Intracavitary therapy of neoplastic effusions with cytokines: comparison among interferon alpha, beta and interleukin-2

Preliminary studies have suggested that the intracavitary administration of cytokines may represent a new effective palliative therapy of malignant effusions. To define further the therapeutic role of cytokines in the treatment of neoplastic fluid accumulation, 70 cancer patients with pleural, pericardial or peritoneal cytologically proven neoplastic effusions were randomized to receive intracavitary cycles with interleukin-2 (IL-2; 6 x 10(6) IU), interferon (IFN alpha; 2 x 10(7) U) or IFN beta (6 x 10(6) U) every week for 2 or 3 weeks. A clinical control of fluid accumulation was obtained in 39/70 (56%) patients. In patients with mesothelioma, the response rate was significantly higher with IL-2 than with IFN alpha or -beta, while there was no difference in patients with tumors other than mesothelioma. Moreover, the duration of the period during which drainage was not required was significantly longer in patients treated with Il-2 than in the other groups. Toxicity was low in all patients. According to preliminary data, this study demonstrates that intracavitary administration of cytokines, including IL-2, IFN alpha and -beta, is a new well-tolerated palliative therapy for malignant effusions, with an efficacy substantially comparable to that described with the most commonly used treatments with tetracyclines or cytostatic agents.     

Thyroid metastasis from rectal carcinoma coexisting with Hashimoto''s thyroiditis: gray-scale and power Doppler sonographic findings

BACKGROUND: Interferon (IFN) alpha and IFN gamma have synergistic in vitro and in vivo effects and have each been used in the treatment of anogenital condylomata acuminata. STUDY GOALS: To compare the efficacy and safety of regional 3 x 10(6) U IFN alpha (Group A), 3 x 10(6) U IFN gamma (Group B), 1.5 x 10(6) U IFN alpha plus 1.5 x 10(6) U IFN gamma (Group C), and 3 x 10(6) U IFN alpha plus 1.5 x 10(6) U IFN gamma (Group D) in the treatment of recalcitrant anogenital condylomata acuminata. STUDY DESIGN: Six-week courses of regional IFNs were administered in a randomized, double-blind, multicenter study. Response was assessed as change in the total area affected by condylomata. RESULTS: The treatments of Groups A, B, and C were similarly effective (complete response in 13.6%, 18.5%, and 16.0%, respectively). Group D had the lowest rate of complete response (3.8%), but this combination was the most effective when partial and complete responses were combined (73.0%). CONCLUSION: Regional IFN is a moderately effective and safe treatment in patients with recalcitrant anogenital condylomata acuminata. Combinations of IFNs alpha and gamma were not superior to IFN monotherapy.     

Intensive regimen of cytokines with interleukin-2 and interferon alfa-2b in selected patients with metastatic renal carcinoma

We conducted a Phase II trial using an intensive regimen combining interleukin-2 (IL2), interferon-alfa-2b (IFN), and lymphokine-activated killer (LAK) cells. The aim of this study was to evaluate the toxicity and the efficacy of this combination in selected patients with metastatic renal cell carcinoma. Thirty-one assessable patients were treated with at least one cycle of a regimen consisting of 20 x 10(6) IU/day s.c. IFN for 5 days, followed 2 days later by i.v. injections of 24 x 10(6) IU/m2/day IL2 every 8 h together with i.v. bolus of 5 x 10(6) IU/m2/day IFN every 8 h during 5 days. After a 6-day break, during which four leukophereses were performed, this i.v. combination was administered along with the LAK cell reinjections for a maximum of 5 days. Twenty-seven patients underwent the two parts of the first course of treatment; respectively, 42% and 46% of the planned dose of IL2 and IFN were administered. Several severe toxicities were observed including two treatment-related deaths. Significant tumor responses were observed in seven patients, including two complete remissions. Two of these patients remain alive without evidence of disease 36 and 40 months after treatment, respectively. This intensive regimen of IL2 together with IFN and LAK cells cannot be recommended even in selected patients with metastatic renal cell carcinoma. In addition, our results argue against the concept of a dose-response relationship in this setting.     

