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We describe three patients with severe refractory cutaneous polyarteritis nodosa, resulting in painful ulcers involving the lower limbs and causing toe necrosis. Due to the severity of the cutaneous manifestations, the three patients received intravenous immunoglobulins at a dose of 1 g/kg/day for 2 days monthly. After the second intravenous immunoglobulin infusion, skin signs dramatically improved and completely healed after the third intravenous immunoglobulin infusion. Our findings indicate that intravenous immunoglobulins can be included in a therapeutic strategy to treat refractory cutaneous polyarteritis nodosa.

Summary Background Impaired regulation of apoptosis is known to be associated with the development of various cancers. Fas receptor (APO-1/CD95) binding to its ligand, Fas-ligand (Fas-L), has been shown to trigger apoptosis in various cell types. Objectives In this study, we examined CD95 and Fas-L expression on primary and metastatic melanoma cells from patients to investigate a potential correlation between these measures of apoptosis and different disease stages. Patients and methods Primary melanoma cells were obtained after surgical resection from 19 patients and metastatic cells from fine-needle aspiration of lymph nodes or palpable subcutaneous lesions in 25 patients. Normal skin cells were obtained at skin biopsy of 10 healthy donors. Results Flow cytometric analysis revealed that CD95 and Fas-L expression was detected in all the kinds of cell studied. In whole cell suspensions, CD95 expression was significantly higher (P , 0·0001) in normal skin cells than in melanoma cells, whatever the stage studied. By contrast, we observed an increase in Fas-L expression in melanoma cells compared with normal ones. Subsequently, using a double staining method, we studied these measures on HMB451 cells, a specific marker for melanoma cells, and found that CD95 expression was significantly higher (Pa 0·0005) in primary than in metastatic cells while Fas-L expression was significantly increased (Pa 0·0004) in metastatic compared with primary cells. Furthermore, a relationship was found between CD95 or Fas-L expression and Breslow thickness; as primary melanoma thickness progressively increased, the percentage of HMB451 CD951 cells decreased while that of HMB451 Fas-L1 cells concurrently increased. Conclusions These results suggest that downregulation of CD95 and upregulation of Fas-L in melanoma might be considered as concomitant with disease progression.

Fotemustine and dacarbazine constitute the most active single chemotherapeutic agents in the treatment of melanoma. In this phase II study we evaluated the activity and toxicity of a combination of fotemustine, dacarbazine and vindesine as a means of increasing response rate and survival time. Between September 1989 and November 1993, 43 patients with advanced melanoma were treated with a combination of 100 mg/m2 fotemustine on days 1 and 8, 250 mg/m2 dacarbazine on days 15 and 16 and 2 mg/m2 vindesine on days 15 and 16 as induction treatment. After a 5-week rest period, the patients exhibiting a response or stable disease received the same drugs administered once every 28 days as maintenance therapy until either progression or toxicity was observed. Among 41 evaluable patients, there were six complete responses and eight partial responses. The overall response rate was 32% (95% confidence interval: 18-46%), with 8 months median duration of response. Median survival time was 10 months. This regimen was well tolerated. From this large phase II study, we conclude that such a combination is active against advanced malignant melanoma and seems to be more effective than fotemustine or dacarbazine used alone, especially on visceral metastatic sites.

Treatment of certain cancers by interleukin-2 (IL-2) and alpha interferon (INF) is currently widely-used in oncology and serious psychological side effects of such treatments have been reported. This study attempts to describe and analyse such side effects in a series of hospitalized cancer patients. Fifty-two patients undergoing a protocol of cisplatinum, intravenous interleukin-2 infusions and subcutaneous alpha interferon injections for metastatic melanoma and renal cancer were systematically screened for psychiatric disorders before, during and after each of four cycles of 4–5 day EL-2 infusions. Fatigue was constant and treatment-limiting in some cases and was highly correlated with depressive symptoms, which were very frequent at the end of the treatment cycle. Patients regularly showed varying degrees of obtundedness at the height of physical symptoms induced by IL-2. Some patients also had transient, predominantly hallucinatory deliria occurring or persisting several days after the termination of the infusions and complete resolution of concurrent somatic distress; neuroleptics were effective treatment. Certain lymphocyte phenotype counts (total lymphocytes, total CD8 cells, total T3s, stimulated Ts, non-stimulated Ts) correlated negatively with depressive symptomatology whereas fatigue tended to correlate negatively with polymorphonuclear leukocyte counts. Delirium correlated positively with total CD8 cells. Hallucinatory delirium, but not fatigue or depression, seems to be a direct cerebral effect of the interleukin-2α interferon combination that is not merely a consequence of the somatic effects. Patients undergoing lymphokine treatments should be carefully screened for psychological side effects and preventive or curative treatments should be given.

