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SummaryImmunotherapy with interferon-alfa has become standard therapy in selected patients with viral hepatitis and chronic myelogenous leukemia. In addition, it is used in a variety of other diseases, both as standard therapy and in clinical trials. Its use is expected to expand in the following decade. Interferon can cause (severe) neuropsychiatric side effects. These side effects are discussed. Adequate management of these side effects is important, as is close collaboration between the oncologist and the psychiatrist. The cornerstone of management is patient education: this prevents interruption of therapy by patients who were not warned for neuropsychiatric side effects. Furthermore, patients should report in case of rapidly arising mood disorders. Interferon-alfa induced mood disorder is reported to be treatable. Three case descriptions illustrate this, but also illustrate some limits to successful treatment.

S100B is a prognostic factor for melanoma as elevated levels correlate with disease progression and poor outcome. We determined its prognostic value based on updated information using serial determinations in stage IIb/III melanoma patients. 211 Patients who participated in the EORTC 18952 trial, evaluating efficacy of adjuvant intermediate doses of interferon alpha 2b (IFN) versus observation, entered a corollary study. Over a period of 36 months, 918 serum samples were collected. The Cox time-dependent model was used to assess prognostic value of the latest (most recent) S100B determination. At first measurement, 178 patients had S100B values = 0.2 mu g/l. Within the first group, 61 patients had, later on, an increased value of S100B (>= 0.2 mu g/l). An initial increased value of S100B, or during follow-up, was associated with worse distant metastasis-free survival (DMFS); hazard ratio (HR) of S100B >= 0.2 versus S100B < 0.2 was 5.57 (95% confidence interval (CI) 3.81-8.16), P < 0.0001, after adjustment for stage, number of lymph nodes and sex. In stage lib patients, the HR adjusted for sex was 2.14 (95% CI 0.71, 6.42), whereas in stage III, the HR adjusted for stage, number of lymph nodes and sex was 6.76 (95% CI 4.50-10.16). Similar results were observed regarding overall survival (OS). Serial determination of S100B in stage IIb-III melanoma is a strong independent prognostic marker, even stronger compared to stage and number of positive lymph nodes. The prognostic impact of S100B >= 0.2 mu g/l more pronounced in stage III disease compared with stage IIb. (C) 2010 Elsevier Ltd. All rights reserved.

Aim of the study Results on tumour characteristics and survival of hereditary breast cancer (BC), especially on BRCA2-associated BC, are inconclusive. The prognostic impact of the classical tumour and treatment factors in hereditary BC is insufficiently known. Methods We selected 103 BRCA2-, 223 BRCA1- and 311 non-BRCA1/2 BC patients (diagnosis 1980–2004) from the Rotterdam Family Cancer Clinic. To correct for longevity bias, analyses were also performed while excluding index patients undergoing DNA testing ⩾2 years after BC diagnosis. As a comparison group, 759 sporadic BC patients of comparable age at and year of diagnosis were selected. We compared tumour characteristics, the occurrence of ipsilateral recurrence (LRR) and contralateral BC (CBC) as well as distant disease-free (DDFS), BC-specific (BCSS) and overall survival (OS) between these groups. By multivariate modelling, the prognostic impact of tumour and treatment factors was investigated separately in hereditary BC. Results We confirmed the presence of the particular BRCA1-phenotype. In contrast, tumour characteristics of BRCA2-associated BC were similar to those of non-BRCA1/2 and sporadic BC, with the exception of a high risk of CBC (3.1% per year) and oestrogen-receptor (ER)-positivity (83%). No significant differences between BRCA2-associated BC and other BC subgroups were found with respect to LRR, DDFS, BCSS and OS. Independent prognostic factors for BC-specific survival in hereditary BC (combining the three subgroups) were tumour stage, adjuvant chemotherapy, histologic grade, ER status and a prophylactic (salpingo-)oophorectomy. Conclusions Apart from the frequent occurrence of contralateral BC and a positive ER-status, BRCA2-associated BC did not markedly differ from other hereditary or sporadic BC. Our observation that tumour size and nodal status are prognostic factors also in hereditary BC implies that the strategy to use these factors as a proxy for ultimate mortality appears to be valid also in this specific group of patients.