Microfilarial clearance in loiasis involves elevation of Th1 and Th2 products and emergence of a specific pattern of T-cell populations

Diethylcarbamazine (DEC) induced clearance of microfilaraemia in loiasis is associated with severe posttreatment reactions. To define the switch from hypo- to hyper-responsiveness associated with DEC treatment, phenotypic alterations of T-lymphocytes, characterized by flow cytometry, and cytokines, determined by enzyme linked immunosorbent assay, were monitored in a microfilaraemic patient. In contrast to reports on onchocerciasis and lymphatic filariases, no elevation of interleukin (IL)-6 and tumour necrosis factor (TNF)-alpha was observed. The most severe side effects coincided with an elevation of interferon (IFN)-gamma on day 3, followed by IL-10, transforming growth factor (TGF)-beta 2 and macrophage inflammatory protein-1 alpha (MIP-1 alpha) peaking on day 5. Phenotypically, T-cell activation markers CD38, CD54 and CD25 were significantly expressed before treatment, with high CD38 expression still existing one year after clearance of microfilaraemia. Treatment-related increases were observed with anti-CD122, anti-HLA-DR and anti-CD69. CD28 was expressed before treatment on almost 100% of CD4+ and CD8+ T cells and dropped to 20% by day 5, reaching again baseline levels on day 21. Furthermore, there emerged 20% TCR alpha beta+/CD3+ T cells and 10% anti-beta V5(c)+ T cells, altogether indicating a specific pattern of T-helper (Th) 1 and Th2 cytokines as well as expansion of certain pauciclonal T-cell populations in response to microfilarial clearance.     

Interferon-gamma potentiates interleukin (IL)-6 and tumor necrosis factor-alpha but not IL-1beta induced by endotoxin in the brain

Because interferon-gamma (IFN gamma) is present in the central nervous system during neurologic diseases associated with inflammation, its effect on endotoxin-induced cytokines was studied. Cerebrospinal fluid (CSF) and serum levels of interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha (TNF alpha), their messenger RNA expression in brain areas (hypothalamus, hippocampus, and striatum) and in spleen were evaluated 2 and 8 h after endotoxin [lipopolysaccharide (LPS), 25 microg/rat i.c.v.], IFN gamma (2.5 microg/rat i.c.v.) or after their coadministration in rats. CSF and serum IL-1beta levels were increased by LPS alone and IFN gamma coadministration did not furtherly increase them. IFN gamma potentiated LPS effect on IL-6 and TNF alpha levels in both CSF and serum. LPS and IFN-gamma coadministration did not alter IL-1beta messenger RNA expression induced by LPS in brain areas and in spleen, but it potentiated that of IL-6 and TNF alpha. The present in vivo data show that i.c.v. coadministration of LPS and IFN gamma results in a potentiation of cytokine production (IL-6 and TNF alpha) which may trigger a cascade of events relevant to neurodegenerative processes. This action is independent of IL-1beta because the production of this cytokine is not altered by IFN gamma treatment.     

The incidence of hepatocellular carcinoma in patients with chronic hepatitis C after interferon treatment

To determine whether serum hepatitis C virus (HCV) RNA disappearance after interferon (IFN) treatment prevents development of hepatocellular carcinoma (HCC), we evaluated retrospectively the incidence of HCC in patients with chronic hepatitis C. A total of 213 patients were monitored for more than 6 months after completion of IFN treatment. Sixty-three of the 213 patients (29.6%) achieved a complete response (CR) to treatment and 150 (70.4%) had no response (NR). HCC developed in 12 (5.6%), all of whom were NR. Logistic analysis showed age, alpha -fetoprotein, and staging of histological finding before IFN treatment were independent factors to development of HCC. The fact that there was no HCC development from CR provides a basis for IFN treatment in chronic HCV infection.     