A variety of molecules with novel mechanisms of action are currently being evaluated for their potential as treatments for sleep disorders. The GABA-A receptor complex remains an important target for hypnotic drugs (eg gaboxadol, indiplon). However, drugs acting through histamine, calcium channels and serotonin receptors may also be of interest for the treatment of insomnia. In the case of the 5HT2A subtype of serotonin receptors, several molecules which improve sleep maintenance and modify sleep architecture by increasing slow wave sleep are currently being tested (eg eplivanserin). Two new drugs with efficacy in excessive sleepiness (modafinil, sodium oxybate) have improved the treatment of this condition. However, the mechanisms of action of these agents are poorly understood. The recent discovery of the hypocretin arousal system in the hypothalamus may aid the identification of additional new drugs. An agonist at receptors for the pineal hormone melatonin is available in some countries (ramelteon) but is currently used only for the treatment of insomnia associated with difficulties of sleep onset. Additional melatonin receptor agonists are being developed and may have potential for treating several conditions including circadian rhythm disorders and depression.

SUMMARY Using flow cytometry, cellular IL-2 receptors were studied before and following chemoimmunotherapy combination in 20 patients with metastatic malignant melanoma (MMM). Patients received cisplatin (100 mg m2) at days 1 and 28, recombinant IL-2 by continuous infusion from days 3 to 6, 17 to 21, 31 to 34, and 45 to 49. Interferon-alpha (IFN-α) was given subcutaneously three times weekly. In terms of clinical response, we observed 55% objective response (complete: 15%), When pretreatment blood samples were compared with those of healthy donors, we did not observe any change in low (α chain) and high affinity receptor (α+β) expression. In contrast, intermediate affinity p75 (β chain) expression was decreased significantly (P ≤ 0.0001) in MMM patients. During treatment, we found a dramatic increase of β chain as well as high affinity (α+β) expression in responding patients, as soon as IL-2 therapy began. Furthermore, the increase of β chain expression was limited to natural killer (NK) cells (CD56+). In non-responding patients, on the other hand, increase of both receptors was seen only at day 31. These data suggest the involvement of β chain expression in the mechanism of cell activation after chemoimmunotherapy. Moreover, this early 3 chain expression is correlated with the clinical response to chemoimmunotherapy.

SUMMARY Immunological parameters following chemoimmunotherapy combination were studied in 31 patients with metastatic malignant melanoina. They received Cisplatni (100 mg/m2) on day 1 and 28, recombinant IL-2 (rIL-2; Eurocetus) in continuous infusion from day 3 to 6, 17 to 21, 31 to 34 and 45 to 49. Interferon-alpha (IFN-α: Roche) was given subcutaneously three times weekly. No significant change in CD4/CD8 ratio at onset or during treatment was observed between responder (n=19) and non-responder (n=12) patients. Regarding the IL-2 receptor (IL-2R) study, the percent age of cells expressing Tac(p55)receptor did not change either for healthy volunteers (n=20) and patients before any therapy, or between responder and non-responder patients. Concerning serum soluble IL-2R shedding before therapy. we observed A significant increase (P=0·001) in patients (79±40 pM) compared with healthy donors (30±15 pM), but no significant variation was seen between responder and non-responder patients. In contrast, during the treatment, the soluble IL-2R level increased in both groups but, interestingly, a significant difference was found between responder and non-responder patients from day 7 (P

Fifty patients (41 females and 9 males, ranging in age from 12 to 79 years) with systemic lupus erythematosus (SLE) and 20 normal controls were evaluated for the presence of plasma cell-free Fc gamma receptor III (Fc gamma RIII) using an ELISA based upon a sandwich of two monoclonal antibodies. The standard curve was obtained with serial dilutions of recombinant Fc gamma RIII. In the patients, the cell-free Fc gamma RIII levels ranged from to 1.76 micrograms/ml, while it did not exceed 0.21 microgram/ml in the controls. Assuming that the cutoff is 0.25 microgram/ml, 11 SLE patients and no controls had elevated cell-free Fc gamma RIII levels in the serum. Among the SLE patients, the level of cell-free Fc gamma RIII was significantly lower (p = 0.05) in 4 patients with sicca syndrome than in the remaining 46. Furthermore, cell-free Fc gamma RIII levels appeared to be lower in 11 patients with renal involvement than in those without. For the biological parameters, we observed that the 27 patients who presented lymphopenia also had a lower level of cell-free Fc gamma RIII when compared to the 23 patients without lymphopenia (0.09 +/- 0.19 versus 0.35 +/- 0.52 microgram/ml; p = 0.05). Circulating cell-free Fc gamma RIII may originate from shedding by presumably activated polymorphonuclear cells.

