Melanoma: Kruit WH

van Everdingen JJ, van der Rhee HJ, Koning CC, Nieweg OE, Kruit WH, Coebergh JW, Ruiter DJ, Anonymous00197. · Kwaliteitsinstituut voor de Gezondheidszorg CBO, Postbus 20.064, 3502 LB Utrecht. · Ned Tijdschr Geneeskd. · Pubmed #16128181 No free full text.

Abstract: The guidelines 'Melanoma' (3rd revision) are evidence-based in nature. A number of outcomes are summarised in this article. Dermatoscopy deserves a standard role in the clinical diagnosis of pigmented skin abnormalities. Pathological findings from a diagnostic excision should be recorded meticulously to include anatomical localisation, type of intervention used, excision margin, diagnosis, Breslow thickness, and the completeness of the removal. The sentinel node procedure should be reserved for patients who want to be as informed as possible about their prognosis. The procedure is not considered a part of standard diagnosis. Sentinel node assessment should include stains for specific markers and should be conducted in multiple sections. The following margins of non-affected skin are recommended for therapeutic re-excision of melanoma: in situ melanoma, 0.5 cm; Breslow thickness < or = 2 mm, 1 cm; Breslow thickness > 2 mm, 2 cm. Pathological assessment of a re-excised specimen depends on the completeness of the first excision. Systematic adjuvant treatment of patients with melanoma is not recommended outside the context of a clinical study. Patients with metastatic melanoma are preferably treated within a clinical study. Outside of a clinical study, these patients should be treated with dacarbazine. There is no evidence to suggest that survival is improved by frequent follow-up. However, follow-up can be a useful way to meet the information needs of patients and care requirements for physicians.

Van Gool AR, Kruit WH, Engels FK, Stoter G, Bannink M, Eggermont AM. · Department of Psychosocial Oncology, Erasmus University Medical Center-Daniel den Hoed Cancer Center, Rotterdam, The Netherlands. · Pharm World Sci. · Pubmed #12661471 No free full text.

Abstract: AIM: Immunotherapy with interferon-alfa (IFN-alfa) is used in a variety of diseases in- and outside clinical trials (e.g., chronic hepatitis, melanoma, chronic myelogenous leukemia, renal cell carcinoma, multiple myeloma). Treatment with IFN-alfa can cause (severe) neuropsychiatric side effects. The purpose of this article is to give an updated review of data on the incidence, manifestations and prediction of psychiatric side effects of immunotherapy with IFN-alfa. Furthermore, the article gives an overview of the management strategies and of the various theories on the pathophysiology of behavioural effects induced by cytokines. METHODS: Use was made of computerized searches and of checking cross-references of articles and book chapters. The data on the incidence, manifestations and prediction are arranged by source of information, by target symptoms and by method of ascertainment. RESULTS: Different sources of information exist, e.g. adverse event reports of clinical trials, case descriptions and research specifically targeted on neuropsychiatric side effects. IFN-alfa is capable of inducing depressive symptoms and syndromes; the evidence for the induction of other psychiatric side effects is weaker. The depressive syndromes induced by IFN-alfa are in need of a more precise characterization. The results of studies on prediction of side effects are contradictory. Guidelines on managing psychiatric side effects predominantly arise from practical experience and common sense. Patient education plays a pivotal role. At this moment, there is no comprehensive theory on the pathophysiology of cytokine-induced psychiatric side effects. CONCLUSION: There is sufficient empirical support for a causal relation between IFN-alfa and the development of depressive symptoms and syndromes. Practical management of neuropsychiatric side effects begins before the start of therapy and should consist of repeated patient education, drug treatment and supportive measures. There are diverging theories on the pathophysiological backgrounds.

Kruit WH, Eggermont AM, Stoter G. · Department of Medical Oncology, Rotterdam Cancer Institute/University Hospital Rotterdam, The Netherlands. · Ann Oncol. · Pubmed #11142493 links to  free full text

Abstract: The cytokine interferon-alpha (IFN-alpha) is increasingly prescribed for a number of indications, especially viral hepatitis and several malignancies. Two patients are described who developed Raynaud's syndrome during treatment with IFN-alpha as adjuvant therapy for high-risk melanoma. With a review of the available literature the symptomatology, possible pathophysiologic mechanisms and treatment options are discussed.

