Prognostic role of the histological subtype of melanoma on the hands and feet in Caucasians.

Acral melanoma (AM) is associated with a poor prognosis in part because of delayed diagnosis, but probably also because of other intrinsic characteristics of location. The aim of this study was to review the specific characteristics and outcome of AM in Caucasians. This was a cross-sectional retrospective clinical-pathological study of 274 patients identified with AM in the database of a referral unit in Europe from 1986 to 2010. The mean age of the patients was 56.6 (SD 17.7) years. 269 cases could be histologically classified and included in the study. In all, 222 (82.5%) were located on feet. According to melanoma subtype, 165 (61.3%) were acral lentiginous melanoma (ALM), 84 (31.2%) were superficial spreading melanoma (SSM), and 20 (7.5%) were nodular melanoma (NM). SSM patients were characterized by female predominance (77.4%), younger age, and classic melanoma-risk phenotype (fair skin and multiple nevi). Among the 198 invasive cases with a mean follow-up of 56.2 months, the mean (SD) Breslow's thickness was 3.1 (3.6) mm, being 1.4 (1.4) mm in SSM, 3.5 (4.1) mm in ALM and 4.9 (2.9) mm in NM (P<0.001). Ulceration was present in 33.3%, 2.9% in SSM, 38.6% in ALM, and 76.9% in NM (P<0.001). A total of 29.3% relapsed (7.3% of SSM, 35% of ALM and 55% of NM) and 24.2% died because of AM. In multivariate analysis, age at diagnosis, Breslow, and histopathological subtype were independent prognostic factors for both disease-free and AM-specific survival. The ALM and NM subtypes presented poorer outcome after weighting Breslow and age (P=0.02). Histological subtype of AM could have an impact on biological behavior, ALM and NM subtypes presenting a poorer prognosis after adjusting for age and Breslow's thickness.

Preoperative assessment of cutaneous melanoma thickness using 10-MHz sonography.

OBJECTIVE: The purpose of this study was to evaluate the prognostic value of 10-MHz sonography in measuring melanoma thickness before biopsy or excision. SUBJECTS AND METHODS: Fifty-four patients with lesions suggestive of melanoma participated in the study. Lesions were measured on sonography using a 10-MHz linear transducer before routine biopsy and histopathologic analysis. Sonographic measurements were compared with histopathologic results (Breslow index) using Pearson's correlation coefficient and concordance analysis. Additional statistical analyses included sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of 10-MHz sonography in identifying lesions > 1 mm thick. RESULTS: Histopathologic analysis identified all 54 lesions as melanoma. On sonography, 34 lesions measured < or = 1 mm and 20 lesions, > 1 mm. Histopathologic analysis showed 32 lesions with a Breslow index of < or = 1 mm and 22 lesions with a Breslow index of > 1 mm. The median thickness of the 54 lesions was 1.33 mm (range, 0-5 mm) by the Breslow index compared with 1.85 mm (range, 0-4.8 mm) by sonography. Comparison of sonographic measurements and Breslow index values gave a correlation coefficient of 0.93 and a concordance coefficient of 0.99. Overall, sonographic measurements showed 86% sensitivity, 97% specificity, 93% accuracy, 95% positive predictive value, and 91% negative predictive value in identifying lesions with a Breslow index of > 1 mm. CONCLUSION: In our series of 54 melanomas, 10-MHz sonography measured lesion thickness with good accuracy compared with histopathology. Sonography was effective in discriminating between tumors < or = 1 mm thick and those > 1 mm thick.

Prognostic implications of protein S-100beta serum levels in the clinical outcome of high-risk melanoma patients.

OBJECTIVE: It was the aim of this study to analyze the clinical value of the determination of serum S-100beta protein in high-risk melanoma patients. PATIENTS AND METHODS: Patients were tested for serum S-100beta protein by luminoimmunometric assay after melanoma surgical excision, before starting interferon-alpha2b and every 3 months thereafter, until treatment was completed. RESULTS: Ninety-seven patients were included in the study. Median follow-up was 62.9 months (range 32.7-87.4). High baseline S-100beta levels were associated with positive lymph node status (p = 0.02). High S-100beta levels (during therapy) showed a relation with positive lymph node status (p = 0.014), number of positive lymph nodes (p = 0.01), macroscopic lymph node involvement (p = 0.002) and second melanoma diagnosis at study entry (p = 0.001). By univariate analysis, high baseline S-100beta levels were associated with disease-free survival (p = 0.004) and overall survival (p = 0.0007). Similarly, high S-100beta levels during therapy were associated with disease-free survival (p < 0.0001) and overall survival (p < 0.0001). In the multivariate analysis, high S-100beta levels during therapy (hazard ratio 1.017, 95% CI 1.008-1.026; p < 0.0001) and high baseline S-100beta levels (hazard ratio 3.31, 95% CI 1.10-9.89; p = 0.032) were independent prognostic factors for overall survival when compared with low levels while on therapy and low baseline S-100beta levels, respectively. CONCLUSIONS: These results provide evidence of the clinical usefulness of serum S-100beta level determination in high-risk melanoma patients. S-100beta serum determination should be considered to be included in clinical trials that test adjuvant therapies in melanoma patients.

