An iterative Multiscale Finite-Volume algorithm converging to the exact solution

The multiscale finite volume (MsFV) method has been developed to efficiently solve large heterogeneous problems (elliptic or parabolic); it is usually employed for pressure equations and delivers conservative flux fields to be used in transport problems. The method essentially relies on the hypothesis that the (fine-scale) problem can be reasonably described by a set of local solutions coupled by a conservative global (coarse-scale) problem. In most cases, the boundary conditions assigned for the local problems are satisfactory and the approximate conservative fluxes provided by the method are accurate. In numerically challenging cases, however, a more accurate localization is required to obtain a good approximation of the fine-scale solution. In this paper we develop a procedure to iteratively improve the boundary conditions of the local problems. The algorithm relies on the data structure of the MsFV method and employs a Krylov-subspace projection method to obtain an unconditionally stable scheme and accelerate convergence. Two variants are considered: in the first, only the MsFV operator is used; in the second, the MsFV operator is combined in a two-step method with an operator derived from the problem solved to construct the conservative flux field. The resulting iterative MsFV algorithms allow arbitrary reduction of the solution error without compromising the construction of a conservative flux field, which is guaranteed at any iteration. Since it converges to the exact solution, the method can be regarded as a linear solver. In this context, the schemes proposed here can be viewed as preconditioned versions of the Generalized Minimal Residual method (GMRES), with a very peculiar characteristic that the residual on the coarse grid is zero at any iteration (thus conservative fluxes can be obtained).

Y-90 Ibritumomab Tiuxetan (Zevalin (R)) Consolidation of First Remission In Advanced Stage Follicular Non Hodgkin's Lymphoma Updated Results After a Median Follow up of 662 Months From the International, Randomized, Phase III First Line Indolent Trial (FIT) In 414 Patients

The FIT trial was conducted to evaluate the safety and efficacy of 90Y-ibritumomab tiuxetan (0.4 mCi/kg; maximum dose 32 mCi) when used as consolidation of first complete or partial remission in patients with previously untreated, advanced-stage follicular lymphoma (FL). Patients were randomly assigned to either 90Y-ibritumomab treatment (n = 207) or observation (n = 202) within 3 months (mo) of completing initial induction therapy (chemotherapy only: 86%; rituximab in combination with chemotherapy: 14%). Response status prior to randomization did not differ between the groups: 52% complete response (CR)/CR unconfirmed (CRu) to induction therapy and 48% partial response (PR) in the 90Y-ibritumomab arm vs 53% CR/CRu and 44% PR in the control arm. The primary endpoint was progression-free survival (PFS) of the intent-to-treat (ITT) population. Results from the first extended follow-up after a median of 3.5 years revealed a significant improvement in PFS from the time of randomization with 90Y-ibritumomab consolidation compared with control (36.5 vs 13.3 mo, respectively; P < 0.0001; Morschhauser et al. JCO. 2008; 26:5156-5164). Here we report a median follow-up of 66.2 mo (5.5 years). Five-year PFS was 47% in the 90Y-ibritumomab group and 29% in the control group (hazard ratio (HR) = 0.51, 95% CI 0.39-0.65; P < 0.0001). Median PFS in the 90Y-ibritumomab group was 49 mo vs 14 mo in the control group. In patients achieving a CR/CRu after induction, 5-year PFS was 57% in the 90Y-ibritumomab group, and the median had not yet been reached at 92 months, compared with a 43% 5-year PFS in the control group and a median of 31 mo (HR = 0.61, 95% CI 0.42-0.89). For patients in PR after induction, the 5-year PFS was 38% in the 90Y-ibritumomab group with a median PFS of 30 mo vs 14% in the control group with a median PFS of 6 mo (HR = 0.38, 95% CI 0.27-0.53). Patients who had received rituximab as part of induction treatment had a 5-year PFS of 64% in the 90Y-ibritumomab group and 48% in the control group (HR = 0.66, 95% CI 0.30-1.47). For all patients, time to next treatment (as calculated from the date of randomization) differed significantly between both groups; median not reached at 99 mo in the 90Y-ibritumomab group vs 35 mo in the control group (P < 0.0001). The majority of patients received rituximab-containing regimens when treated after progression (63/82 [77%] in the 90Y-ibritumomab group and 102/122 [84%] in the control group). Overall response rate to second-line treatment was 79% in the 90Y-ibritumomab group (57% CR/CRu and 22% PR) vs 78% in the control arm (59% CR/CRu, 19% PR). Five-year overall survival was not significantly different between the groups; 93% and 89% in the 90Y-ibritumomab and control groups, respectively (P = 0.561). To date, 40 patients have died; 18 in the 90Y-ibritumomab group and 22 in the control group. Secondary malignancies were diagnosed in 16 patients in the 90Y-ibritumomab arm vs 9 patients in the control arm (P = 0.19). There were 6 (3%) cases of myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML) in the 90Y-ibritumomab arm vs 1 MDS in the control arm (P = 0.063). In conclusion, this extended follow-up of the FIT trial confirms the benefit of 90Y-ibritumomab consolidation with a nearly 3 year advantage in median PFS. A significant 5-year PFS improvement was confirmed for patients with a CR/CRu or a PR after induction. Effective rescue treatment with rituximab-containing regimens may explain the observed no difference in overall survival between both patient groups who were - for the greater part - rituximab-naïve.