Treatment of chronic viral hepatitis

Recent advances have been made in the treatment of chronic viral hepatitis, mainly with recombinant interferon (IFN) alpha. However, the present treatment of chronic viral hepatitis is not entirely satisfactory because the efficacy is inconstant and/or incomplete. In chronic hepatitis B IFN-alpha induces a sustained interruption of hepatitis B virus (HBV) replication, with a HBeAg to anti-HBe seroconversion in about 30% of patients. Patients most likely to respond are those with no immunosuppression, HBV infection acquired during adulthood or active liver disease with low HBV replication. Responders usually show a significant decrease in serum HBV DNA levels during the first 2 months of therapy, followed by a significant increase in the level of aminotransferases. New nucleoside analogues might be useful in combination with IFN-alpha in the treatment of those who do not respond to IFN therapy. In chronic hepatitis B-D, the rate of sustained response to IFN-alpha therapy is low. To be effective, IFN-alpha must be used at a high dosage (9-10 mega units) with a long duration (1 year). In chronic hepatitis C, IFN-alpha at a dosage of 3 mega units over 6 months, induces a sustained response in about 20% of patients. A higher dosage of IFN (5-10 mega units) and a longer duration of treatment increases the rate of sustained response but is associated with poor tolerance. Non-responders to a first course of IFN do not respond to a second course of treatment. In patients who respond but relapse after treatment, the rate of sustained response after a second course of IFN needs to be assessed. Ribavirin, which has a significant antiviral effect on hepatitis C virus, might be useful in combination with IFN-alpha. At the dosage (3-6 mega units) usually used, IFN-alpha is relatively well tolerated. In about 10% of the patients therapy is interrupted, mainly because of severe fatigue, thyroid dysfunction or depression.     

Interleukin 7 enhances the proliferation and effector function of tumor-infiltrating lymphocytes from renal-cell carcinoma

Previous studies have documented the effects of IL2 on the growth and effector function of tumor-infiltrating lymphocytes (TIL) in cancer patients. Since IL7 is known to induce T- and NK-cell responses in the peripheral blood, we examined the immuno-enhancing effects of IL7 on TIL derived from human renal-cell carcinoma (RCC). Whereas IL2 induced the growth of freshly isolated TIL in vitro, IL7 was ineffective alone and failed to increase the total number of cells proliferating to IL2. However, IL7 did provide a proliferative signal to TIL that were initially expanded in culture with either IL2 or IL2/IL7 for 2 weeks. IL7 also induced the proliferation of CD4+ and CD8+ TIL lines that have specificity for RCC. The proliferative response induced by IL7 was independent of IL2, since anti-IL2 antibodies did not block IL7-induced proliferation of TIL. IL7 did cooperate with anti-CD3 stimulation for the induction of proliferation; however, the magnitude of this interaction was variable and the response usually additive. In addition, IL7 synergized with anti-CD3 to induce the secretion of IFN gamma from short-term-cultured TIL and from a TIL line. Although IL7 did not promote the development of a tumor-specific T-cell response from IL2-expanded TIL, IL7 enhanced lymphokine-activated killer (LAK) activity from some short-term-cultured TIL. These results illustrate that IL7 can potentiate the growth and production of IFN gamma from RCC-reactive TIL and, to a lesser extent, enhance IL2-induced LAK activity of TIL.     

