administered to individuals with a genetic risk of cancer was studied in two lines of transgenic mice expressing rat HER-2/neu oncogene in the mammary gland. Female BALB/c (H-2(d)) mice carrying the activated HER-2/ neu oncogene show no morphological abnormalities of the mammary gland until 3 wk of age. They then progress through atypical hyperplasia to in situ lobular carcinoma and at 33 wk of age all 10 mammary glands display invasive carcinomas. Adult FVB mice (H-2(q)) carrying the HER-2/neu protooncogene develop mammary carcinomas with a longer latency (38-49 wk) and a lower multiplicity (mean of 2.6 tumors/mice). Treatment with IL-12 (5 daily intraperitoneal injections, 1 wk on, 3 wk off; the first course with 50 ng IL-12/day, the second with 100 ng IL-12/day) begun at 2 wk of age in BALB/c mice and at 21 wk of age in FVB mice markedly delayed tumor onset and reduced tumor multiplicity. Analogous results were obtained in immunocompetent and permanently CD8(+) T lymphocyte-depleted mice. In both transgenic lines, tumor inhibition was associated with mammary infiltration of reactive cells, production of cytokines and inducible nitric oxide synthase, and reduction in microvessel number, in combination with a high degree of hemorrhagic necrosis.

Inhibition of interferon-gamma may suppress allograft reactivity by T lymphocytes in vitro and in vivo.

The addition to mixed-leukocyte reactions of monoclonal antibodies to interferon-gamma abrogated alloantigen recognition and induction of cytotoxic T lymphocytes by inducing early and highly effective suppressor T lymphocytes. This inhibitory activity was not confined to in vitro models, since daily injection of the antibodies into CBA/J mice blocked the usual rejection of allogenic tumor cells.

CCL16 enhances the CD8+ and CD4+ T cell reactivity to human HER-2 elicited by dendritic cells loaded with rat ortholog HER-2.

T cells from HLA-A2+ healthy donors were co-cultured with autologous dendritic cells (DC) loaded with apoptotic tumor cells expressing rat neu, and were induced to mature by tumor necrosis factor (TNF)alpha and interleukin (IL)-1beta (mDC(neu)) or by the CCL16 chemokine (CCL16/mDC(neu)). Priming by CCL16/mDC(neu) induces a larger population of T cells that express cytoplasmatic interferon (IFN)gamma, TNFalpha, perforin and granzyme B compared to those primed by mDC(neu). T cells primed by CCL16/mDC(neu) release IFNgamma in response to human HER-2+ cells and kill human HER-2+ target cells more efficiently than those primed by mDC(neu). Our results show that both the loading of DC with xenogeneic rat neu and their maturation by CCL16 are two issues of critical importance for the elicitation of an effective response to human HER-2 in T cells from normal donors.

Randomised clinical trial: sofosbuvir and ledipasvir in patients with transfusion-dependent thalassaemia and HCV genotype 1 or 4 infection.

BACKGROUND: Patients with thalassaemia major depend on blood transfusions. In Italy, up to 80% of thalassaemia patients bear HCV antibodies due to HCV contaminated transfusions before 1990. Thalassaemia patients with HCV infection have high risk of developing HCC. Treatment based on Pegylated-IFN (Peg-IFN) and Ribavirin (RBV) was limited by relevant side effects. AIM: To evaluate the impact of Sofosbuvir/Ledipasvir (SOF/LDV) fixed dose combination for 12 weeks without RBV, in patients with thalassaemia major and HCV Genotype 1 or 4 (GT1/4). METHODS: Open label, historically-controlled, nationwide multicentre study in thalassaemia patients including naïve with cirrhosis and prior treatment failure without cirrhosis. SOF/LDV single pill was administered for 12 weeks to 100 patients of whom 16% had cirrhosis. The control group included 96 patients with comparable baseline characteristics treated with Peg-IFN/RBV. The primary end point was sustained virologic response at follow-up week 12 or 24 after IFN-free or Peg-IFN/RBV, respectively. RESULTS: In the study group, sustained virological response (SVR) was reported in 98% of patients (95% CI 95.3%-100%). Cirrhotic as well as prior treatment failure achieved 100% SVR. In the control group, SVR was 47.9% (95% CI 37.9%-57.9%). Adverse events including fatigue, headache, nausea, decrease in haemoglobin or increase in ferritin levels were rare and significantly less common in the study than in the historical control group. CONCLUSIONS: In conclusion, SOF/LDV for 12 weeks provides simple, highly effective and safe Peg-IFN/RBV-free treatment for HCV GT1/4 thalassaemia patients. EUDRACT number 2015-002401-1.