The ominous prognosis of metastatic malignant melanoma has led to a large number of clinical treatment trials [1, 2]. Some improvement in terms of response rate seems to have been achieved, but the main question asked by clinicians remains: is there a biological predictive factor for the therapeutic response to IL-2 therapy ? It is now well established that IL-2 plays a pivotal role in the immune response, both in its own receptor expression and other cytokine release. To exert its biological effect, IL-2 interacts with specific membrane receptors. Three types of IL-2 binding sites have been described: a 55 kD protein (α-chain, TAC) low-affinity receptor unable to deliver a signal to the cell, a 70 kD (β-chain) intermediate-affinity receptor which can transduce a signal and a high-affinity receptor made up of both the p 55 and p 70 molecules. More recently a third receptor has been cloned: 7-chain. Moreover, activated T cells release a truncated form of the γ-chain molecule as a soluble Interleukin-2 receptor (sIL-2R) [3, 4]. We report here the study of immunological events both cellular and humoral following CDDP, IL-2 and Interferon-α in 31 patients treated for malignant metastatic melanoma.

Neo-Adjuvant chemotherapy in breast cancer means that chemotherapy is used as the first therapeutic tool and that the locoregional treatment is considered as an adjuvant. The term has been contested and others were proposed, but induction treatment is too specific for the first chemotherapy combination used in leukemia to achieve complete remission. Primary treatment does not encompass the consolidation phase which belongs to our strategy so that even if it is not quite satisfactory we keep the term Neo-Adjuvant which has been coined in the seventies by E. Frei for head and neck cancers.

Psychoneuroimmunology is a fast-growing field that explores the relationship of psychological factors and the immune system. In particular, much research has focussed on the impact of psychological events on immune parameters. An equally interesting but less studied situation, however, is the occurrence of psychological side effects after administration of immune substances in humans. In this regard, lymphokines could be of particular interest, since they are regularly used to treat certain cancers. One such substance is Interleukin-2 (IL-2), which is often infused in metastatic cancer patients at substantial doses over several days. Such infusions represent a unique, « quasi-experimental » opportunity to study the psychological side effects accompanying the lymphokine. However, IL-2 is rarely the sole therapeutic agent used in the cancer setting (Siegel & Puri, 1991). In particular, α-Interferon (INF) is often co-administered.

A sandwich enzyme-linked immunosorbent assay was developed to assess Fc-gamma receptor III (Fc gamma RIII), based on a combination of two non-competing monoclonal antibodies. This receptor was detectable in the serum of eight out of 23 patients with primary Sjogren's syndrome and two out of 23 normal controls. The proportion of Fc gamma RIII-carrying polymorphonuclear (PMN) cells was lower (P < 0.05) in the patients with cell-free Fc gamma RIII (90.4 +/- 7.5%) than in the remainder (84.8 +/- 8.3%). The PMN cell functions were evaluated and the diminished adherence (71.7, geometric mean) and chemotaxis (1.23) paralleled the Fc gamma RIII release. The relative inefficiency of PMN cells in SS might be due to phagocytosis of immune complexes.

Optimistic results were obtained in the treatment of 39 patients with surgically incurable metastatic malignant melanoma using a regimen including 2 to 3 monthly induction cycles of cis-diamminedichloroplatinum (CDDP), recombinant interleukin-2 (rIL-2) and interferon alpha-2a (IFN alpha-2a). 33 of 39 patients were pretreated with chemotherapy (dacarbazine and/or fotemustine:31, CDDP:6) and 17 of 39 with IFN alpha-2a. Overall response rate was 54% with 13% achieving a complete response for up to 59+ weeks. Moderate to severe side-effects were reversible on rIL-2 cessation and toxicity was manageable in a routine inpatient setting. These results are especially encouraging as they were seen in previously treated patients, classically low responders, including 3 who were resistant to cisplatin or other platinum complexes. The question remains if this regimen bypasses traditional mechanisms of drug resistance.

3548 Background: the aim of this study was to evaluate the different Computed Tomography (CT) parameters, characterizing tissue perfusion by contrast medium in metastatis to define their relation w...

