Metastasis of hepatocellular carcinoma presented as a tumor of the maxillary sinus and retrobulbar tumor.

INTRODUCTION: Hepatocellular carcinoma (HCC) is the most frequent primary malignant tumor of the liver. It is usually seen in the 6th and 7th decades of life and chronic hepatitis B is the most frequent cause. Extrahepatic metastasis of HCC is an indicator of a poor prognosis and the most common sites are lungs, bones, lymph nodes, kidneys and adrenal glands. We reported a case of isolated metastasis in the right maxilla, which had been found initially, before the tumor in the liver was diagnosed. CASE REPORT: A 70-year-old man underwent dental surgery of the upper right molar. Prolonged bleeding control was difficult for up to two weeks, so the biopsy was performed. Histopathological analysis revealed a metastatic hepatocellular carcinoma. Computerized tomography (CT) of the abdomen revealed a diffusely heterogeneous liver parenchyma with irregular borders and two foci of mass lesions. There were metastasis in the spleen and also two pathological retroperitoneal lymph nodes were detected, but no ascit, liver cirrhosis, cholestasis or portal vein thrombosis were seen. CT of the orbital and maxillary regions revealed a tumor mass in the right maxillary sinus, spreading to the alveolar sinus, nasal cavity and partially infratemporal space. A tumor mass was in the right orbit as well, infiltrating the surrounding bones and muscles. Clinically, there was proptosis of the right eye accompanied by amaurosis. The treatment started with chemotherapy based on 5-fluorouracil (sorafenib was not available). After three cycles, control CTs showed a stable disease in the liver, but progression in the right maxillary sinus and orbit. Enucleation of the right eye was performed and postoperative radiotherapy was planed. The patient deteriorated rapidly and died, about 6 months after the disease had been diagnosed. CONCLUSION: Extrahepatic metastasis of HCC represents a progressive phase of the disease with poor prognosis, so the main aim of the treatment should be palliation and care of symptoms.

Phase III trial of carboplatin plus paclitaxel with or without gemcitabine in first-line treatment of epithelial ovarian cancer.

PURPOSE: One attempt to improve long-term survival in patients with advanced ovarian cancer was thought to be the addition of more non-cross-resistant drugs to platinum-paclitaxel combination regimens. Gemcitabine was among the candidates for a third drug. PATIENTS AND METHODS: We performed a prospective, randomized, phase III, intergroup trial to compare carboplatin plus paclitaxel (TC; area under the curve [AUC] 5 and 175 mg/m(2), respectively) with the same combination and additional gemcitabine 800 mg/m(2) on days 1 and 8 (TCG) in previously untreated patients with advanced epithelial ovarian cancer. TC was administered intravenously (IV) on day 1 every 21 days for a planned minimum of six courses. Gemcitabine was administered by IV on days 1 and 8 of each cycle in the TCG arm. RESULTS: Between 2002 and 2004, 1,742 patients were randomly assigned; 882 and 860 patients received TC and TCG, respectively. Grades 3 to 4 hematologic toxicity and fatigue occurred more frequently in the TCG arm. Accordingly, quality-of-life analysis during chemotherapy showed a disadvantage in the TCG arm. Although objective response was slightly higher in the TCG arm, this did not translate into improved progression-free survival (PFS) or overall survival (OS). Median PFS was 17.8 months for the TCG arm and 19.3 months for the TC arm (hazard ratio [HR], 1.18; 95% CI, 1.06 to 1.32; P = .0044). Median OS was 49.5 for the TCG arm and 51.5 months for the TC arm (HR, 1.05; 95% CI, 0.91 to 1.20; P = .5106). CONCLUSION: The addition of gemcitabine to carboplatin plus paclitaxel increased treatment burden, reduced PFS time, and did not improve OS in patients with advanced epithelial ovarian cancer. Therefore, we recommend no additional clinical use of TCG in this population.