Toxicity of combined treatment of adjuvant irradiation and interferon alpha2b in high-risk melanoma patients.

Surgically resected stage III melanoma patients commonly receive adjuvant therapy with interferon (IFN) alpha2b. For those patients with high-risk features of draining node recurrence, radiation therapy can also be considered as a treatment option. The purpose of this retrospective study was to assess the efficacy and radiation-related toxicity of this combined therapy. Eighteen patients receiving adjuvant IFNalpha2b therapy during radiation therapy, or within 1 month of its completion, were reviewed retrospectively and analysed for outcome. Radiation was delivered at 600 cGy dose per fraction, in 16 out of 18 patients, twice a week, and at 200 cGy dose per fraction in two patients five times a week. Total radiation dose and number of fractions were as follows: 30 Gy/5 fr (n=8), 36 Gy/6 fr (n=8) and 50 Gy/25 fr (n=2). The percentage of disease-free patients, with no local recurrence, at 3 years was 88%. In 10 patients, IFNalpha2b was administered concurrently with radiotherapy; in three, within 30 days before or after radiation; and in five, more than 30 days after radiation. All the patients experienced acute skin reactions, grade I on the Radiation Therapy Oncology Group (RTOG) scale. Late radiation-related toxicity was seen in one patient with grade III (RTOG) skin reaction and two with grade IV (RTOG) radiation-induced myelitis. Concurrent use of adjuvant radiotherapy and IFNalpha2b might enhance radiation-induced toxicity, and special care should be taken when the spinal cord is included in the radiation field.

Clinical outcome after surgical resection of lung metastases from melanoma.

BACKGROUND: Surgical therapy plays an important role in the management of selected patients with metastatic melanoma. PURPOSE: A retrospective review of 13 patients who underwent surgical resection of lung metastases from melanoma from 1996 to 2003 was performed. The aim of the study was to analyze the clinical outcome and survival time. MATERIALS AND METHODS: Mean age was 45 years old (range: 31-64). Complete tumour resection was confirmed histologically. Nine patients presented one single pulmonary lesion, two lesions (n = 3) and three lesions (n = 1) but in all cases confined in the same pulmonary lobe. RESULTS: Median survival time (MST) for the entire group was 20 months (95% confidence interval (CI): 16-24 months). The median time to disease progression after lung metastasectomy was 5 months (95% CI: 3-7 months). MST, according to the prognostic groups proposed by the International Registry of Lung Metastases, was 17 months (95% CI: 6-28 months) for group I (n = 6), MST of 20 months (95% CI: 16-24 months) for group II (n = 5) and MST of 4 months for group III (n = 2), without differences statistically significant (log-rank p = 0.423). MST regarding the time of disease free interval from diagnostic of primary tumour and lung metastases (< 36 months [n = 5] vs > 36 months [n = 8]) was 20 months and 17 months respectively, without differences statistically significant (log rank p = 0.222). CONCLUSIONS: Surgical resection when feasible provides survival rates superior to any available nonsurgical therapy. In carefully selected patients, when the resection is performed with curative intent, it may result in improved survival.

Whole brain irradiation and temozolomide based chemotherapy in melanoma brain metastases.