Cutaneous malignant melanoma has been characterized by rapid and steady increases in incidence and mortality in white populations. Some reports mentioned declining trends in the mean thickness of these tumours, but other studies suggested a stable incidence of thick melanomas. The aim of this study was to describe the stage distribution of melanomas across Europe, with particular reference to temporal trends. Twenty-three cancer registries provided data sets containing information on stage and histology, 21 of which were used for a general description and nine for trends analyses. Despite a preponderance of missing data, interesting patterns emerged: a less favourable stage distribution in populations with relatively low incidence, but high case-fatality rates, and a favourable trend in stage and histology distribution over time, including a shift from later to earlier stages in recent years. Early detection campaigns raising awareness for thin lesions can potentially improve melanoma survival rates. Monitoring of stage-specific trends in melanoma incidence can assess the impact of such interventions. This paper demonstrates the potential utility of high-quality, timely cancer registry data in pursuing such public health objectives and addresses the need for more complete information on diagnostic features of melanoma patients. This will allow more informative evaluations of preventive strategies.

Between 1988 and 1996, the European Organisation for Research and Treatment of Cancer Melanoma Group (EORTC-MG) performed a prospective, randomised phase III adjuvant trial to evaluate the efficacy and toxicity of low dose recombinant interferon-alpha 2 b (rIFN-alpha2b) (1 MU) or recombinant interferon gamma (rIFN-gamma), (0.2 mg) both given subcutaneously (s.c.), every other day (qod), for 12 months in comparison with an untreated control group. The German Cancer Society (DKG) added a fourth arm with Iscador M, a popular mistletoe extract. High-risk stage II patients (thickness >3 mm) and stage III patients (positive lymph nodes) without distant metastasis were randomised and followed until their first progression or death. An intention-to-treat analysis was performed. From 1988 to 1996, a total of 830 patients were randomised: 423 in the three-arm EORTC 18871 trial and 407 patients in the four-arm DKG 80-1 trial. The median follow-up was 8.2 years and a total of 537 relapses and 475 deaths were reported. At 8 years, the disease-free interval (DFI) rate was 32.4% and the overall survival (OS) rate was 40.0%. In terms of the DFI, the hazard ratio estimates (95% Confidence Intervals (CI)) were: 1.04 (0.84, 1.30) for the comparison of rIFN-alpha2b versus control, 0.96 (0.77, 1.20) for rIFN-gamma versus control, and 1.32 (0.93, 1.87) for Iscador M versus control. In terms of OS, the corresponding estimates (95% CI) for the 3 treatment comparisons were: for IFN-alpha2b 0.96 (0.76, 1.21), for rIFN-gamma 0.87 (0.69, 1.10) and for Iscador M 1.21 (0.84, 1.75), respectively. The results show no clinical benefit for adjuvant treatment with low dose rIFN-alpha2b or rIFN-gamma or with Iscador M in high-risk melanoma patients.