Epidemiologic and actual importance of entero-hemorrhagic E. coli in Northern Bavaria (1996)

OBJECTIVES: To compare peripheral type 1 (T1) and type 2 (T2) T cell activities in rheumatoid arthritis (RA) patients with that found for osteoarthritic (OA) patients and healthy controls and to correlate peripheral T1/T2 cell activity in RA with parameters of the disease. METHODS: Peripheral blood mononuclear cells were isolated from patients with RA (n = 66), OA (n = 19), and healthy controls (n = 15). Primary T cell activity in these mononuclear cells was enhanced by means of anti-CD3/anti-CD28, which mimicks stimulation of T cells by activation of the T cell receptor and a major co-stimulatory signal. Interferon gamma (IFN gamma) production and interleukin 4 (IL4) production in the three groups were quantified as measures of T1 and T2 cell activity, respectively, and compared. Serum tumour necrosis factor alpha (TNF alpha), erythrocyte sedimentation rate (ESR), C reactive protein (CRP), and joint destruction assessed radiographically of RA patients were determined as parameters of disease activity and correlated with T1/T2 cell activity. RESULTS: Peripheral T cells from RA patients produced significantly less IFN gamma and more IL4 than T cells from both age and sex matched OA patients and healthy controls. Moreover, in RA patients both a decrease in IFN gamma and an increase in IL4 production correlated with an increase in serum TNF alpha, ESR, CRP, and joint destruction. CONCLUSIONS: These results suggest a role for differential T cell activity in RA. In view of the intra-articular T1 cell predominance the results might be explained by selective T1 cell migration into the joint or peripheral suppression of T1 cell activity.     

Group A streptococcal necrotizing fasciitis. Diagnosing and treating the "flesh-eating bacteria syndrome"

Current research has still not clarified the biological role of soluble interleukin(IL)-2 receptor (sIL-2R) and the significance of its increase in the serum of colon cancer patients compared to healthy subjects. To address these questions at the immunological level in a group of patients and healthy subjects, we determined the sIL-2R level in the serum and its release from peripheral blood mononuclear cells (PBMC) as a function of tumour necrosis factor (TNF) alpha, IL-1 alpha, IL-1 beta, IL-2, interferon (IFN) gamma, IL-4, IL-6 and IL-10 levels in the serum and PBMC production; and PBMC proliferative responses to IL-2, IL-4 and anti-CD3 monoclonal antibody (CD3), variously combined. The level of sIL-2R in patients' serum was higher than in healthy subjects and correlated with the stage of advancement. Moreover, while in healthy subjects the serum level of sIL-2R was not significantly correlated with other parameters, in patients it was positively related to IL-4, IL-6 and IL-10 serum levels, PBMC IL-4 production and to the PBMC proliferative response to CD3 and CD3 + IL-2; it was negatively correlated to IL-2 serum level and IL-1 beta PBMC release. A negative connection between IFN gamma serum level and the PBMC production of sIL-2R was also found. This suggests that the increase of sIL-2R in the serum of patients, compared to healthy subjects, is involved in the inappropriate expansion of the T helper (TH2) suppressive immune response, which we previously reported. The multivariate statistical method supported the above suggestions and we also found that, in healthy subjects, the up- and down-regulation of sIL-2R in the serum within the physiological ranges seems to have a regulating role in the relationships between TNF alpha, IFN gamma and IL-4, IL-6, contributing to the operation of the cytokine network between TH1 and TH2 cells. However, in patients compared to healthy subjects the increased sIL-2R serum level seems to direct the immune response towards a suppressive type, which may be due to an alteration in the above-mentioned physiological regulating role.     

Characterization of anticapsular monoclonal antibodies that regulate activation of the complement system by the Cryptococcus neoformans capsule