Eggermont AM, Suciu S, Santinami M, Testori A, Kruit WH, Marsden J, Punt CJ, Salès F, Gore M, Mackie R, Kusic Z, Dummer R, Hauschild A, Musat E, Spatz A, Keilholz U, Anonymous00008. · Erasmus University Medical Center, Rotterdam, Netherlands. · Lancet. · Pubmed #18620949 No free full text.

Abstract: BACKGROUND: Any benefit of adjuvant interferon alfa-2b for melanoma could depend on dose and duration of treatment. Our aim was to determine whether pegylated interferon alfa-2b can facilitate prolonged exposure while maintaining tolerability. METHODS: 1256 patients with resected stage III melanoma were randomly assigned to observation (n=629) or pegylated interferon alfa-2b (n=627) 6 mug/kg per week for 8 weeks (induction) then 3 mug/kg per week (maintenance) for an intended duration of 5 years. Randomisation was stratified for microscopic (N1) versus macroscopic (N2) nodal involvement, number of positive nodes, ulceration and tumour thickness, sex, and centre. Randomisation was done with a minimisation technique. The primary endpoint was recurrence-free survival. Analyses were done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00006249. FINDINGS: All randomised patients were included in the primary efficacy analysis. 608 patients in the interferon group and 613 patients in the observation group were included in safety analyses. The median length of treatment with pegylated interferon alfa-2b was 12 (IQR 3.8-33.4) months. At 3.8 (3.2-4.2) years median follow-up, 328 recurrence events had occurred in the interferon group compared with 368 in the observation group (hazard ratio 0.82, 95% CI 0.71-0.96; p=0.01); the 4-year rate of recurrence-free survival was 45.6% (SE 2.2) in the interferon group and 38.9% (2.2) in the observation group. There was no difference in overall survival between the groups. Grade 3 adverse events occurred in 246 (40%) patients in the interferon group and 60 (10%) in the observation group; grade 4 adverse events occurred in 32 (5%) patients in the interferon group and 14 (2%) in the observation group. In the interferon group, the most common grade 3 or 4 adverse events were fatigue (97 patients, 16%), hepatotoxicity (66, 11%), and depression (39, 6%). Treatment with pegylated interferon alfa-2b was discontinued because of toxicity in 191 (31%) patients. INTERPRETATION: Adjuvant pegylated interferon alfa-2b for stage III melanoma has a significant, sustained effect on recurrence-free survival.

Bannink M, Fekkes D, Van Gool AR, Kruit WH, Sleijfer S, van der Holt B, Eggermont AM, Stoter G, Hengeveld MW. · Department of Psychiatry, Erasmus Medical Center, Rotterdam, The Netherlands. · Neuropsychobiology. · Pubmed #17873497 No free full text.

Abstract: BACKGROUND: Interferon-alpha (IFN-alpha) treatment is often associated with psychiatric side effects and has been found to lower the amount of tryptophan (TRP) available to the brain. The alterations in tryptophan metabolism might underlie the psychiatric side effects during treatment with IFN-alpha. METHODS: In this study, 43 oncology patients treated with IFN-alpha were included. In order to study de novo depressions, depressed patients at baseline were excluded. Psychiatric evaluation comprising clinical judgment combined with a structured psychiatric interview and observer-based and self-report rating scales was performed at baseline and at 4 weeks, 8 weeks and 6 months after the start of treatment with IFN-alpha, and in the case of emerging psychopathology. Blood samples were drawn at the same evaluation times and assessed for concentrations of TRP, large neutral amino acids, kynurenine, 5-hydroxyindole acetic acid, neopterin and biopterin. RESULTS: During treatment with IFN-alpha, several alterations in laboratory parameters occurred that were consistent with an increased degradation of peripheral TRP. Psychometric ratings revealed hardly any psychiatric changes. No consistent associations were found between changes in the laboratory assessments determined and the diverse psychiatric measures. CONCLUSION: In this study, IFN-alpha was found to alter TRP metabolism without inducing psychiatric side effects. Therefore, a possible relationship between TRP metabolism and depression was not substantiated by this study.

Punt CJ, Suciu S, Gore MA, Koller J, Kruit WH, Thomas J, Patel P, Lienard D, Eggermont AM, Keilholz U. · Department of Medical Oncology, St. Radboud University Nijmegen Medical Center, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. <> · Eur J Cancer. · Pubmed #17023156 No free full text.