Improvement of antibiotic prescription in outpatient care: a cluster-randomized intervention study using a sentinel surveillance network of physicians.

OBJECTIVES: To assess the effectiveness of implementing guidelines, coupled with individual feedback, on antibiotic prescribing behaviour of primary care physicians in Switzerland. METHODS: One hundred and forty general practices from a representative Swiss sentinel network of primary care physicians participated in this cluster-randomized prospective intervention study. The intervention consisted of providing guidelines on treatment of respiratory tract infections (RTIs) and uncomplicated lower urinary tract infections (UTIs), coupled with sustained, regular feedback on individual antibiotic prescription behaviour during 2 years. The main aims were: (i) to increase the percentage of prescriptions of penicillins for all RTIs treated with antibiotics; (ii) to increase the percentage of trimethoprim/sulfamethoxazole prescriptions for all uncomplicated lower UTIs treated with antibiotics; (iii) to decrease the percentage of quinolone prescriptions for all cases of exacerbated COPD (eCOPD) treated with antibiotics; and (iv) to decrease the proportion of sinusitis and other upper RTIs treated with antibiotics. The study was registered at ClinicalTrials.gov (NCT01358916). RESULTS: While the percentage of antibiotics prescribed for sinusitis or other upper RTIs and the percentage of quinolones prescribed for eCOPD did not differ between the intervention group and the control group, there was a significant increase in the percentage of prescriptions of penicillins for all RTIs treated with antibiotics [57% versus 49%, OR=1.42 (95% CI 1.08-1.89), P=0.01] and in the percentage of trimethoprim/sulfamethoxazole prescriptions for all uncomplicated lower UTIs treated with antibiotics [35% versus 19%, OR=2.16 (95% CI 1.19-3.91), P=0.01] in the intervention group. CONCLUSIONS: In our setting, implementing guidelines, coupled with sustained individual feedback, was not able to reduce the proportion of sinusitis and other upper RTIs treated with antibiotics, but increased the use of recommended antibiotics for RTIs and UTIs, as defined by the guidelines.

Complete longitudinal analyses of the randomized, placebo-controlled, phase III trial of sunitinib in patients with gastrointestinal stromal tumor following imatinib failure.