A completely automated CAD system for mass detection in a large mammographic database.

Mass localization plays a crucial role in computer-aided detection (CAD) systems for the classification of suspicious regions in mammograms. In this article we present a completely automated classification system for the detection of masses in digitized mammographic images. The tool system we discuss consists in three processing levels: (a) Image segmentation for the localization of regions of interest (ROIs). This step relies on an iterative dynamical threshold algorithm able to select iso-intensity closed contours around gray level maxima of the mammogram. (b) ROI characterization by means of textural features computed from the gray tone spatial dependence matrix (GTSDM), containing second-order spatial statistics information on the pixel gray level intensity. As the images under study were recorded in different centers and with different machine settings, eight GTSDM features were selected so as to be invariant under monotonic transformation. In this way, the images do not need to be normalized, as the adopted features depend on the texture only, rather than on the gray tone levels, too. (c) ROI classification by means of a neural network, with supervision provided by the radiologist's diagnosis. The CAD system was evaluated on a large database of 3369 mammographic images [2307 negative, 1062 pathological (or positive), containing at least one confirmed mass, as diagnosed by an expert radiologist]. To assess the performance of the system, receiver operating characteristic (ROC) and free-response ROC analysis were employed. The area under the ROC curve was found to be Az = 0.783 +/- 0.008 for the ROI-based classification. When evaluating the accuracy of the CAD against the radiologist-drawn boundaries, 4.23 false positives per image are found at 80% of mass sensitivity.

Interaction of H-2 and non-H-2 genes in spontaneous resistance to adenocarcinoma ADK-1t in F1 mice.

The genetic control of spontaneous resistance in vivo to increasing doses of a poorly immunogenic spontaneous adenocarcinoma (ADK-1t) of BALB/c origin was studied in F1 hybrid mice. The spontaneous resistance of homozygous parental BALB/c mice was not increased in F1 hybrids of BALB/c and BALB.B or BALB.K mice, even with small tumor challenges (10(3) cells). By contrast, it was significantly enhanced in F1 hybrids of BALB/c and several strains on A or B10 background. Resistance due to the acquisition of a new set of background genes was, however, markedly enhanced or suppressed by the presence of particular alleles located within or closely linked to the H-2 complex, as demonstrated by increasing the tumor challenge to 10(4) or 10 (5) cells. Spontaneous resistance, effective even with high tumor inocula, thus depended on a complex interplay between background and H-2 genes.

Mutant lines of guinea pig L2C leukemia. II. Comparative cytogenetic studies and banding analyses of normal and leukemic karyotypes.

Chromosomes of normal guinea pig (strain 2) cells and of cell lines dervied from a spontaneously arising leukemia were analyzed in detail. All cell lines studied, LG-L2C, GH-L2-C, BZ-LC, and EN-L2C, contained one M1 marker and two X chromosomes, in addition to other chromosome abnormalities specific for each cell line. The presence of the M1 marker and the two X chromosomes confirmed that all of these leukemic cell lines are derived from one ancestral line. Comparison of the chromosome markers and immunologic characteristics of these lines revealed that possibly the gene involved in the determination of C3 receptor sites is located on the terminal portion of the long arm of chromosome No. 2, but no other correlations could be made.

Effect of prolonged administration of low doses of dietary retinoids on cell-mediated immunity and the growth of transplantable tumors in mice.

A study was conducted on the activity exerted by prolonged dietary supplementation with progressive amounts of retinoids on cell-mediated immune responses and the growth of transplantable tumors in mice. A few groups of BALB/c mice received 0 (group C), 50 (group A 50), 200 (group A 200), 500 (group A 500), and 1,000 (group A 1000) IU retinol palmitate/mouse/day in drinking water for 150 days. At progressive intervals mice from each group were tested for proliferative responses to concanavalin A (Con A), Escherichia coli lipopolysaccharide, interleukin-2, and interferon-gamma release to Con A. Ten mice from each group were also challenged with the 90-100% tumor-inducing dose of 3 distinct transplantable tumors. At the end of the experiment the principal organs were histologically examined, and the accumulation of vitamin A was evaluated. In groups A 200, A 500, and A 1000, an increase in the proliferative responses and production of lymphokines as compared to those in group C occurred after 60-90 days, but vanished after 150 days. The takes of the 3 tumors were impaired when the challenges were performed on days 75 and 150. This enhancement of distinct functions of cellular reactivity and resistance to transplantable tumors showed a linear relationship with the amount of supplemental retinol palmitate for the first 60-90 days. After 150 days, however, these enhancement effects vanished or tended to decrease.