Angiostatin is a tumor-derived angiogenesis inhibitor consisting of an internal fragment of plasminogen. Little is known about the production of angiostatin by human tumors. In this study, we examined the in vitro angiostatin-generating capacities of a panel of human tumor cell lines (total n = 75) and the proteolytic molecule(s) involved. Angiostatin formation was determined by assessing the level of plasminogen digestion in conditioned medium by Western-blot analysis. We found that the capacity to produce angiostatin is a common feature of many cell lines, depending on the tumor type. All 6 bladder-carcinoma and 6 out of 7 prostate-carcinoma cell lines showed intermediate to potent angiostatin-generating activity. In contrast, only 2 out of 7 colon-carcinoma and 2 out of 9 renal-cell carcinoma cell lines were able to generate angiostatin at intermediate levels. Out of 25 melanoma cell lines, only one line failed to generate angiostatin. In the other cell-line groups (cervix, breast and ovary), angiostatin formation varied. Remarkably, angiostatin bands were not of equal size in all plasminogen digests. Since reported data have indicated that plasminogen activators (uPA and tPA) were able to excise the angiostatin fragment from the plasminogen parent molecule via plasmin generation, we determined levels of uPA and tPA and PAI-1 antigen in the conditioned media, and correlated the results with angiostatin-generating capacity. Whereas prostate- and bladder-carcinoma lines capable of generating high levels of angiostatin showed high uPA levels, angiostatin generation in melanoma cell lines was correlated with tPA levels. Generally, angiostatin non-producers did not express uPA or tPA. In 6 out of 75 cell lines, however, we found angiostatin generation combined with low or absent levels of plasminogen activator, suggesting the involvement of alternative proteolytic pathways in the generation of angiostatin. Int. J. Cancer 86:760–767, 2000. © 2000 Wiley-Liss, Inc.

Trials in high-risk melanoma patients evaluating the role of postoperative adjuvant treatment with interferons or other cytokines, ganglioside-based vaccines, or vaccines based on melanoma cells are ongoing or planned internationally. In Europe, the two largest randomised trials are carried out by the European Organization for Research and Treatment of Cancer-Melanoma Cooperative Group (EORTC-MCG). In stage IIA patients (T3N0M0) with a moderate risk of micrometastatic disease (35-40%), Trial 18,961 compares observation with ganglioside GM2 vaccination. This trial will be activated during the spring of 1998 and is expected to enrol 1000 patients. In stage IIB-IIIB (T4N0M0-TxN12M0) patients with a high risk of micrometastatic disease (approximately 80%), trial 18,952 compares observation with adjuvant therapy using two intermediate dosage regimens of interferon alfa-2b (IFN-alpha 2b). These trials and the philosophy of the EORTC-MCG programme allow more toxic treatment regimens to be investigated in patients with high-risk disease and only treatments with minimal toxicity to be evaluated in patients with moderate- to low-risk disease. Recently completed and other ongoing trials also are discussed. Overall, if clinical efficacy is demonstrated, the toxicity, impact on quality of life and treatment costs determine the acceptance and applicability of a treatment.

Twenty-nine stage IIIA/B melanoma patients treated by isolated limb perfusion (ILP) with a high dose of recombinant human tumour necrosis factor alpha (rHuTNF alpha), interferon gamma (IFN gamma), and melphalan were histologically documented with emphasis on therapy-induced changes of the tumour vasculature. Sequential biopsies were taken at various intervals before and after the treatment to compare the morphological change. In order to visualize microvascular changes, immunostaining was performed for von Willebrand factor (VWF), type IV collagen, alpha-smooth muscle actin, endothelial antigen PAL-E, tissue factor, CD41 (thrombocyte marker), and fibrin. In biopsies prior to perfusion, necrosis, haemorrhage, and fibrin thrombi were not found. Within 3 h following triple combination therapy, a change in the distribution of VWF staining occurred, from a discrete endothelial pattern in the untreated lesions to a fuzzy perivascular and subepidermal pattern in the treated lesions. Within 24 h, this was accompanied by intravascular thrombocyte aggregation and erythrostasis, in the absence of tissue factor and fibrin deposits. These findings indicate that the thrombocyte aggregation observed is not caused by local procoagulant activity, but is rather the result of the therapy-associated vascular damage or haemostasis. Although it is difficult to derive the dynamics of this process from static images, we assume that TNF alpha induced endothelial cell damage, leading to VWF release. Release VWF may play a role in the adhesion between thrombocytes and the damaged endothelium or the denuded subendothelium. As a consequence, the blood flow is impaired, leading to congestion and oedema, compatible with an early stage of haemorrhagic infarction.