PURPOSE: To evaluate the effectiveness of adding interferon (IFN) alfa-2b to chemotherapy in the induction treatment of low-grade non-Hodgkin's lymphoma (NHL), and to assess the role of maintenance IFN. PATIENTS AND METHODS: A multicenter, two-phase controlled trial with double randomization was conducted in 155 patients with low-grade NHL. In the first randomization, 78 patients received cyclophosphamide, vincristine, and prednisone (CVP) and IFN, 3 MU/m2 three times a week for 3 months, and 77 patients received CVP alone. Responding patients were randomized to receive IFN for 1 year versus observation. RESULTS: Of 144 assessable patients, 73 received CVP + IFN and 71 received CVP. Responses were similar: CVP + IFN 79% versus CVP 76% (P = .62). The number of patients who did not complete the treatment was higher in the CVP + IFN group than in the CVP group (18% v 4%; P = .009), although the received dose-intensity of chemotherapy was comparable. Duration of response and progression-free survival (PFS) were significantly higher in the CVP + IFN group than in the CVP group (P = .0004). However, we observed no differences in overall survival (OS) (P = .30), with a median follow-up for the surviving patients of 3 years. Grade 3/4 granulocytopenia was the most frequent toxicity and was similar in both groups (33% v32%). Eighty-three (74%) of the 112 responding patients were randomized to maintenance IFN or observation. The duration of response was similar between 42 patients that received IFN compared with 41 control patients (P = .83), independently of treatment previously administered. CONCLUSION: Adding IFN alfa-2b to induction CVP in low-grade NHL did not induce a higher response rate, but it significantly increased the duration of the responses. We found significant differences in PFS that favored the patients who received CVP + IFN, but not in OS. To date, no additional benefit has been seen from the administration of IFN for maintenance.     

Cytokines and therapeutic oligonucleotides

Non-infectious UV-inactivated transmissible gastroenteritis virus (TGEV) was previously shown to induce interferon alpha (IFN alpha) secretion following in vitro incubation with blood mononuclear cells. In this study, pig foetuses at different stages of gestation were injected in utero with (a) partially UV-inactivated wild TGEV or (b) fully UV-inactivated wild or dm49-4 mutant TGEV coronavirus. Nucleated cells from foetal liver, bone marrow, spleen and blood were isolated 10 or 20 h after injection and assayed ex vivo for IFN alpha secretion by ELISPOT and ELISA techniques. The administration of TGEV induced IFN alpha-secreting cells in foetal lymphohaematopoietic organs at mid-gestation. In contrast, IFN alpha was not detected in control sham-operated foetuses. A specific point mutation in the amino acid sequence of the viral membrane glycoprotein M of TGEV mutant dm49-4 was associated with lower or absent IFN alpha in utero inducibility by mutant virus as compared with wild virus. Flow cytometry analysis did not show differences in leukocyte surface marker expression between control and TGEV- or between dm49-4 and wild virus-treated foetus cells, with the exception of a reduction in percentages of polymorphonuclear cells in TGEV-treated lymphohaematopoietic tissues, which is probably due to IFN alpha secretion. The present data provided in vivo evidence of IFN alpha secretion at the cell level in foetal lymphohaematopoietic organs. Such IFN alpha-secreting cells in lymphohaematopoietic tissues may be the source of IFN alpha detected during foetal infections.     

Cytokines modulate expression of cell-membrane complement inhibitory proteins in human lung cancer cell lines