Doxorubicin and paclitaxel versus fluorouracil, doxorubicin and cyclophosphamide as first-line therapy for women with advanced breast cancer: long-term analysis of the previously published trial.

BACKGROUND: The aim of this study was to perform an independent review of the efficacy data and to determine whether the efficacy difference observed in a phase III randomised clinical trial that compared doxorubicin plus paclitaxel (AT) versus fluorouracil/doxorubicin/cyclophosphamide (FAC) in first-line chemotherapy of metastatic breast cancer was maintained after a longer follow-up period. MATERIAL AND METHODS: A blinded independent review of original radiological images and original case report forms (CRFs) was conducted by an expert radiologist and an expert medical oncologist, respectively. The analysis of the updated data included time to progression (TTP) and overall survival (OS). RESULTS: CRFs for all 267 patients randomised in the study were available for medical review. The results of the independent review were consistent with the original analysis. At a median follow-up of 69 months, the difference in median TTP and OS in favour of the AT arm remained significant (median TTP 8.1 vs. 6.2 months, (p = 0.036); OS 23.0 vs. 18.3 months, (p = 0.005), respectively). CONCLUSIONS: This blinded independent review and analysis of updated data confirmed the advantage for AT over FAC with regard to TTP and OS in patients with metastatic breast cancer.

Some patients with NHL possessed immunoreactivity to gliadin and to cow's milk proteins.

Non-Hodgkin lymphoma (NHL) represents heterogeneous group of diseases either B, or T cell origin. In order to assess whether food antigens contribute to the imbalance of immune response, the aim of this work was screening the sera of patients with (mostly) B cell NHL, and of people with non-malignant health disorders (NMD), as well as of healthy people for their immunoreactivity to food constituent gliadin, and to cow's milk proteins. Data obtained by ELISA tests show the existence of the enhanced immunoreactivity to food antigens in some NHL patients, as well as in some people with NMD. The high degree of coincidence in the presence of enhanced levels of immune complexes in circulation (CIC) and of immunoreactivity with gliadin in immunofixation (after the serum protein electrophoresis in agarose gel in veronal buffer, at pH 8.6) especially in NHL patients points that some antigliadin immunoreactivity unrevealed in ELISA tests could be hidden in CIC. This, only in the presence of malignant genotype, as well as the enhanced levels of CIC in some of NHL patients could both, at least partially contribute to the persistent non-specific support of disease. They call for the new research of the clinical importance of both, the elevated humoral immunity to food antigens (gluten, cow's milk proteins) for the course of this very severe hematological disease.

Different levels of humoral immunoreactivity to different wheat cultivars gliadin are present in patients with celiac disease and in patients with multiple myeloma.