We present survival outcomes of patients registered in the Dutch population-based Eindhoven Cancer Registry (ECR).Data on patients diagnosed with a melanoma between 1980 and 2002 were obtained from the ECR. Data on vital status up to 1 January 2005 were obtained, up-to-date survival rates were calculated using period analysis. Multivariate analyses were carried out using Cox proportional hazards model.Ten-year crude survival rates were 82% for women and 60% for men (P0.05). Thin melanomas (Breslow thicknessor= 2.0 mm) had 5-year crude survival rates74%, for melanomas4.0 mm these rates were65% (P0.05). In the early 1980s, 5-year relative survival rates were 84% and 62% for young (60 years) women and men, and 66% and 69%, respectively, for the elderly (aged 60+). In the period 2000-2002, these rates had improved to90% for females and to72% for males. Multivariate analyses showed increased hazard ratios with increasing age and Breslow thickness, being male, having a melanoma on the trunk or unknown sites and having a nodular melanoma.Despite the absence of improvements in treatment options for melanoma, survival improved significantly, except for elderly males.

The aim of this study was to evaluate the effect of pegylated interferon-alpha (PEG-IFN-alpha) on the plasma citrulline/arginine ratio, regarded as an index of nitric oxide (NO) synthesis, in patients with high-risk melanoma. Forty patients were randomly assigned to either PEG-IFN-alpha treatment (n = 22) or to observation only (control group, n = 18). The treatment group received 6 microg PEG-IFN-alpha/kg once a week during 8 weeks, followed by a maintenance dose of 3 microg/kg/wk. Blood was collected at different time points, plasma concentrations of citrulline and arginine were measured and the ratio of citrulline/arginine was calculated. Patients treated with PEG-IFN-alpha showed a significant decrease in the concentrations of citrulline and in the citrulline/arginine ratio during the whole study period, both compared to baseline values and to the control group. The data suggest that therapy with PEG-IFN-alpha results in a marked decrease in the synthesis of NO in melanoma patients.

Rising trends in the incidence of and mortality from cutaneous melanoma in the Netherlands: a Northwest to Southeast gradient?de Vries E, Schouten LJ, Visser O, Eggermont AM, Coebergh JW; Working Group of Regional Cancer Registries.Department of Public Health, Erasmus Medical Centre, Dr Molewaterplein 50, 3015 GD Rotterdam, The Netherlands. e.devries@erasmusmc.nlThe aim of this study was to determine characteristics of the trends in incidence of and mortality from cutaneous malignant melanoma in The Netherlands. We used incidence data from the Netherlands Cancer Registry since 1989 and the causes of death registry of Statistics Netherlands since 1950. Data were age-adjusted and age-specific rates were calculated. Age-period-cohort modelling was applied to the mortality data. Between 1989 and 1998, age-adjusted incidence rates increased, mainly among those aged 45 years and older. Incidence rates were highest in the North-West and lowest in the South-East. Mortality rates increased in all age-categories, but more so among males than females. For women, an age-period model fitted the data, with decreasing relative risks after 1972. Age-period-cohort models were needed for males. The most likely explanation for the higher incidence is increasing intermittent over-exposure to ultraviolet (UV) radiation. The regional differences in melanoma incidence rates would correspond with host characteristics opportunities for and recreational exposure. Melanomas were detected at earlier stages in females, possibly explaining the flattening out of the female mortality rates