Transduction of the IL2 gene into human acute leukemia cells: induction of tumor rejection without modifying cell proliferation and IL2 receptor expression.

BACKGROUND: Previous studies have suggested that some of the limitations associated with the administration of high-dose exogenous interleukin 2 (IL2) may be overcome, at least partly, by cytokine gene transfer modalities. These findings have prompted investigations into whether human tumor cells may be transduced with the IL2 gene and whether tumor cell lines could be engineered to release IL2. PURPOSE: The purpose of this study was to evaluate the possibility of inducing a productive transfer of the IL2 gene into human acute leukemia cells and to assess the phenotypic and proliferative changes generated in the engineered cells, as well as their tumorigenic potential in nude mice. METHODS: Three retroviral vectors (DC/TK/IL2, DC/AD/R/IL2, and N2/CMV/IL2) carrying the IL2 gene were used to transduce three human leukemic cell lines: K562 and U937 (myeloid) and ST4 (lymphoid). Messenger RNA expression of the IL2 gene was analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR) and productive IL2 release using a human IL2 assay and an enzyme-linked immunosorbent assay kit. The expression of the p55 (alpha) and p75 (beta) chains of the IL2 receptor were determined by RT-PCR and indirect immunofluorescence. The kinetics of in vitro growth and proliferation of parental and engineered cells were also measured. Parental and IL2 gene-transduced ST4 lymphoblasts were injected into immunosuppressed nude mice that had their tumors measured twice weekly. RESULTS: The productive insertion of the IL2 gene was achieved in all three cell lines studied. The amounts of IL2 constitutively released by the engineered neoplastic cells ranged between 1 and 11 U/mL of IL2 produced from 10(6) cells in 72 hours. A fivefold increase in IL2 production was obtained in ST4 cells by further limiting dilution cloning of the bulk-infected cells. The stable integration of the IL2 gene did not modify the phenotype of the leukemic cells, the expression of the IL2 receptor alpha and beta chains and of several cytokine genes, or the kinetics of in vitro growth and proliferation. In nude mice injected with various IL2-producing ST4 clones, tumor growth associated inversely with the amounts of IL2 secreted by the leukemic cells. CONCLUSIONS: The results of this study demonstrate that the IL2 gene can be productively transduced into human myeloid and lymphoid leukemic cells without modifying their phenotypic and proliferative properties and that this transduction leads to a reduced or abrogated in vivo tumorigenic potential.

Antitumor efficacy of adenocarcinoma cells engineered to produce interleukin 12 (IL-12) or other cytokines compared with exogenous IL-12.

BACKGROUND: Numerous animal model studies have examined the ability of genetically engineered tumor cells to release cytokines and to elicit an immune memory against the parental tumor. Often only a single cytokine is studied, and few comparative studies have been conducted. PURPOSE: We evaluated the antitumor efficacy of adenocarcinoma cells engineered to release interleukin (IL)-12 in a mouse model system. The efficacy of this cytokine was compared with that of other cytokines released by engineered adenocarcinoma cells and that of exogenous IL-12 administered both locally and intraperitoneally. METHODS: BALB/cAnCr mice were inoculated with syngeneic parental mammary adenocarcinoma (TSA) cells in quantities sufficient to lead to tumors in all inoculated mice. TSA cells engineered to release IL-12 (TSA-IL12) were also injected into normal and selectively immunosuppressed BALB/cAnCr mice. Tumor incidence, growth, and rejection patterns were evaluated by the measurement of neoplastic masses and by the study of the histologic and ultrastructural features of the tumor site. The effects of local or intraperitoneal administration of recombinant IL-12 (rIL-12) on tumor-bearing animals were also studied. RESULTS: Most mice rejected TSA-IL12 cells through a CD8-positive, T-lymphocyte-dependent reaction associated with macrophage infiltration, vessel damage, and necrosis. The systemic immunity of mice that had rejected TSA-IL12 cells to a subsequent challenge with parental TSA cells was less efficient than that elicited by TSA cells engineered to release IL-4 or IL-10 but equivalent to that elicited by TSA cells engineered to release IL-2, IL-7, and interferon alfa. Compared with TSA cells engineered to produce other cytokines, TSA-IL12 cells were the most efficient in curing mice with established TSA tumors; injection of 0.1 million proliferating cells contralaterally to the tumor growth area cured five of 15 mice bearing 1-day-old tumors; injection of the same dose of proliferating cells into the tumor growth area cured two of 20 tumor-bearing mice. However, two 5-day courses with a nontoxic dose (0.1 microgram) of rIL-12 given intraperitoneally cured a similar proportion of these animals (six of 20). Only two of 20 mice with 7-day-old TSA tumors were cured by vaccination with proliferating TSA-IL12 cells, whereas 24 of 30 mice with such tumors were cured by intraperitoneal administration of rIL-12. CONCLUSIONS: TSA cells engineered to release IL-12 are rejected by most mice; the ensuing immune memory for TSA parental cells, however, was less efficient than that elicited by proliferating TSA cells engineered to release other cytokines (e.g., IL-4, IL-10, and possibly interferon gamma). The immune reaction elicited by TSA-IL12 cells was the most efficient in curing mice with established TSA tumors; notably though, the same or a better cure rate was obtained with rIL-12 given intraperitoneally.