BACKGROUND: Immunity to food antigens (gliadin, cow's milk proteins) is in the centre of the attention of modern medicine focused on the prevention of diseases, prevention which is based on the use of appropriate restriction diet. Detection of the enhanced levels of the immune reactions to antigen(s) present in food is from this point of view of great importance because there are reports that some of health disturbances, like celiac disease (CD) and some premalignant conditions, like monoclonal gammopathy of undetermined significance (MGUS), were vanished after the appropriate restriction diets. It is well known that gliadin is toxic to small bowel mucosa of relatively small population of genetically predisposed individuals, who under this toxic action develop celiac disease (CD). As the quantity of immunogenic gliadin could vary between different wheat species, the first aim of this work was to determine the percentage of immunogenic gliadin in ten bread wheat cultivars and in three commercially grown durum wheat cultivars. The second part of the study was initiated by results of previous publication, reporting that sera of some of multiple myeloma (MM) patients showed the presence of elevated levels of anti-gliadin IgA, without the enhanced levels of anti-gliadin IgG antibodies, determined with commercial ELISA test. It was designed to assess is it possible to reveal is there any hidden, especially anti-gliadin IgG immunoreactivity, in serum of mentioned group of patients. For this purpose we tested MM patients sera, as well as celiac disease (CD) patients sera for the immunoreaction with the native gliadin isolated from wheat species used for bread and pasta making in corresponding geographic region. RESULTS: Gliadin was isolated from wheat flour by two step 60% ehanolic extraction. Its content was determined by commercial R5 Mendez Elisa using PWG gliadin as the standard. Results obtained showed that immunogenic gliadin content varies between 50.4 and 65.4 mg/g in bread wheat cultivars and between 20 and 25.6 mg/g in durum wheat cultivars. Anti-gliadin IgA and IgG immunoreactivity of patients' sera in (IU/ml) was firstly determined by commercial diagnostic Binding Site ELISA test, and then additionally by non-commercial ELISA tests, using standardized ethanol wheat extracts -gliadin as the antigen. In both patients groups IgA immunoreactivity to gliadin from different cultivars was almost homogenous and in correlation with results from commercial test (except for one patient with IgA(lambda) myeloma, they were more then five times higher). But, results for IgG immunoreactivity were more frequently inhomogeneous, and especially for few MM patients, they were more then five times higher and did not correlate with results obtained using Binding Site test. CONCLUSION: Results obtained showed different content of immunogenic gliadin epitopes in various species of wheat. They also point for new effort to elucidate is there a need to develop new standard antigen, the representative mixture of gliadin isolated from local wheat species used for bread production in corresponding geographic region for ELISA diagnostic tests.

Polymorphism of alpha-1-antitrypsin in hematological malignancies.

Alpha-1-antitrypsin (AAT) or serine protease inhibitor A1 (SERPINA1) is an important serine protease inhibitor in humans. The main physiological role of AAT is to inhibit neutrophil elastase (NE) released from triggered neutrophils, with an additional lesser role in the defense against damage inflicted by other serine proteases, such as cathepsin G and proteinase 3. Although there is a reported association between AAT polymorphism and different types of cancer, this association with hematological malignancies (HM) is, as yet, unknown. We identified AAT phenotypes by isoelectric focusing (in the pH 4.2-4.9 range) in 151 serum samples from patients with HM (Hodgkins lymphomas, non-Hodgkins lymphomas and malignant monoclonal gammopathies). Healthy blood-donors constituted the control group (n = 272). The evaluated population of patients as well as the control group, were at Hardy-Weinberg equilibrium for the AAT gene (χ(2) = 4.42, d.f.11, p = 0.96 and χ(2) = 4.71, d.f.11, p = 0.97, respectively). There was no difference in the frequency of deficient AAT alleles (Pi Z and Pi S) between patients and control. However, we found a significantly higher frequency of PiM1M1 homozygote and PiM1 allele in HM patients than in control (for phenotype: f = 0.5166 and 0.4118 respectively, p = 0.037; for allele: f = 0.7020 and 0.6360 respectively, p = 0.05). In addition, PiM homozygotes in HM-patients were more numerous than in controls (59% and 48%, respectively, p = 0.044). PiM1 alleles and PiM1 homozygotes are both associated with hematological malignancies, although this is considered a functionally normal AAT variant.