INTRODUCTION: Whole brain irradiation (WBRT) remains a recommended treatment for patients with brain metastases from malignant melanoma in terms of symptom palliation, especially when extracranial systemic disease is present. Temozolomide (TMZ) has shown efficacy in the treatment of metastatic melanoma. The objective was to evaluate the potential benefit in survival of two different schedules of total dose and fractionation (20 Gy/5 fractions vs 30 Gy/10 fractions) and further TMZ based chemotherapy. MATERIALS AND METHOD: We have conducted a retrospective study in a group of twenty-one patients (RTOG Recursive Partitioning Analysis class II) of the use of WBRT with 20 Gy/5 fractions (n = 11) and 30 Gy/10 fractions (n = 10). All patients received further TMZ based chemotherapy administered as a single chemotherapeutic agent or in combination with chemo-immunotherapy. RESULTS: Prognostic variables such as: age, Karnofsky performance status, extracranial metastases and number of brain metastases, were analyzed in both groups of treatment without statistically significant differences. The median survival time (MST) for WBRT 20 Gy group was 4 months (CI 95%: range 2- 6 months) and for WBRT 30 Gy group was 4 months (CI 95%: range 0-7 months) without statistically significant differences (Log rank p = 0.74). There was one complete response and two partial responses. CONCLUSIONS: The results suggest that MST was not significantly affected by the total dose/fractionation schedule.

Whole brain irradiation and temozolomide based chemotherapy in melanoma brain metastases

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Introduction. Whole brain irradiation (WBRT) remainsa recommended treatment for patients withbrain metastases from malignant melanoma interms of symptom palliation, especially when extracranialsystemic disease is present. Temozolomide(TMZ) has shown efficacy in the treatment ofmetastatic melanoma. The objective was to evaluatethe potential benefit in survival of two differentschedules of total dose and fractionation (20 Gy/5fractions vs 30 Gy/10 fractions) and further TMZbased chemotherapy.Materials and method. We have conducted a retrospectivestudy in a group of twenty-one patients(RTOG Recursive Partitioning Analysis class II) ofthe use of WBRT with 20 Gy/5 fractions (n = 11)and 30 Gy/10 fractions (n = 10). All patients receivedfurther TMZ based chemotherapy administered asa single chemotherapeutic agent or in combinationwith chemo-immunotherapy.Results. Prognostic variables such as: age, Karnofskyperformance status, extracranial metastases andnumber of brain metastases, were analyzed in bothgroups of treatment without statistically significantdifferences. The median survival time (MST) forWBRT 20 Gy group was 4 months (CI 95%: range 2-6 months) and for WBRT 30 Gy group was 4 months(CI 95%: range 0-7 months) without statistically significantdifferences ( Log rank p = 0.74). There wasone complete response and two partial responses.Conclusions. The results suggest that MST was notsignificantly affected by the total dose/fractionationschedule

Antiproliferative effect of STI571 on cultured human cutaneous melanoma-derived cell lines.

Standard antineoplastic treatment for metastatic melanoma is ineffective in the large majority of patients. Therefore, alternative approaches need to be investigated. STI571 is a new antineoplastic compound, which selectively inhibits the tyrosine kinase activity of ABL, c-Kit and platelet-derived growth factor receptor (PDGFR). Melanoma may express all of these proteins. The aim of this study was to investigate whether STI571 inhibits the in-vitro growth of melanoma cells. Nineteen cell lines were obtained from four primary and 15 metastatic melanomas of cutaneous origin. The percentages of positive cells for the putative targets of STI571 were as follows: ABL, 41-100%; c-Kit, 8-97%; PDGFR-alpha, 41-98%; PDGFR-beta, 51-99%. 3-(4,5-Dimethylthiazol-yl)-2,5-diphenyltetrazolium (MTT) and viability assays showed that STI571 clearly inhibits the proliferation of eight of the 19 (42.1%) cell lines. No relationship could be established between the expression of c-Kit, ABL, PDGFR-alpha or PDGFR-beta and the response of cell lines to STI571. Our study shows, for the first time, an antiproliferative effect of STI571 on human melanoma cell lines of cutaneous origin, raising the possibility of the future clinical use of STI571. The identification of the target of STI571 in human cutaneous melanoma cells would allow the selection of patients who could benefit from this treatment.

Biochemotherapy with temozolomide, cisplatin, vinblastine, subcutaneous interleukin-2 and interferon-alpha in patients with metastatic melanoma.