Aims: Isolated limb perfusion (ILP) with recombinant tumour necrosis factor-alpha (rTNF-α) and melphalan has recently been reported to induce major tumour responses and permit limb salvage in over 80% of patients with unresectable soft-tissue sarcomas of the extremities. We investigated whether TNF-based ILP could allow limb-sparing surgery in patients with primary, recurrent or metastatic bone sarcoma to the lower extremity who met the criteria for an amputation and had failed or refused chemotherapy. Methods: From August 1992 to December 1997, we employed ILP with rTNF-α and melphalan in 13 patients with unresectable bone sarcoma of the lower extremity, all of whom were candidates for amputation. The aim was to reduce tumour size and allow the performance of a limb-sparing surgery (LSS). Results: Following ILP, none of the patients had severe local toxicity and only one patient experienced significant systemic side-effects. LSS was subsequently performed in nine of the 13 patients. LSS was feasible in an additional three patients but was not performed because of the emergence of diffused metastatic disease. Conclusions: ILP with rTNF-α and melphalan can allow limb salvage in patients wih locally advanced bone sarcomas who had failed standard treatment options. Its potential role in the treatment of unresectable bone sarcomas of the extremities merits further evaluation.

A 57-year-old woman presented with the second recurrence of a high-grade malignant fibrous histiocytoma of the right foot, following previous local resection plus curative adjuvant radiotherapy. The first recurrence of the lesion was treated by isolated limb perfusion with cisplatin; the second recurrence was treated by isolated limb perfusion with tumor necrosis factor, interferon, and melphalan. The tumor and the area that had been irradiated showed a bluish color a few hours after tumor necrosis factor perfusion. Amputation of the right foot and leg below the knee had to be performed because of severe necrosis. ( Arch Surg. 1996;131:672-674 )

From 1978 to 1990, 32 patients with Clark V melanoma were treated by wide excision of the primary and adjuvant regional isolated perfusion with melphalan. M.D. Anderson stage of disease was stage I in 22 and stage IIIb in 10 patients. Five-year survival rates were 58% and 27%, respectively. Seven patients developed a recurrence in the perfused limb [stage I, 2, stage IIIb, 5 patients (P = 0.03)], and 4 of 17 patients developed regional lymph node metastases. Of the well-known prognostic variables, only ulceration of the primary tumor significantly influenced survival (P = 0.03). We did not see any improvement in survival rates compared with literature data on nonperfused patients. In the absence of data on locoregional recurrence rates in nonperfused Clark V melanoma patients, we cannot say whether adjuvant perfusion diminished this risk. Therefore, the results of the prospective randomized EORTC/WHO trial in primary high-risk extremity melanoma have to be awaited.

8512 Background: SN status as the important prognostic factor reflects the likelihood of metastatic melanoma and the MSLT-1 trial showed similar 5ys-survival rates of ∼85% both in the SN-staged group and in the watch&wait group. SN-staging far outperforms PET-scanning, since PET is only reliable for detection of metastatic lesions > 125 mm3. SN-staging is an invasive procedure and better screening methods are required to identify early disease in SNs. This ongoing study examines the role of US to demonstrate SN metastasis thus avoiding surgical SN- staging in a proportion of melanoma pts. Methods: In this prospective study 503 consecutive melanoma pts. underwent scintigraphy and then US-exam prior to scheduled SLNB. When US was suspicious for malignant deposits in the SN, pts underwent a FNAC. So far we determined outcome in 400 AJCC staged pts (median Br 2.7 mm). Interim FU-data are updated until 10/06 (mean/median FU 26/24 (1 - 64) mo. For pts with a positive SN we considered the pre-SN US/US-FNAC pos. if either US and/or FNAC were positive. If both were only suspicious, it was considered negative. Results: US identified the SN in 52/80 (86%). Specificity was 99% (317/320) with a PPV of 95% and NPV of 92%. SN identification rate by FNAC increased from 40% in stage pT1a/b to 79% in stage pT4a/b according to the higher probability for nodal disease in higher pT stages (4% in pT1ab vs 57% in pT4ab). FNAC became more sensitive with increasing tu load: SN with deposits of 0.50–1.99 mm were verified in 13/25 (52%), whereas with deposits > 2 mm in 13/16 (83%). 80/400 SNs were histologically malignant with 15/80 (22%) submicroscopic involvement ( No significant financial relationships to disclose.