Polymorphism of alpha-1-antitrypsin in hematological malignancies

Alpha-1-antitrypsin (AAT) or serine protease inhibitor A1 (SERPINA1) is an important serine protease inhibitor in humans. The main physiological role of AAT is to inhibit neutrophil elastase (NE) released from triggered neutrophils, with an additional lesser role in the defense against damage inflicted by other serine proteases, such as cathepsin G and proteinase 3. Although there is a reported association between AAT polymorphism and different types of cancer, this association with hematological malignancies (HM) is, as yet, unknown. We identified AAT phenotypes by isoelectric focusing (in the pH 4.2-4.9 range) in 151 serum samples from patients with HM (Hodgkins lymphomas, non-Hodgkins lymphomas and malignant monoclonal gammopathies). Healthy blood-donors constituted the control group (n = 272). The evaluated population of patients as well as the control group, were at Hardy-Weinberg equilibrium for the AAT gene (χ2 = 4.42, d.f.11, p = 0.96 and χ2 = 4.71, d.f.11, p = 0.97, respectively). There was no difference in the frequency of deficient AAT alleles (Pi Z and Pi S) between patients and control. However, we found a significantly higher frequency of PiM1M1 homozygote and PiM1 allele in HM patients than in control (for phenotype: f = 0.5166 and 0.4118 respectively, p = 0.037; for allele: f = 0.7020 and 0.6360 respectively, p = 0.05). In addition, PiM homozygotes in HM-patients were more numerous than in controls (59 percent and 48 percent, respectively, p = 0.044). PiM1 alleles and PiM1 homozygotes are both associated with hematological malignancies, although this is considered a functionally normal AAT variant.

Humoral immunoreactivity to gliadin and to tissue transglutaminase is present in some patients with multiple myeloma.

BACKGROUND: Multiple myeloma (MM) is a clonal B-cell disorder with many immunological disturbances. The aim of this work was to assess whether some of food antigens contribute to the imbalance of immune response by screening the sera of MM patients for their immunoreactivity to food constituent gliadin, to tissue transglutaminase-2 (tTG-2) and to Ro/SSA antigen.Sera from 61 patients with MM in various stages of disease, before, or after some cycles of conventional therapy were analyzed by commercial Binding Site ELISA tests. The control group consisted of 50 healthy volunteers. Statistical analysis of data obtained was performed by Mann Whitney Test. RESULTS: The higher serum IgA immunoreactivity to gliadin was found in 14/56 patients and in one of control people. The enhanced serum IgG immunoreactivity to gliadin was found in only two of tested patients and in two controls. The enhanced IgA immunoreactivity to tTG-2 was found in 10/49 patients' sera, while 4/45 patients had higher serum IgG immunoreactivity. The enhanced serum IgG immunoreactivity to RoSSA antigen was found in 9/47 analyzed MM patients' sera. Statistical analysis of data obtained revealed that only the levels of anti-tTG-2 IgA immunoreactivity in patients with MM were significantly higher than these obtained in healthy controls (P < 0.02) CONCLUSION: Data obtained showed the existence of the enhanced serum immunoreactivity to gliadin, tTG-2 and Ro/SSA antigens in some patients with MM. These at least partially could contribute to the immunological imbalance frequently found in this disease.

Decreased oxygen transfer capacity of erythrocytes as a cause of 5-fluorouracil related ischemia.

Various mechanisms have been proposed to account for chemotherapy related ischemia, but none of them can explain the available clinical data. In order to explore the possibility that the decreased ability of erythrocytes to deliver oxygen to the heart could be responsible for cardiotoxicity, we have performed an ex vivo and in vivo study of the effects of cisplatin/5-FU on erythrocytes, using a variety of biophysical techniques. Combining EPR and microscopy it was concluded that both cardiotoxic 5-FU and non-cardiotoxic cisplatin have similar effects on the erythrocyte membrane, thus eliminating those changes as a potential source of cardiotoxicity. On the contrary, 31P-NMR and polarography showed that the effects of these cytostatics on the intracellular milieu differ significantly. 5-FU provoked a pronounced decrease of the O2 level in blood and affected the metabolism of phosphate compounds, while cisplatin had no such effects. When combined these two drugs showed synergistic effects, which matches the higher frequency of cardiotoxicity of the combination relative to the sole application of 5-FU. Preliminary results acquired on blood of patients receiving cisplatin/5-FU therapy verified observations obtained ex vivo. These results open a possibility of applying NMR in preclinical trials of new drugs in order to predict their ischemic potential.

Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer.