Human lung cancers overexpress several cell-membrane complement inhibitory proteins (CIP). These complement inhibitory proteins are membrane cofactor protein (CD46), decay-accelerating factor (DAF; CD55), and CD59 (protectin). These cell-membrane proteins have a wide normal tissue distribution, are known to protect normal host cells from homologous complement-mediated lysis, and are thought to facilitate tumor escape from immunosurveillance. To study whether proinflammatory cytokines that are involved in cancer growth can modulate cell-membrane CIP expression in lung cancer cells, we studied the effect of interleukin (IL)-1alpha, tumor necrosis factor (TNF)-alpha, and interferon (IFN)-gamma on two human lung cancer cell lines. ChaGo K-1 and NCI-H596 cell lines, undifferentiated carcinoma and lung adenosquamous carcinoma, respectively, were stimulated with different cytokines, and the effects of incubation time and cytokine concentration on cell-membrane CIP expression were studied. Cell-membrane CIP expression was evaluated using flow cytometry and cytokine effect was calculated as percent change in mean fluorescence intensity of each CIP molecule from its untreated control. We found that DAF was the lung cancer cell-membrane CIP molecule that was the most responsive to cytokine stimulation. Maximal stimulatory effect was usually noted 72 h after a cytokine was introduced. In ChaGo K-1 and NCI-H596 lung cancer cell lines, IL-1alpha and TNF-alpha increased DAF expression. IL-1alpha (100 U/ml/72 h) increased DAF expression up to a maximal mean of 45 and 48%, respectively, in comparison with untreated cells. TNF-alpha (1, 000 U/ml/72 h) increased DAF expression up to a mean of 131 and 46%, respectively. IFN-gamma (1 U/ml/72 h) increased DAF expression in NCI-H596 cells up to a mean of 100%, but had a slight inhibitory effect on DAF expression in ChaGo K-1 cells, decreasing expression by a mean of 17% in comparison with untreated cells. We conclude that cell-membrane DAF expression in the studied human lung cancer cell lines is modulated by IL-1alpha, TNF-alpha, and IFN-gamma, and speculate that cytokine-mediated modulation of cell-membrane DAF in human lung cancer cells might affect lung cancer cell biology.     

An update on cytokines in the pathogenesis of insulin-dependent diabetes mellitus

Correlation studies between cytokines expressed in islets and autoimmune diabetes development in NOD mice and BB rats have demonstrated that beta-cell destructive insulitis is associated with increased expression of proinflammatory cytokines (IL-1, TNF alpha, and IFN alpha) and type 1 cytokines (IFN gamma, TNF beta, IL-2 and IL-12), whereas non-destructive (benign) insulitis is associated with increased expression of type 2 cytokines (IL-4 and IL-10) and the type 3 cytokine (TGF beta). Cytokines (IL-1, TNF alpha, TNF beta and IFN gamma) may be directly cytotoxic to beta-cells by inducing nitric oxide and oxygen free radicals in the beta-cells. In addition, cytokines may sensitize beta-cells to T-cell-mediated cytotoxicity in vivo by upregulating MHC class I expression on the beta-cells (an action of IFN gamma), and inducing Fas (CD95) expression on beta-cells (actions of IL-1, and possibly TNF alpha and IFN gamma). Transgenic expression of cytokines in beta-cells of non-diabetes-prone mice and NOD mice has suggested pathogenic roles for IFN alpha, IFN gamma, IL-2 and IL-10 in insulin-dependent diabetes mellitus (IDDM) development, and protective roles for IL-4, IL-6 and TNF alpha. Systemic administrations of a wide variety of cytokines can prevent IDDM development in NOD mice and/or BB rats; however, a given cytokine may retard or accelerate IDDM development, depending on the dose and frequency of administration, and the age and the diabetes-prone animal model studied (NOD mouse or BB rat). Islet-reactive CD4+ T-cell lines and clones that adoptively transfer IDDM into young NOD mice have a Th1 phenotype (IFN gamma-producing), but other islet-specific Th1 clones that produce TGF beta can adoptively transfer protection against IDDM in NOD mice. NOD mice with targeted deletions of IL-12 and IFN gamma genes still develop IDDM, albeit delayed and slightly less often. In contrast, post-natal deletions of IL-12 and IFN gamma, also IL-1, TNF alpha, IL-2, and IL-6--by systemic administrations of neutralizing antibodies, soluble receptors and receptor antagonists, and receptor-targeted cytotoxic drugs--significantly decrease IDDM incidence in NOD mice and/or BB rats. These cytokine deletion studies have provided the best evidence for pathologic roles for proinflammatory cytokines (IL-1, TNF alpha, and IL-6) and type 1 cytokines (IFN gamma, IL-2 and IL-12) in IDDM development.     