Abstract: BACKGROUND: Chemoimmunotherapy for patients with metastatic melanoma is associated with high toxicity, and only a subset of patients will benefit. This randomised phase II study was performed with the primary objective of exploring whether two cycles of dacarbazine monotherapy could select the subset of patients that would benefit most from more intensive chemoimmunotherapy. PATIENTS AND METHODS: Patients with metastatic melanoma were randomised to either receive chemoimmunotherapy with dacarbazine, cisplatin, interferon-alpha and interleukin-2 (arm A) or initial treatment with two cycles of dacarbazine monotherapy followed irrespective of response by the same 4-drug regimen of chemoimmunotherapy (arm B). Chemoimmunotherapy was continued in the absence of disease progression for a maximum of four cycles. Primary end-point was the disease stabilisation rate. RESULTS: A total of 93 patients were randomised, and 89 patients were eligible. Disease stabilisation (complete/partial response or stable disease) was achieved in 19 patients (42.2%) in arm A and 9 patients (20.5%) in arm B. In arm B 32 of the 44 patients continued chemoimmunotherapy after two cycles of dacarbazine. Of 20 patients with progressive disease (PD) after two cycles of dacarbazine in arm B, only 2 patients achieved an objective response. Median overall survival (OS) in arms A and B was 10.5 months and 9.5 months, respectively. CONCLUSIONS: Despite a lower initial stabilisation rate, the strategy of starting with 2 courses of DTIC prior to a 4-drug regimen led to comparable median overall survival. Only few transient responses were achieved with the 4-drug regimen in patients with disease progression on DTIC, suggesting frequent cross resistance. Two cycles of dacarbazine monotherapy cannot be recommended to select patients for more intensive chemoimmunotherapy.

Kruit WH, van Ojik HH, Brichard VG, Escudier B, Dorval T, Dréno B, Patel P, van Baren N, Avril MF, Piperno S, Khammari A, Stas M, Ritter G, Lethé B, Godelaine D, Brasseur F, Zhang Y, van der Bruggen P, Boon T, Eggermont AM, Marchand M. · Erasmus Medical Center-Daniel den Hoed Cancer Center, Department of Internal Oncology, Rotterdam, The Netherlands. · Int J Cancer. · Pubmed #15945101 No free full text.

Abstract: The purpose of this phase 1/2 study was to evaluate toxicity, tumor evolution and immunologic response following administration of a fixed dose of a recombinant MAGE-3 protein by subcutaneous and intradermal routes in the absence of immunologic adjuvant. Thirty-two patients with detectable metastatic melanoma expressing gene MAGE-3 were included and 30 received at least one injection with a fixed dose of a ProtD-MAGE-3 fusion protein. The immunization schedule included 6 intradermal and subcutaneous injections at 3-week intervals. Afterward, patients without major tumor progression who required other treatments received additional vaccinations at increasing time intervals. The vaccine was generally well tolerated. Among the 26 patients who received at least 4 vaccinations, we observed 1 partial response and 4 mixed responses. For these 5 responding patients, time to progression varied from 3.5 to 51+ months. An anti-MAGE-3 CD4 T-lymphocyte response was detected in 1 out of the 5 responding patients. The majority of patients had no anti-MAGE-3 antibody response. The clinical and immunologic responses generated by the vaccine are rather limited. Nevertheless, given the potential antitumor efficacy and the very mild toxicity of vaccinations, further studies combining MAGE proteins and/or peptides with potent immunologic adjuvants are warranted, not only in metastatic melanoma, but also in the adjuvant setting.

Bannink M, Kruit WH, Van Gool AR, Mulder PG, Sleijfer S, Eggermont AM, Stoter G, Fekkes D. · Department of Psychiatry, Erasmus MC-Daniel den Hoed Cancer Center, P.O. Box 5201, 3008 AE Rotterdam, The Netherlands. · Prog Neuropsychopharmacol Biol Psychiatry. · Pubmed #15610952 No free full text.