The aim of this study was to determine the efficacy and tolerability of a biochemotherapy regimen, including low-dose subcutaneous interleukin-2 and temozolomide, in patients with metastatic melanoma. Treatment consisted of temozolomide (150 mg/m per day on days 1-5), cisplatin (20 mg/m per day intravenously on days 1-4), vinblastine (1.5 mg/m per day on days 1-4), interleukin-2 (4.5 MU/m per day subcutaneously on days 5-8) and interferon-alpha2b (5 MU subcutaneously on days 5-9, 11, 13, 15, every 28 days). Thirty-six patients were included. Patients with poor prognostic factors were not excluded. Seventeen patients (47%) had been treated previously in an adjuvant setting with interferon-alpha. Four patients (11%) had been treated previously with chemotherapy and six (17%) had been treated with other biochemotherapy regimens. The distribution by American Joint Committee on Cancer staging was as follows: M1a in two patients (6%), M1b in 11 patients (31%) and M1c in 23 patients (64%). At inclusion, seven patients (19.4%) had cerebral metastases that had previously been treated with whole brain radiotherapy. For thirty-four evaluable patients, seven (20.5%) achieved an objective response. Overall, metastatic disease was substantially decreased or temporarily stabilized in 11 patients (32.4%; 95% confidence interval, 17.4-50.5). Responses were observed for all locations. The central nervous system was the initial site of relapse in two responding patients. The median survival was 10 months. The main toxicities noted were haematological (grades 3-4): neutropenia (1.8%), thrombocytopenia (1.8%) and anaemia (1.2%). It can be concluded that this regimen is well tolerated and has a modest activity despite the poor prognosis of our patient population. The low haematological toxicity rate obtained suggests that higher doses could be tried.

Biochemotherapy with low doses of subcutaneous interleukin-2 in patients with melanoma: results of a phase II trial.

INTRODUCTION: Metastatic melanoma has an ominous prognosis. Bio-chemotherapy regimens can increase the response rate but with a high degree of toxicity due, mainly, to the use of high-dose intravenous interleukin-2. OBJECTIVES: To test the feasibility and activity profile of a bio-chemotherapy regimen of low-dose subcutaneous interleukin-2. MATERIAL AND METHODS: Administration scheme: dacarbazine at 200 mg/m2/d on days 1-4, cisplatin at 20 mg/m2/d intravenous on days 1-4, vinblastine at 1.5 mg/m2/d on days 1-4, IL-2 at 4.5 MUI/m2/d subcutaneous on days 5-8, IFN-alpha at 5 MU subcutaneous on days 5-9, 11, 13, 15 of every 21-day cycle. RESULTS: Objective response was obtained in 11 patients (39.3%; 95%CI: 21-59) including 4 with complete response (14.3%; 95%CI: 4-33). With an extended follow-up of 49 months and 60 months, respectively, 2 patients continue with complete response. The main toxicities were haematological: grade 3-4 neutropenia in 8.2% of cycles, thrombocytopenia in 1.2% and anaemia in 3.2%. CONCLUSIONS: The regimen is safe and has a good activity profile. The presence of long-term survivors, despite the use of lower doses and subcutaneous IL-2, is encouraging.

Malignant melanoma with metastasis into the capitate.

Metastases to the hand and wrist are rare, with fewer than 200 cases reported in the literature. Phalanges are more commonly involved than metacarpal and wrist. The lung, breast and kidneys are the more common sites of primary lesions than metastasize in the hand. We present an exceptional case of melanoma that metastasized to the capitate. Melanoma can give bone metastases, but we are not aware of reports of this tumour metastatising to the carpal bones. In our knowledge, we have only found a report of metastases in the capitate, a clear-cell sarcoma of the right foot, a tumour close to melanoma with some cytogenetic differences. Hand metastases in a patient who is suffered melanoma should be ruled out if a lytic aggressive lesion appears on x-ray film or positive technetium bone scan is demonstrated.

Biochemotherapy with low doses of subcutaneous interleukin-2 in patients with melanoma: results of a phase II trial

Introduction. Metastatic melanoma has an ominous prognosis. Bio-chemotherapy regimens can increase the response rate but with a high degree of toxicity due, mainly, to the use of high-dose intravenous interleukin-2. Objectives. To test the feasibility and activity profile of a bio-chemotherapy regimen of low-dose subcutaneous interleukin-2. Material and methods. Administration scheme: dacarbazine at 200 mg/m²/d on days 1-4, cisplatin at 20 mg/m²/d intravenous on days 1-4, vinblastine at 1.5 mg/m²/d on days 1-4, IL-2 at 4.5 MUI/m²/d subcutaneous on days 5-8, IFN-alpha at 5 MU subcutaneous on days 5-9, 11, 13, 15 of every 21-day cycle. Results. Objective response was obtained in 11 patients (39.3%; 95%CI: 21-59) including 4 with complete response (14.3%; 95%CI: 4-33). With an extended follow-up of 49 months and 60 months, respectively, 2 patients continue with complete response. The main toxicities were haematological: grade 3-4 neutropenia in 8.2% of cycles, thrombocytopenia in 1.2% and anaemia in 3.2%. Conclusions. The regimen is safe and has a good activity profile. The presence of long-term survivors, despite the use of lower doses and subcutaneous IL-2, is encouraging

Role of the CDKN2A locus in patients with multiple primary melanomas.