8540 Background and aims: Circulating vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) were described as prognostic factors in several cancers. The aim of this study is to evaluate the prognostic values of these parameters in metastatic malignant melanoma diseases. Methods and Patients: Using enzyme-linked immunosorbent assays, VEGFs (A, C, D) and their receptors (1, 2, and 3) were measured in sera of 75 patients with metastatic malignant melanoma in comparison to 30 healthy controls. Disease free survival (DFS) and overall survival (OS) were calculated from the beginning of the treatment until either the progression or the death and analyzed using the Kaplan-Meier method. Results: Pretreatment median sVEGF-A, sVEGF-C as well as VEGFR-3 levels were significantly higher in MMM patients as compared to healthy ones p=0.0017, p=0.005, p2=6.64, p= 0.014) and overall survival (χ2=8.03, p= 0.0046). Conclusions: Our results suggest that, in metastatic malignant melanoma patients, soluble VEGF-A and VEGF-R3 pretreatment levels may prospectively identify high-risk patients with a worse prognosis; serum VEGFR-1 level may be a predictive factor of time to progression and overall survival. A multivariate analysis (Cox test) is ongoing in order to confirm if this parameter is an independent prognostic factor. No significant financial relationships to disclose.

18004 Background: The presence of metastases is a strong indicator of poor survival in many types of cancer. It has recently been shown that vascular endothelial growth factor-C (VEGF-C), and its receptor Flt-4 (VEGF-R3) are increased in a variety of tumours and may play a pivotal role in the promotion of metastasis. We previously demonstrated that high soluble VEGF-C level was correlated to high tumor burden. Objectives: This study was designed to i) detect and evaluate whether soluble VEGF-R3 play a role in metastatic malignant melanoma patients ii) to determine if they have any relationship with clinicobiological parameters, clinical response and survivals. Methods: Using a sensitive enzyme-linked immunosorbent assays, VEGF-R3 was retrospectively measured in sera of 60 patients with a fully documented history of melanoma disease in comparison with 30 healthy controls. Disease free survival (DFS) and overall survival (OS) were calculated from the beginning of treatment until either the progression (DFS) or death (OS) and analyzed using the Kaplan-Meier method. Results: Pretreatment circulating VEGF-R3 was detectable in all samples from either melanoma patients or healthy donors. Furthermore, median level of sVEGF-R3 was significantly higher (p = 0.000015) in melanoma patients as compared to healthy donors. (38890 vs 30773 pg/ml respectively). No significant association was noted between sVEGF-R3 levels and gender, age or LDH level. Median serum VEGF-R3 level was significantly higher in patients with high tumor burden as compared to patients with low tumor burden (p = 0.045). The pretreatment sVEGF-R3 level was significantly different (p = 0.025) between responder (n = 27) and non-responding patients (n = 33). Lastly, the relapse-free survival was higher in the group with low sVEGF-R3 concentration compared to the high one’s (14.1 vs 11,9 months) as well as for OS (14.3 Vs 12.6 months) but theses differences were not significant (χ2 = 2,30, p = 0.12 & χ2 = 0.74, p = 0.37 respectively). Conclusion: these results suggest that high pretreatment sVEGF-R3 level is related to bad prognosis in melanoma patients. No significant financial relationships to disclose.

8049 Background: Vascular endothelial growth factor (VEGF-A) and its circulating form (sVEGF-A) play a major role in tumor progression and angiogenesis. However, the clinical implications of circulating VEGF-A in metastatic malignant melanoma patients and its role in tumor-associated lymphangiogenesis and lymphatic metastasis remained unclear. Objectives: The aim of this study is to evaluate the potential role of circulating VEGF-A levels in lymphangiogenesis and its usefulness in metastatic malignant melanoma patients. Methods and Patients: using a sensitive enzyme-linked immunosorbent assays, VEGF-A level was measured in sera of 65 patients treated by biochemotherapy with a fully documented history of disease in comparison with 30 healthy controls. Results: A wide range (0- 566 pg/ml) of pretreatment sVEGF-A level was detected in the serum of MMM patients and the median level (40.5 pg/ml) was significantly higher (p=0.0007) than that of healthy donors (7.5 pg/ml). Age, gender and LDH were not associated with sVEGF-A levels. Regarding tumor burden, median pretreatment sVEGF-A level was higher in patients with high tumor burden (n= 40) as compared to patients with low tumor burden (n=25). Furthermore, the most surprising finding of our study was that patients with only lymph node metastasis (n=23) had a significantly (p= 0.021) higher median sVEGF-A levels (45.7 pg/ml) as compared to the 42 patients with different metastatic sites (16.6 pg/ml). Conclusion: these results suggest that sVEGF-A levels may predict lymph node metastasis in metastatic malignant melanoma patients. In addition, it may be promising targets for new therapeutic strategies in melanoma disease. No significant financial relationships to disclose.