Abstract: Depression and cognitive disturbance are well-known neuropsychiatric side effects of therapy with interferon-alfa (IFN-alfa). Aggression and irritability are also reported as side effects. Probably, central nervous system (CNS) serotonergic dysfunction is one of the underlying pathophysiological mechanisms of IFN-alfa-induced neuropsychiatric toxicity. Platelet activity of monoamine oxidase-B (MAO; EC1.4.3.4) is a possible indicator of central serotonergic function. Moreover, low platelet MAO activity is linked to impulsiveness, addiction and personality disorder. In this exploratory study in 17 high-risk melanoma patients, platelet counts, whole blood MAO, and platelet MAO activity were measured before and during therapy with IFN-alfa. Patients were randomized to treatment either with pegylated IFN-alfa (PEG-IFN-alfa) once a week at a dose of 6 microg/kg/week subcuteanously (s.c.) during 8 weeks, followed by a maintenance treatment of 3 microg/kg/week s.c. for a total of 5 years, or to observation only. Blood samples were taken at baseline, 4 and 8 weeks and 3 months. During treatment with IFN-alfa, platelet counts decreased at 4 and 8 weeks and 3 months, while platelet MAO activity increased, both compared to baseline and compared to non-treated controls. Compared to non-treated controls, platelet MAO activity increased with 86.4% (95 CI: 52.9-127.2). No significant changes in platelet MAO activity were observed in the control group. This indicates that platelet MAO activity is influenced by IFN-alfa. Since platelet MAO activity is a model for CNS MAO-B activity, it may be speculated that CNS MAO-B activity will also be increased. This could influence serotonin (5-HT) metabolism and thereby contribute to the development of psychiatric disturbance. However, a preferential inhibition of platelet production cannot be ruled out. Hypothetically, the antiproliferative effects of IFN-alfa could interfere more strongly with the synthesis of platelets than with the synthesis of mitochondria. In that case, increased platelet MAO activity reflects an increased number of mitochondria per platelet.

Van Gool AR, van Ojik HH, Kruit WH, Bannink M, Mulder PG, Eggermont AM, Stoter G, Fekkes D. · Department of Psychiatry, Erasmus MC-Daniel den Hoed Cancer Center, Rotterdam, The Netherlands. · Anticancer Drugs. · Pubmed #15205601 No free full text.

Abstract: Our objective was to study the influence of pegylated interferon-alpha2b (PEG-IFN-alpha) on the metabolism of amino acids and pteridines. We used an exploratory study into plasma concentrations of large neutral amino acids, 5-hydroxyindolacetic acid (5-HIAA), total biopterin (BIOP) and neopterin (NEOP) in 40 high-risk melanoma patients. Patients were randomized to treatment with PEG-IFN-alpha once a week in a dose of 6 microg/kg/week s.c. during 8 weeks, followed by a maintenance treatment of 3 microg/kg/week s.c. or to observation only. We found that treatment with PEG-IFN-alpha decreases tryptophan (TRP) concentrations in the first 3 months of treatment to a maximum of 25.3% compared to controls [95% confidence interval (CI): 14.9 to 34.4]. The TRP:LNAA ratio, an index for the availability of TRP to the central nervous system (CNS), decreases during 6 months with 18.8% (95% CI: 11.9 to 25.2). Concentrations of NEOP rose; however, concentrations of BIOP, the sum of tetrahydrobiopterin [BH4] and its oxidative products, did not decrease. The ratio of phenylalanine to tyrosine was increased with 11.7% (95% CI: 1.0 to 23.5) during 6 months. We conclude that, like conventional IFN-alpha, PEG-IFN-alpha lowers TRP concentrations and decreases the availability of TRP to the CNS. PEG-IFN-alpha has a similar influence on pteridine metabolism as standard IFN-alpha. If a lowered availability of TRP and a consequent decrease of serotonergic neurotransmission are indeed a mechanism underlying neuropsychiatric side-effects of IFN-alpha, patients on PEG-IFN-alpha are not at a lower risk of developing neuropsychiatric side-effects as patients on conventional IFN-alpha.

Van Gool AR, Fekkes D, Kruit WH, Mulder PG, Ten Hagen TL, Bannink M, Maes M, Eggermont AM. · Department of Psychosocial Oncology, Erasmus Medical Center - Daniel den Hoed Cancer Center, P.O. Box 5201, 3008 AE, Rotterdam, The Netherlands. · Psychiatry Res. · Pubmed #12860366 No free full text.