PURPOSE: To analyze final long-term survival and clinical outcomes from the randomized phase III study of sunitinib in gastrointestinal stromal tumor patients after imatinib failure; to assess correlative angiogenesis biomarkers with patient outcomes. EXPERIMENTAL DESIGN: Blinded sunitinib or placebo was given daily on a 4-week-on/2-week-off treatment schedule. Placebo-assigned patients could cross over to sunitinib at disease progression/study unblinding. Overall survival (OS) was analyzed using conventional statistical methods and the rank-preserving structural failure time (RPSFT) method to explore cross-over impact. Circulating levels of angiogenesis biomarkers were analyzed. RESULTS: In total, 243 patients were randomized to receive sunitinib and 118 to placebo, 103 of whom crossed over to open-label sunitinib. Conventional statistical analysis showed that OS converged in the sunitinib and placebo arms (median 72.7 vs. 64.9 weeks; HR, 0.876; P = 0.306) as expected, given the cross-over design. RPSFT analysis estimated median OS for placebo of 39.0 weeks (HR, 0.505, 95% CI, 0.262-1.134; P = 0.306). No new safety concerns emerged with extended sunitinib treatment. No consistent associations were found between the pharmacodynamics of angiogenesis-related plasma proteins during sunitinib treatment and clinical outcome. CONCLUSIONS: The cross-over design provided evidence of sunitinib clinical benefit based on prolonged time to tumor progression during the double-blind phase of this trial. As expected, following cross-over, there was no statistical difference in OS. RPSFT analysis modeled the absence of cross-over, estimating a substantial sunitinib OS benefit relative to placebo. Long-term sunitinib treatment was tolerated without new adverse events.

Randomized trial of pacemaker and lead system for safe scanning at 1.5 Tesla.

BACKGROUND: Magnetic resonance imaging (MRI) of pacemakers is a relative contraindication because of the risks to the patient from potentially hazardous interactions between the MRI and the pacemaker system. Chest scans (ie, cardiac magnetic resonance scans) are of particular importance and higher risk. The previously Food and Drug Administration-approved magnetic resonance conditional system includes positioning restrictions, limiting the powerful utility of MRI. OBJECTIVE: To confirm the safety and effectiveness of a pacemaker system designed for safe whole body MRI without MRI scan positioning restrictions. METHODS: Primary eligibility criteria included standard dual-chamber pacing indications. Patients (n = 263) were randomized in a 2:1 ratio to undergo 16 chest and head scans at 1.5 T between 9 and 12 weeks postimplant (n = 177) or to not undergo MRI (n = 86) post-implant. Evaluation of the pacemaker system occurred immediately before, during (monitoring), and after MRI, 1-week post-MRI, and 1-month post-MRI, and similarly for controls. Primary end points measured the MRI-related complication-free rate for safety and compared pacing capture threshold between MRI and control subjects for effectiveness. RESULTS: There were no MRI-related complications during or after MRI in subjects undergoing MRI (n = 148). Differences in pacing capture threshold values from pre-MRI to 1-month post-MRI were minimal and similar between the MRI and control groups. CONCLUSIONS: This randomized trial demonstrates that the Advisa MRI pulse generator and CapSureFix MRI 5086MRI lead system is safe and effective in the 1.5 T MRI environment without positioning restrictions for MRI scans or limitations of body parts scanned.

Anti-TNF therapy in acute sciatica reduces the long-term need for surgery: A three-year follow-up of a randomized double blind placebo controlled trial

Introduction: Two subcutaneous injections of adalimumab in severeacute sciatica have demonstrated a significant benefit on the numberof back surgeries in a short-term randomized controlled clinical trial[1]. This 3-year follow-up study aimed to determine whether theshort-term benefit was sustained over a longer period of time.Methods: Information on surgery was retrieved in 56/61 patients(93%). We used a Cox proportional hazard models to determinefactors predisposing to surgery.Results: Twenty-three (41%) patients had back surgery within 3 years,8/29 (28%) in the adalimumab group and 15/ 27 (56%) in the placebogroup, p = 0.038. Adalimumab injections reduced the need for backsurgery by 61% (Hazard Ratio (HR): 0.39 (95% CI: 0.17-0.92). In amultivariate model, treatment with a TNF-α antagonist remained thestrongest protective factor (HR 0.17, p = 0.002). Other significantpredictors of surgery were a good correlation between symptomsand MRI findings (HR = 11.6, p = 0.04), baseline intensity of leg pain(HR = 1.3, p = 0.06), intensity of back pain (HR = 1.4, p = 0.03)and duration of sickness leave (HR = 1.01 per day, p = 0.03).Conclusion: A short course of adalimumab in patients with severeacute sciatica significantly reduces the need for back surgery.