Inhibition of replication of virus-transformed fibroblasts by antibodies to RNA.

The activity of 7S immunoglobulins (Ig) antibody to RNA, obtained in rabbits after a prolonged immunization with RNA-methylated bovine serum albumin complex was evaluated in vitro on normal (3T3) and simian virus 40-transformed (SV 3T3) mouse fibroblasts. The presence of anti-RNA antibody in the culture medium inhibited both the SV 3T3 cell proliferation and the [3H]thymidine incorporation. In contrast, an increased [3H]uridine incorporation was evident within 48 and 96 hr of culture. No significant modification in these 3 parameters was observed in 3T3 cultures treated in the same manner. Both 3T3 and SV 3T3 showed cytoplasmic fluorescence when cultured in the presence of fluoresceinated anti-RNA Ig. However, with the indirect fluorescence technique anti-RNA Ig were detected in SV 3T3 cytoplasm only. These data suggest that anti-RNA Ig were taken up by both 3T3 and SV 3T3, but only in SV 3T3 did the anti-RNA Ig retain their antigenic properties and block cellular proliferation.

Immunoprevention of cancer: is the time ripe?

Immunotherapy applied to patients with established tumors rarely leads to an objective response, whereas patients apparently free from disease after conventional treatment and at risk of recurrence are beginning to receive vaccination. New classes of patients or not-yet patients are those with a high genetic or environmental risk of developing cancer. They may draw benefit from a "soft" treatment such as vaccination. This overview discusses the prospects of immune stimulation as a means of cancer prevention by inducing various forms of nonspecific or even specific immunity. Attainment of this goal provides the rationale and motivation for embarking on such a new and potentially rewarding enterprise.

Strain- and sex-linked effects of dietary polyunsaturated fatty acids on tumor growth and immune functions in mice.

In the present paper, we studied the influence of different levels of dietary polyunsaturated fatty acids (PUFA) on the immune system and tumor growth in young mice. Female BALB/c mice fed a PUFA-rich diet display an enhanced body growth, proliferative response to mitogens in vitro, and rate of growth of a spontaneous transplantable adenocarcinoma as compared to PUFA-poor diet-fed females. Such effects are, however, limited by sex and strain background genes located outside the H-2 complex. In effect, the influence of dietary PUFA content is evident in female but not in male BALB/c mice. Moreover, in female DBA/2 mice with the same haplotype (H-2d) of the major histocompatibility complex as that of BALB/c mice, low dietary PUFA determines a reduced tumor growth only, but it does not affect body growth and proliferative response to mitogens in vitro.

Immune events associated with the cure of established tumors and spontaneous metastases by local and systemic interleukin 12.

The antitumor activity of recombinant murine interleukin-12 (rIL-12) is documented by a large set of data from numerous mouse models. Because the cellular and molecular mechanisms by which rIL-12 impairs tumor growth are still not fully defined, we compared the effects of local and systemic rIL-12 administration in mice harboring an invasive 7-day-old moderately differentiated and spontaneously metastasizing mammary adenocarcinoma (TSA). Whereas the immune events elicited via the two routes of rIL-12 administration seem to be the same, systemic rIL-12 is markedly more effective; tumor destruction is dependent on a prompt antitumor response resulting from the cooperation of several subsets of reactive cells. The reactions that seem to play a key role are: (a) indirect inhibition of angiogenesis by secondary cytokines (mainly IFN-gamma) and third-level chemokines (inducible protein 10 and monokine induced by IFN-gamma); (b) systemic activation of leukocyte subsets capable of producing proinflammatory cytokines, CTLs, and antitumor antibodies; and (c) destruction of tumor vessels by polymorphonuclear cells. The markedly higher efficacy of systemic rIL-12 seems to rest on its ability to recruit these systemic reactions more quickly and efficiently than local rIL-12.