Abstract: Immunotherapy with interferon-alpha (IFN-alpha) induces neuropsychiatric side effects, most notably depression. One of the presumed pathophysiological mechanisms is an effect on tryptophan metabolism. As tryptophan is the precursor of serotonin, decreased availability of tryptophan to the central nervous system could result in serotonin deficiency. Tetrahydrobiopterin (BH((4))) is a cofactor for one of the enzymes synthesizing serotonin. We conducted an exploratory study into the serum concentrations of large neutral amino acids (AA), biopterin (BIOP) and neopterin (NEOP), of 67 patients with high-risk melanoma, who were either treated with two different doses of IFN-alpha or were part of an observation-only control group. We found evidence for IFN-alpha to decrease concentrations of all AA except phenylalanine. The decrease in tryptophan concentration was most prominent and consistent. These changes persisted throughout a year of maintenance treatment. Concentrations of NEOP rose sharply, whereas, those of BIOP did not change. Except for the increase in NEOP and the increase in the ratio between phenylalanine (PHE) and tyrosine (TYR), no support for derangement in BH((4)) metabolism was found. The increase in the ratio between PHE and TYR suggests inhibition of the enzyme phenylalanine hydroxylase. Patients with IFN-alpha induced anxiety and depression had higher pretreatment concentrations of NEOP. Changes in tryptophan metabolism may play a role in the pathophysiology of the neuropsychiatric side effects of IFN-alpha, and further research into the predictive potential of NEOP is warranted.

Kivelä T, Suciu S, Hansson J, Kruit WH, Vuoristo MS, Kloke O, Gore M, Hahka-Kemppinen M, Parvinen LM, Kumpulainen E, Humblet Y, Pyrhönen S. · Ocular Oncology Service, Department of Ophthalmology, Helsinki University Central Hospital, Haartmaninkatu 4, PL 220, Finland. · Eur J Cancer. · Pubmed #12736111 No free full text.

Abstract: This EORTC multicentre study analysed the efficacy and tolerability in patients with metastatic uveal melanoma of BOLD chemotherapy in combination with recombinant interferon alpha-2b. The dose of bleomycin was 15 mg on days 2 and 5, of vincristine 1 mg/m(2) on days 1 and 4, of lomustine 80 mg on day 1, and of dacarbazine (DTIC) 200 mg/m(2) on days 1-5, given every 4 weeks for a minimum of two cycles. Subcutaneous (s.c.) interferon alpha-2b at a dose of 3 x 10(6) IU was initiated on day 8 of the first cycle, and continued at a dose of 6 x 10(6) IU three times per week after 6 weeks. A median of two cycles were administered to 24 patients (median age 60.5 years). None achieved an objective response (0%; 95% Confidence Interval (CI): 0-14), 2 (8.3%) remained stable, 20 showed progression, and 2 (8.3%) were invaluable. The median progression-free survival was 1.9 months (95% CI: 1.8-3.4) and overall survival 10.6 months (95% CI: 6.9-16.4). Overall survival improved with increasingly favourable pretreatment characteristics (median, 14.7 versus 6.9 versus 6.0 months for Helsinki University Central Hospital (HUCH) Working Formulation stages IVBa, IVBb and IVBc, respectively; P=0.018). Grade 3 alopecia and neurotoxicity occurred in 13% of the patients. This multicentre study did not confirm earlier reports that BOLD with human leucocyte or recombinant interferon would induce at least 15% objective responses in metastatic uveal melanoma.

Marchand M, Punt CJ, Aamdal S, Escudier B, Kruit WH, Keilholz U, Håkansson L, van Baren N, Humblet Y, Mulders P, Avril MF, Eggermont AM, Scheibenbogen C, Uiters J, Wanders J, Delire M, Boon T, Stoter G. · Ludwig Institute for Cancer Research, Brussels Branch, Brussels, Belgium. · Eur J Cancer. · Pubmed #12504661 No free full text.

Abstract: Fifty-seven patients with MAGE-3-positive measurable metastatic cancer, most of them with melanoma, were vaccinated with escalating doses of a recombinant MAGE-3 protein combined with a fixed dose of the immunological adjuvant SBAS-2, which contained MPL and QS21. The immunisation schedule included 4 intramuscular (i.m.) injections at 3-week intervals. Patients whose tumour stabilised or regressed after 4 vaccinations received 2 additional vaccinations at 6-week intervals. The vaccine was generally well tolerated. Among the 33 melanoma patients who were evaluable for tumour response, we observed 2 partial responses, 2 mixed responses and 1 stabilisation. Time to progression in these 5 patients varied from 4 to 29 months. In addition, a partial response lasting 10 months was observed in 1 of the 3 metastatic bladder cancer patients included. None of the tumour responses described above involved visceral metastases. Immunological responses to the vaccine will be reported separately.