7540 Background and Objectives: Angiogenesis is essential for tumor growth & metastasis. It is controlled by angiogenic factors, one of the most important being vascular endothelial growth factor (...

7541 Background: Vascular endothelial growth factor (VEGF) and its receptors (VEGFRs) play an essential role in tumor angiogenesis and are closely related with malignancies. However, the prognostic...

7551 Background and aims: Circulating vascular endothelial growth factor (VEGF), soluble EGFR and soluble interleukin-6 (IL-6) are associated with metastatic malignant melanoma disease. However, their relationship remains unclear. The aims of this study is to correlate serum IL-6 to sVEGF-A, or EGFR levels and to investigate the clinical significance of these parameters on the overall survival in metastatic malignant melanoma. Methods and Patients: using a sensitive enzyme-linked immunosorbent assays, VEGF-A, EGFR and IL-6 were measured in sera of 64 patients with a fully documented history of metastatic malignant melanoma patients in comparison with 30 healthy controls. Results: serum levels of VEGF-A, EGFR, and IL-6 were significantly increased in melanoma patients compared with healthy controls (p

7531 Background: high blood levels of vascular endothelial growth factor (VEGF) appear to be associated with a poor prognosis in advanced cancer, probably as a consequence of its angiogenic and immunosuppressive effects. The prognostic significance of serum VEGF levels and its variation during cancer treatment is still unknown. Objectives: The aim of this study is to evaluate the clinical usefulness of active serum vascular endothelial growth factor (sVEGF-A) levels in metastatic malignant melanoma patients and to investigate the possible relationship between sVEGF-A variations and clinical response during biochemotherapy. Patients and Treatment: The study included 73 patients with a fully documented history of metastatic malignant melanoma. Biochemotherapy consisted of Cisplatinum, rIL-2 and Alpha-interferon in two induction cycles. The assessment of clinical response was performed according to WHO criteria. Sixty seven patients were evaluable: 43 % (29/67) were responding (RC&RP) and 57 % were non-respo...

Ninety-eight patients with locally advanced breast cancer (Stage IIIA-IIIB) were entered into a pilot study combining intensive induction (neoadjuvant) chemotherapy (VTMFAP) with or without hormonochemotherapy, external and interstitial radiotherapy, and consolidation chemotherapy with or without hormonochemotherapy. Tumor regression over 50% was observed in 91% patients after chemotherapy, and complete clinical remission occurred in 100% patients after irradiation. The rate of local relapse is 13%. The 3-year disease-free survival is 62% and 3-year global survival is 77%. Initial chemotherapeutic tumor regression greater than 75% is the main predictive factor for disease-free survival.

A case of dermatitis herpetiformis in a 60-year-old woman with polycystic kidney disease on hemodialysis is reported. Bullous dermatoses associated with hemodialysis are analyzed.

BackgroundPatients with diffuse cutaneous systemic sclerosis (dcSSc) have a poor prognosis. The importance of monitoring subjective measures of functioning and disability, such as the Health Assessment Questionnaire-Disability Index (HAQ-DI), is important as dcSSc is rated by patients as worse than diabetes or hemodialysis for quality of life impairment. This European Scleroderma Trials and Research (EUSTAR) database analysis was undertaken to examine the importance of impaired functionality in dcSSc prognosis. The primary objectives were to identify predictors of death and HAQ-DI score progression over 1 year. HAQ-DI score, major advanced organ involvement, and death rate were also used to develop a comprehensive model to predict lifetime dcSSc progression.MethodsThis was an observational, longitudinal study in patients with dcSSc registered in EUSTAR. Death and HAQ-DI scores were, respectively, analyzed by Cox regression and linear regression analyses in relation to baseline covariates. A microsimulation Markov model was developed to estimate/predict natural progression of dcSSc over a patient’s lifetime.ResultsThe analysis included dcSSc patients with (N = 690) and without (N = 4132) HAQ-DI score assessments from the EUSTAR database. Baseline HAQ-DI score, corticosteroid treatment, and major advanced organ involvement were predictive of death on multivariable analysis; a 1-point increase in baseline HAQ-DI score multiplied the risk of death by 2.7 (p p p ConclusionsHAQ-DI score and major advanced organ involvement were comparable predictors of mortality risk in dcSSc. Baseline mRSS and baseline HAQ-DI score were predictive of HAQ-DI score progression at 1 year, indicating a correlation between these endpoints in monitoring disease progression. It is hoped that this EUSTAR analysis may change physician perception about the importance of the HAQ-DI score in dcSSc.