Interferon alpha 2b as maintenance therapy in low grade malignant lymphoma improves duration of remission and survival

We assessed the efficacy and toxicity of interferon alpha 2b (IFN) as maintenance therapy in patients with low grade malignant lymphoma. Between March 1986 and December 1989, 98 patients with low-grade malignant lymphoma in complete remission after conventional chemotherapy were randomly assigned to received IFN, 5.0 MU three times a week for one year, as maintenance therapy (n = 48), or to receive no treatment (control group, n = 50). In March 1994, the median duration of response had not yet been reached in the patients treated with IFN compared to 46 months in the control group. At 9-years 62% of the patients in the IFN arm remain in first complete remission compared to only 25% in the control group (p <.001). In addition, the median duration of survival has not yet been reached in either the IFN arm compared to 74 months in the control group (p <.001). Quality of life was excellent in both groups and severe side effects secondary to IFN treatment were not observed. All patients completed the planned dose of IFN. We conclude that IFN as maintenance therapy in low-grade malignant lymphoma is an excellent therapeutic option because it improves the duration of remission and survival without producing severe side effects or reducing the quality of life.     

Salvage immunotherapy with subcutaneous recombinant interleukin 2 (rIL-2) and alpha-interferon (A-IFN) for stage D3 prostate carcinoma failing second-line hormonal treatment

Immunotherapy with subcutaneous rIL-2 and alpha IFN was administered to stage D3 prostate cancer patients after failure of secondary treatment with oral estramustine phosphate. Of a total of 15 patients, 2 are in partial response, with estramustine maintained after 44+ and 36+ weeks, respectively. Response to estramustine was observed initially in 7 of 13 patients, with a median duration of 12 weeks (range 8-20). No response to estramustine was observed in the remaining 6 patients. After the failure of estramustine, 13 patients were treated with immunotherapy. After the first cycle, progression of disease no therapy was given to those patients. A reduction of PSA levels was observed during the first cycle in 2 patients (15.3%); levels subsequently increased during the second cycle of treatment. A partial response was observed in 4 patients (30.7%), with a reduction of PSA levels in 3. The duration of response was 28 and 32 weeks in 2 patients who survived after failure for 18 and 21 weeks, respectively. Two patients are still alive, with continued partial response at 62+ and 42+ weeks. Side effects were represented mainly by a flu-like syndrome, associated with fever and nausea in all patients. The serum concentration of IL-10 was measured in 8 patients under study and in 11 matched controls. Levels higher than mean + 2D of controls before, during, or after immunotherapy were correlated with treatment failure, whereas levels below 6 ng/ml were encountered among the patients who showed a clinical response and a reduction of PSA during treatment. Within the limitations of this pilot study, it appears difficult to distinguish between a spontaneously slowly progressing disease and a true response to therapy.     

Clinical and epidemiologic aspects of ankylosing spondylitis and spondyloarthropathies

In our previous randomized trial of advanced gastric cancer patients, the addition of epirubicin (EPI) to 5-fluorouracil (FU) with folinic acid (FA) resulted in an improved response rate and survival in the responder patients. Preclinical studies also showed an enhancement of FU and anthracyclines with interferon. To evaluate the possibility of human lymphoblastoid interferon (IFN) to enhance the therapeutic activity of the FA-FU + EPI combination regimen, 39 advanced gastric cancer patients received: FU at 375 mg/m2 i.v. immediately after FA (l-isomer form) at 100 mg/m2 i.v. for 5 consecutive days; EPI at 60 mg/m2 i.v. on day 1, and IFN 3 MU s.c. for 7 consecutive days, starting 2 days before the FA-FU administration. Thirty-seven patients were evaluable for response and toxicity. Twelve partial responses were observed with an overall response rate of 32% (95% CI, 17-48%). The median response duration was 6 months, and the median survival time was 8 months. Toxicity was mild and no grade 4 side effects or treatment-related deaths were observed. However, the addition of IFN to the FA-FU + EPI regimen did not improve response, duration of response or survival.