Stam TC, Swaak AJ, Kruit WH, Eggermont AM. · Department of Surgical Oncology, University Hospital Rotterdam, Daniel den Hoed Cancer Centre, 3008 AE Rotterdam, The Netherlands. · Eur J Clin Invest. · Pubmed #11886436 No free full text.

Abstract: BACKGROUND: Adult onset of Still's disease is characterized by very high serum ferritin levels, in disproportion with other acute phase proteins (APPs). Because interferon-alpha (IFN-alpha) was observed to cause hyperferritinaemia in three healthy people without increase of other APPs, we hypothesized that IFN-alpha stimulates specifically the synthesis of ferritin. To test this hypothesis, we studied ferritin and other APP levels in patients treated with IFN-alpha. PATIENTS AND METHODS: Fifteen patients treated with IFN-alpha-2b 3-5 times a week, as adjuvant treatment after excision of a high-risk melanoma, were compared with six patients without adjuvant treatment (controls). Serum levels of C-reactive protein (CRP) and secretory phospholipase A2 (sPLA2) were measured using ELISA. Levels of ferritin, alpha1-acid glycoprotein (AAG) and albumin were determined by nephelometry. RESULTS: CRP was decreased significantly after 4 weeks (P < 0.01) in the patients treated with IFN-alpha compared with the nontreated patients, after 6 months of treatment it was still decreased although not significantly. Ferritin increased significantly in the IFN-alpha-treated patients: 187% of pretreatment value after 4 weeks and 217% after 6 months (P < 0.01), while ferritin levels decreased in the nontreated patients. AAG increased significantly in IFN-alpha-treated patients (107, 114%) compared with the control-patients (91, 76%) but differences were less compared with CRP and ferritin. sPLA2 had a variable course, while albumin remained constant within the normal range in both patient groups. CONCLUSIONS: IFN-alpha induced a significant increase in ferritin, with a significant decrease in CRP, little increase in AAG, varying response of sPLA2 and no change in albumin. This finding suggests a specific role for IFN-alpha in the synthesis or secretion of ferritin. This mechanism may also be involved in the marked hyperferritinaemia in adult onset of Still's disease.

Bouwhuis MG, Suciu S, Collette S, Aamdal S, Kruit WH, Bastholt L, Stierner U, Salès F, Patel P, Punt CJ, Hernberg M, Spatz A, ten Hagen TL, Hansson J, Eggermont AM, Anonymous00068. · Department of Surgical Oncology, Erasmus University MC-Daniel den Hoed Cancer Center, 301 Groene Hilledijk, Rotterdam, the Netherlands. · J Natl Cancer Inst. · Pubmed #19509353 No free full text.

Abstract: BACKGROUND: Appearance of autoantibodies and clinical manifestations of autoimmunity in melanoma patients treated with adjuvant interferon (IFN)-alpha2b was reported to be associated with improved prognosis. We assessed the association of the appearance of autoantibodies after initiation of treatment with recurrence-free interval in two randomized trials that compared intermediate doses of IFN with observation for the treatment of melanoma patients. METHODS: Serum levels of anticardiolipin, antithyroglobulin, and antinuclear antibodies were determined using enzyme-linked immunosorbent assays in 187 and 356 patients in the European Organization for Research and Treatment of Cancer (EORTC) 18952 and Nordic IFN trials, respectively, immediately before and up to 3 years after random assignment. The association of the presence of at least one of the three autoantibodies with risk of recurrence was assessed by three Cox models in patients negative for all three autoantibodies at baseline (125 from the EORTC 18952 trial and 230 from the Nordic IFN trial): 1) a model that considered appearance of autoantibodies as a time-independent variable, 2) one that considered a patient autoantibody positive once a positive test for an autoantibody was obtained, and 3) a model in which the status of the patient was defined by the most recent autoantibody test. All statistical tests were two-sided. RESULTS: When treated as a time-independent variable (model 1), appearance of autoantibodies was associated with improved relapse-free interval in both trials (EORTC 18952, hazard ratio [HR] = 0.41, 95% confidence interval [CI] = 0.25 to 0.68, P < .001; and Nordic IFN, HR = 0.51, 95% CI = 0.34 to 0.76, P < .001). However, on correction for guarantee-time bias, the association was weaker and not statistically significant (model 2: EORTC 18952, HR = 0.81, 95% CI = 0.46 to 1.40, P = .44; and Nordic IFN, HR = 0.85, 95% CI = 0.55 to 1.30, P = .45; model 3: EORTC 18952, HR = 1.05, 95% CI = 0.59 to 1.87, P = .88; and Nordic IFN, HR = 0.78, 95% CI = 0.49 to 1.24, P = .30). CONCLUSIONS: In two randomized trials of IFN for the treatment of melanoma patients, appearance of autoantibodies was not strongly associated with improved relapse-free interval when correction was made for guarantee-time bias.