PURPOSE: We have studied a consecutive case series of patients with multiple primary melanoma (MPM) for the involvement of the melanoma susceptibility loci CDKN2A and CDK4. PATIENTS AND METHODS: One hundred four MPM patients (81 patients with two primary melanomas, 14 with three, five with four, one with five, two with six, and one with seven) were included. RESULTS: Seven different CDKN2A germline mutations were identified in 17 patients (16.3%). In total, we identified 15 CDKN2A exon 2, one exon 1alpha missense mutation, and one exon 1beta frameshift mutation. The age of onset was significantly lower and the number of primary melanomas higher in patients with mutations. CDKN2A mutations were more frequent in patients with familial history of melanoma (35.5%) compared with patients without (8.2%), with a relative risk (RR) of 4.32 (95% CI, 1.76 to 10.64; P = .001), and in patients with more than two melanomas (39.1%) compared with patients with only two melanomas (10%) with an RR of 3.29 (95% CI, 1.7 to 6.3; P = .002). The A148T polymorphism was more frequent in patients with MPMs than in the control population (P = .05). A variant of uncertain significance, A127S, was also detected in one patient. No CDK4 mutations were identified, suggesting that it has a low impact in susceptibility to MPM. CONCLUSION: MPM patients are good candidates for CDKN2A mutational screening. These patients and some of their siblings should be included in a program of specific follow-up with total body photography and digital dermoscopy, which will result in the early detection of melanoma in this subset of high-risk patients and improve phenotypic characterization.

Intramedullary spinal cord metastases of melanoma.

Intramedullary spinal cord metastases (ISCMs) are extremely rare. An exact diagnosis may be difficult even when the primary tumour is known. Patients usually present with back pain and signs and symptoms of spinal cord compression, such as hemiparesis or hemisensory impairments. Magnetic resonance imaging (MRI) is considered to be the main diagnostic tool for intramedullary lesions as it is very sensitive, but non-specific, in distinguishing between ISCMs and primary cord tumours. Optimal treatment in patients with ISCMs remains controversial. We report a case of ISCMs of melanoma, with a review of the clinical and radiological characteristics of these medullary lesions and their prognosis, as well as the different therapeutic approaches.

Small cell melanoma and ulceration as predictors of positive sentinel lymph node in malignant melanoma patients.

Malignant melanoma (MM) early lymph node (LN) metastasis usually appears first in the sentinel LN (SLN). Breslow thickness is the main factor considered in the selection of patients to be submitted to SLN biopsy. The present study aimed to describe other independent prognostic factors useful in SLN candidate selection. During one year, 94 MM patients (90 primary cutaneous MM with Breslow thickness > or = 0.76 mm, and four cutaneous relapses), were submitted to SLN biopsy in the Melanoma Unit at the Hospital Clinic, Barcelona, Spain. The prognostic factors studied were: Breslow thickness, Clark's level of invasion, mitotic rate, cellular type (small, epithelioid, fusocellular, sarcomatoid), vertical growth phase, regression > 50%, severe vascularization, infiltrate (lymphocytic, plasmocytic), ulceration, neurotropism, intravascular/intraneural invasion, protein p16 expression and recurrence. Nineteen SLN (20.2%) were positive and 75 (79.8%) negative. No positive SLN occurred in MM with Breslow thickness < or = 1.0 mm. Breslow thickness > or = 2 mm (P = 0.005), severe vascularization (P = 0.005), small cell (P = 0.000) and ulceration (P = 0.005) were significant prognostic factors by univariate analysis. Small cell (P = 0.008) and ulceration (P = 0.05) were also significant prognostic factors in a multivariate analysis. The probability of finding a positive SLN for small cell was 56.9% [95% confidence interval (CI), 26.8-82.6%]. The probability of positive SLN for ulceration was 35.5% (95% CI, 14.2-64.7%). For small cell and ulceration together the probability increased to 86.3% (95% CI, 54.3-97.1%). The results of this study corroborated ulceration as a prognostic factor for SLN candidate selection and for the first time we have described small cell melanoma morphology as a significant factor associated with positive SLN.

[Temozolomide in patients with melanoma brain metastases treated with whole brain irradiation]. / Temozolomida en pacientes con metástasis cerebrales de melanoma tratados con irradiación holocraneal.