BACKGROUND: Phase 2 studies suggest that the standard regimen of cisplatin and fluorouracil (PF) plus docetaxel (TPF) improves outcomes in squamous-cell carcinoma of the head and neck. We compared TPF with PF as induction chemotherapy in patients with locoregionally advanced, unresectable disease. METHODS: We randomly assigned eligible patients between the ages of 18 and 70 years who had stage III or stage IV disease and no distant metastases to receive either TPF (docetaxel and cisplatin, day 1; fluorouracil by continuous infusion, days 1 to 5) or PF every 3 weeks for four cycles. Patients without progression of disease received radiotherapy within 4 to 7 weeks after completing chemotherapy. The primary end point was progression-free survival. RESULTS: A total of 358 patients underwent randomization, with 177 assigned to the TPF group and 181 to the PF group. At a median follow-up of 32.5 months, the median progression-free survival was 11.0 months in the TPF group and 8.2 months in the PF group (hazard ratio for disease progression or death in the TPF group, 0.72; P=0.007). Treatment with TPF resulted in a reduction in the risk of death of 27% (P=0.02), with a median overall survival of 18.8 months, as compared with 14.5 months in the PF group. There were more grade 3 or 4 events of leukopenia and neutropenia in the TPF group and more grade 3 or 4 events of thrombocytopenia, nausea, vomiting, stomatitis, and hearing loss in the PF group. The rates of death from toxic effects were 2.3% in the TPF group and 5.5% in the PF group. CONCLUSIONS: As compared with the standard regimen of cisplatin and fluorouracil, induction chemotherapy with the addition of docetaxel significantly improved progression-free and overall survival in patients with unresectable squamous-cell carcinoma of the head and neck. (ClinicalTrials.gov number, NCT00003888 [ClinicalTrials.gov].).

Antibodies contained in "M" component of some patients with multiple myeloma are directed to food antigens?

Multiple myeloma is malignant disease that is characterized in most patients, by the presence in the serum of monoclonal gamma globulins, which in agarose gel after electrophoresis appear as protein band of restricted mobility, "M" component. The aim of this study was to determine are the antibodies contained in M-component directed to some antigen chronically present in the organism, to some of food antigens. Seventeen patients with secretory plasmacytoma were included in the study: eight of them had IgG(kappa), three had IgG(lambda), and one had biclonal IgG(kappa) and IgA(kappa), while two had IgA(kappa), the other two IgA(lambda) and one IgM(lambda) as paraproteins. M-proteins were detected analyzing patients' sera by agarose gel electrophoresis in 0.09 M barbital buffer. The each M-protein was confirmed by immunotyping (immunofixation) with corresponding antihuman antibodies directed to heavy or light chains of immunoglobulins. After the patients serum separation on agarose gel by electrophoresis, fresh 0.4% solution of crude gliadin (Sigma) in 1% SDS was put over the slides for immunoprecipitation. Preliminary results showed the interaction of gliadin with patient's serum proteins present in the protein fraction of the same mobility as it was the mobility of the M-component, in 6 from 17 investigated sera. These results are the first reporting that in sera of some patients with multiple myeloma antibodies from M-component could be directed to some of gliadin antigens. As the serum antigliadin immunoreactivity is present in patients with gluten intolerance, celiac disease, it could be of importance to elucidate is the multiple myeloma more severe form of gluten intolerance than celiac disease.

What is the best sequence of chemotherapy in advanced colorectal cancer? Final results of a five-arm study.