Kruit WH, Anonymous00425. · Erasmus MC-Daniel den Hoed Oncologisch Centrum, afd. Interne Oncologie, Postbus 5201, 3075 EA Rotterdam. · Ned Tijdschr Geneeskd. · Pubmed #18402325 No free full text.

Abstract: The sentinel lymph node procedure provides prognostic information for patients with cutaneous melanoma, but its therapeutic implications were unclear until now. The international multicentre selective lymphadenectomy trial has shown that sentinel lymph node biopsy confers no survival benefit for patients with cutaneous melanoma. The presence of melanoma cells in a sentinel lymph node, however, has prognostic value. Therefore, the Dutch Melanoma Working Group recommends discussing this procedure with all patients with melanoma of Breslow thickness 1.2-3.5 mm. There is no evidence to suggest that the sentinel lymph node procedure is beneficial when the Breslow thickness is less than 1.2 mm or greater than 3.5 mm.

Bannink M, Kruit WH, Van Gool AR, Sleijfer S, van der Holt B, Eggermont AM, Stoter G, Hengeveld MW. · Dept. of Psychiatry, Erasmus Medical Center, Rotterdam, the Netherlands. · Psychosomatics. · Pubmed #18212177 links to  free full text

Abstract: Interferon-alpha (IFN-alpha) treatment in both oncological and hepatological settings is associated with depression. If IFN-alpha treatment induces depression in high numbers, it could serve as a model for studying the pathophysiology of depression, in general. The authors therefore studied 43 oncology patients treated with standard or pegylated IFN-alpha with baseline psychiatric assessment and at regular time-points in the first 6 months of treatment. Apart from a severe depression because of brain metastases, authors observed only two clinically relevant depressive states. Contrary to findings in most of the literature, most depressive episodes in this study were self-limiting and short-lasting and were associated with either episodes of flu-like symptoms common at the start of the treatment or with concurrent psychosocial events. In the group as a whole, scores on both observer-based and self-report rating scales did not show clinically relevant changes. The results of this study indicate that IFN-alpha treatment is not suitable as a study model for depression in general.

Fekkes D, Bannink M, Kruit WH, Van Gool AR, Mulder PG, Sleijfer S, Eggermont AM, Stoter G. · Department of Neuroscience, Erasmus MC, The Netherlands. · Amino Acids. · Pubmed #16622596 No free full text.

Abstract: 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.

Van Gool AR, Van Ojik HH, Kruit WH, Mulder PG, Fekkes D, Bannink M, Scharpé S, Stoter G, Eggermont AM, Maes M, Verkerk R. · Department of Psychiatry, Erasmus MC-Daniel den Hoed Cancer Center, Rotterdam, The Netherlands. · J Interferon Cytokine Res. · Pubmed #15296652 No free full text.

Abstract: Immunotherapy with interferon-alpha (IFN-alpha) induces neuropsychiatric side effects, most notably depression. In hepatitis patients treated with IFN-alpha, severity of depression correlates with a decrease in serum activity of dipeptidyl peptidase IV (DPP-IV, EC 3.4.14.5), a membrane-bound protease involved in the cleavage of cytokines and neuroactive peptides. Abnormal serum activity of the cytosolic peptidase prolyl endopeptidase (PEP, EC 3.4.21.26, postprolyl cleaving enzyme, prolyl oligopeptidase) has been documented in patients with a variety of psychiatric disorders, most consistently in mood disorders. The serum activity of PEP and DPP-IV was measured before and after 4 weeks of high-dose induction treatment with IFN-alpha in 18 patients with high-risk melanoma. In this exploratory study, we show a clear decrease in the serum activity of PEP after 4 weeks of treatment with IFN-alpha. This decrease was not related to changes in hematologic parameters. In contrast, serum activity of DPP-IV did not change. Further studies focusing on a possible role of PEP in the pathophysiology of IFN-alpha-induced depression are warranted.