BACKGROUND AND OBJECTIVE: Whole brain irradiation (WBRT) remains a recommended treatment for patients with brain metastases from malignant melanoma. Temozolomide (TMZ) displays efficacy for the treatment of metastatic melanoma. Our objective was to evaluate the potential benefit of TMZ administered along with WBRT. PATIENTS AND METHOD: We have conducted a retrospective study in a group of 26 patients comparing WBRT (n = 10) (20 Gy/5 fr) with WBRT+TMZ (n = 16) administered as a single chemotherapeutic agent (200 mg/m2) or in combination with chemoimmunotherapy (150 mg/m2). RESULTS: The median survival of the total group (n = 26) was 3 months (CI 95%, 2-4 months). The median survival of the WBRT+TMZ group was 6 months (CI 95%, 0-12 months), while the median survival of the WBRT group was 1 month (CI 95%, 1-2 months) (p < 0.0001). The analysis of survival at different time intervals (90, 180 and 270 days) showed a clear benefit for the group treated with WBRT + TMZ (p = 0.016). CONCLUSIONS: These results suggests a benefit of TMZ added to WBRT in terms of long-term survival for patients with melanoma brain metastases.

Is the identification of in-transit sentinel lymph nodes in malignant melanoma patients really necessary?

The sentinel lymph node (SLN) is the first node in a nodal basin to receive the direct lymphatic flow from a malignant melanoma. However, in some patients, lymphoscintigraphic study reveals the presence of lymphatic nodes in the area between the primary melanoma and the regional basin. These nodes are called "in-transit nodes" or "interval nodes" and, by definition, are also SLNs. The purpose of this study was to determine the incidence and location of in-transit SLNs in patients with malignant melanoma and to assess whether it is really necessary to harvest them. The evaluation involved 600 consecutive malignant melanoma patients. Lymphoscintigraphy was performed on the day before surgery following intradermal injection of 74-111 MBq of (99m)Tc-nanocolloid in four doses around the primary melanoma or the biopsy scar. Dynamic and static images were obtained and revealed SLNs in 599 out of 600 patients. The SLN was intraoperatively identified with the aid of patent blue dye and a hand-held gamma probe. Lymphoscintigraphy showed in-transit SLNs in 59/599 patients (9.8%). During surgery, all these in-transit SLNs were harvested, with those in the popliteal and epitrochlear regions being the most difficult to identify and excise. Metastatic cell deposits were subsequently identified in ten (16.9%) of these in-transit SLNs. In conclusion, lymphoscintigraphy has a key role in the identification of in-transit SLNs. Although the incidence of these nodes is relatively low in malignant melanoma patients, such SLNs present metastatic deposits in a significant percentage of cases and therefore the identification of in-transit SLNs in these patients is really necessary.

Treatment of patients with progressive unresectable metastatic melanoma with a heterologous polyvalent melanoma whole cell vaccine.

Unresectable metastatic melanoma has no elective treatment. Neither chemotherapy, intravenous IL-2 nor biochemotherapy clearly improves the overall survival. Recent assays with therapeutic vaccines have been recently yielded promising results. Here, we describe the application, clinical tolerance and antitumoural activity of a heterologous polyvalent melanoma whole cell vaccine in patients with metastatic melanoma. Twenty-eight AJCC stage III/IV melanoma patients with progressive unresectable metastatic disease were treated with our heterologous polyvalent melanoma whole cell vaccine between July 1, 1998 and July 1, 2002. All patients had already been unsuccessfully treated with high doses of IFN-alpha2 and/or polychemotherapy and/or biochemotherapy and/or perfusion of extremities, or could not receive other treatments due to their age or underlying illness. Twenty-three were assessable. The vaccine was constituted by 10 melanoma cell lines, derived from primary, lymph node and metastatic melanomas. Prior to intradermal inoculation, the cells were irradiated and mixed with BCG, and 50% were treated with DNFB. After a median follow-up of 19 months, 26% of patients responded: 3 CR (18, 16+, and 26+ months), 2 PR (8 and 22 months) and 1 MR (36+ months). The median survival of the whole group was 20.2 months. None of the 28 patients initially included in the study presented significant toxicity. This vaccination program had specific antitumoural activity in advanced metastatic melanoma patients and was well tolerated. The clinical responses and the median survival of our group of patients, together with the low toxicity of our polyvalent vaccine, suggest that this approach could be applied to earlier metastatic melanoma patients.