One hundred and ninety-three patients were assigned to receive 5-FU/LV, irinotecan and oxaliplatin in five different sequential treatment groups: Mayo Clinic Regimen (MCR) + LV5FU2 (group A); MCR + irinotecan (350 mg/m(2)) (group B); MCR + FOLFIRI (group C); MCR + FOLFOX4 (group D); FOLFIRI + FOLFOX4 (group E). The results were as follows: group A (32 patients), median overall survival (OS) 14 months, median time to progression (TTP1) 6 months, median TTP2 5 months, response rate (RR1) 22%, RR2 25%; group B (27 patients), OS 11 months, TTP1 6 months, TTP2 3 months, RR1 22%, RR2 19%; group C (43 patients), OS 14 months, TTP1 5 months, TTP2 5 months, RR1 12%, RR2 19%; group D (45 patients), OS 15 months, TTP1 5 months, TTP2 4 months, RR1 18%, RR2 20%; group E (46 patients), OS 19 months, TTP1 9 months, TTP2 5 months, RR1 39%, RR2 25%. There was a significant difference in OS (p < 0.005) between groups E vs. B and A, D vs. B. Sequential therapy with 3 active drugs (FOLFIRI + FOLFOX4) was the most efficacious combination in comparison with any other two drug combinations applied in our study.

[Treatment of metastatic neck squamous cell carcinomas with unknown primary]. / Terapija metastatskih planocelularnih karcinoma vrata sa neutvrdenim primarnim tumorom.

INTRODUCTION: Treatment of metastatic neck squamous cell carcinomas of unknown primary is one of the most serious problems in head and neck oncology. MATERIAL AND METHODS: Fifty-one patients were analyzed during the period 1977-1997. All patients underwent clinical examination of head and neck, hematological and laboratory tests, X-ray of paranasal sinuses, esophagus and lungs, scintigraphy of the thyroid gland, epipharyngoscopy, esophagoscopy and laryngotracheobronchoscopy, biopsy of suspected changes and blind biopsy of suspected regions (epipharynx, tongue base, piriform sinus), ipsilateral tonsillectomy (17 patients), examination of gastrointestinal tract, kidneys, prostate, testicles, and breasts and ovaries, respectively. RESULTS: Almost half of metastases developed in the II level of the neck (49.01%; 25/51). Most metastases were 3-6 cm in diameter (N2)--60.76% (31/51). Forty patients were surgically treated by various neck dissection methods and postoperative radiotherapy (60 Gy). Palliative radiotherapy was applied in patients with inoperable metastases. Eighteen patients had a five-year disease free survival (35.29%). DISCUSSION: Metastases localized in the II and III levels of the neck and in the upper two-thirds of the V level, should be primarily treated by neck dissection. Lymph nodes up to 3 cm in diameter (N1) are operated by a modified radical neck dissection. Lymph nodes over 3 cm (N2) and 6 cm in diameter (N3) are operated by radical or extended radical neck dissection. CONCLUSION: Primary surgery plus postoperative radiotherapy provide satisfactory results in therapy of metastatic squamous cell carcinomas of the neck with unknown primary.

[Jugular neck dissection for supraglottic laryngeal carcinoma with negative clinical findings in the neck (N0)]. / Jugularna disekcija vrata kod subraglotisnih karcinoma larinksa sa klinicki negativnim nalazom na vratu (N0).

INTRODUCTION: Appropriate management of patients with supraglottic laryngeal carcinoma and negative findings in the neck is still controversial. A prospective and retrospective study comprised 193 patients who were treated primary surgically between 1976 and 1993. They all had clinically and ultrasound negative findings on the neck (N0). Supraglottic carcinomas usually spread regionally. Metastases develop in the jugular group, between level II-IV. The incidence of metastases has been reported to vary from 12 to 62.5%. The size and localization of the primary tumor, its histological grade, genotype of the malignant cells, immunological and other elucidated factors can all affect the incidence of regional spread. AIM: Aim of this study was to specify the incidence of occult cervical metastases; to analyze the distribution of occult metastases related to tumor localization; to specify the distribution of occult metastases related to local spread; to analyze the distribution of occult metastases according to localization in the neck. RESULTS: All patients had primary surgery of primary tumor and bilateral jugular, selective neck dissection at the level II-IV with histological examination of removed lymphoid tissue. Out of 193 patients, metastatic deposits were detected in 35 (18%). Occult metastases were found in patients with carcinoma of the epilarynx in 19% (14/72) of cases, and in 17% (21/121) patients with carcinoma of the supraglottis excluding the epilarynx. This difference in frequency is not statistically significant. The incidence of occult metastases in epilaryngeal tumors did not depend on the degree of local spread. Even relatively small tumors (T1 and T2) yielded occult metastases in 33% (5/15), and 24% (6/25) of patients, respectively. In patients with T1 tumors localized at the supraglottis, excluding the epilarynx, occult metastases were not found. In the supraglottis excluding the epilarynx increased local spread was associated an increase of occult metastases. The incidence of occult metastases was directly related to the degree of the local spread of the tumor in the supraglottis excluding the epilarynx (Table 1). Occult metastases were usually ipsilateral, like the palpable ones. In medially localized tumors bilateral metastases were possible. Ipsilateral metastases were more frequent than both bilateral and contralateral ones. The possibility of contralateral and bilateral occult metastases necessitated bilateral neck dissection. Postoperative radiotherapy (60 Gy) was given to all patients with verified occult metastases. Only in two patients (1%) of the total did metastases develop subsequently, indicating the effectiveness of planned postoperative radiotherapy. DISCUSSION: Controversies in application of jugular, selective neck dissection are present since it has been in use, because of the unclear role which regional lymph tissue play in antitumor immune response. Jugular, selective neck dissection was advocated in all patients with a primary supraglottic laryngeal carcinomas. It was suggested that selective neck dissection was needed only in advanced (T3 and T4) tumors. Selective dissection is believed to be needed only when tumor has spread into the vallecula, the base of the tongue, or the medial wall of the piriform sinus. The idea of selective neck dissection has been opposed since the protective role of the cervical lymph tissue has been stressed. Ultrasound and computerized tomography of the neck cannot detect occult metastases. Today, only removal and histological examination of the lymph tissue can determine occult metastasis. The importance of selective neck dissection is considered in diagnostic biopsy procedure by which occult metastatic spread in the neck region is established. CONCLUSION: Due to the tendency of supraglottic carcinoma resulting in occult cervical metastases, early detection is imperative in order to apply the appropriate therapy. Occult cervical metastases are usually ipsilateral, but bilateral and contralateral may be found as well. Due to the aforementioned, it is necessary to perform bilateral jugular, selective cervical dissection of the neck level II-IV with histological evidence of removed lymph tissue. When metastases is verified histologically, postoperative radiotherapy is indicated as being efficient in hampering the development of palpable metastases. Five-year survival with no evidence disease is 86% (166/193).

IL-2-mediated augmentation of NK-cell activity and activation antigen expression on NK- and T-cell subsets in patients with metastatic melanoma treated with interferon-alpha and DTIC.

Considering that well-defined and comprehensive immunological monitoring is the basis for the evaluation of the obtained immunmodulatory effects, we evaluated NK-cell activity, the number of CD3+ CD4+, CD3+ CD8+ T cells and CD16+ CD56+ NK cells, as well as the expression of activation antigens, CD69, CD38 and HLA-DR on CD56+ NK cells, CD8+ and CD3+ T cells, simultaneously with IL-2 and TNF-alpha production, during chemoimmunotherapy with dacarbazine (DTIC) and interferon-alpha (IFN-alpha) in 39 patients with metastatic melanoma. In the first cycle of therapy, there was a significant rise in NK-cell activity, CD4+ T helper cell number, CD4/CD8 T-cell ratio, and the expression of activation antigens CD69 and CD38, on NK and T cells, respectively. However, in the following cycles there was a significant increase only in activation antigens without an increase in the percent or activity of NK cells. The early, but transient, immunopotentiation, present only in the first cycle of combined DTIC and IFN-alpha therapy, suggests that, in spite of increased IL-2 level, associated with augmented NK-cell activity, this therapy has a limited effect probably owing to the adverse effect of persistently high level of TNF-alpha in metastatic disease.