Effect of a general school-based physical activity intervention on bone mineral content and density: A cluster-randomized controlled trial.

Background: Specific physical loading leads to enhanced bone development during childhood. A general physical activity program mimicking a real-life situation was successful at increasing general physical health in children. Yet, it is not clear whether it can equally increase bone mineral mass. We performed a cluster-randomized controlled trial in children of both gender and different pubertal stages to determine whether a school-based physical activity (PA) program during one school-year influences bone mineral content (BMC) and density (BMD), irrespective of gender.Methods: Twenty-eight 1st and 5th grade (6-7 and 11-12 year-old) classes were cluster randomized to an intervention (INT, 16 classes, n = 297) and control (CON; 12 classes, n = 205) group. The intervention consisted of a multi-component PA intervention including daily physical education with at least 10 min of jumping or strength training exercises of various intensities. Measurements included anthropometry, and BMC and BMD of total body, femoral neck, total hip and lumbar spine using dual-energy X-ray absorptiometry (DXA). PA was assessed by accelerometers and Tanner stages by questionnaires. Analyses were performed by a regression model adjusted for gender, baseline height and weight, baseline PA, post-intervention pubertal stage, baseline BMC, and cluster.Results: 275 (72%) of 380 children who initially agreed to have DXA measurements had also post-intervention DXA and PA data. Mean age of prepubertal and pubertal children at baseline was 8.7 +/- 2.1 and 11.1 +/- 0.6 years, respectively. Compared to CON, children in INT showed statistically significant increases in BMC of total body, femoral neck, and lumbar spine by 5.5%, 5.4% and 4.7% (all p < 0.05), respectively, and BMD of total body and lumbar spine by 8.4% and 7.3% (both p < 0.01), respectively. There was no gender*group, but a pubertal stage*group interaction consistently favoring prepubertal children.Conclusion: A general school-based PA intervention can increase bone health in elementary school children of both genders, particularly before puberty. (C) 2010 Elsevier Inc. All rights reserved.

Effects of motive-oriented therapeutic relationship in early-phase treatment of borderline personality disorder: a pilot study of a randomized trial.

Motive-oriented therapeutic relationship (MOTR, also called complementary therapeutic relationship) was postulated to be a particularly helpful therapeutic ingredient in the early-phase treatment of patients with personality disorders, in particular borderline personality disorder (BPD). The present pilot study of randomized controlled trial using an add-on design aims to investigate the effects of MOTR in early-phase treatment (up to session 10), with BPD patients on therapeutic alliance, session impact, and outcome. In total, N = 25 patients participated in the study. BPD patients were randomly allocated to a manual-based investigation process in 10 sessions or to the same investigation process infused with MOTR. Adherence ratings were performed and yielded satisfactory results. The results suggested a specific effectiveness of MOTR on the interpersonal problem area, on the quality of the therapeutic alliance and the quality of the therapeutic relationship, as rated by the patient. These results may have important clinical implications for the early-phase treatment of patients presenting with BPD.

A randomized phase II trial of a drug eluting bead in the treatment of hepatocellular carcinoma by transcatheter arterial chemoembolization

Background: Transcatheter arterial chemoembolization (TACE) has been shown to offer a survival benefit for patients with intermediate-stage hepatocellular carcinoma (HCC). A widely accepted TACE regimen includes the administration of a doxorubicin-in-oil emulsion followed by gelatine sponge particles. Recently, a drug-eluting bead (DEB) has been developed to enhance drug delivery to the tumor and reduce its systemic availability. Purpose of this randomized trial was to compare conventional TACE with DEB-TACE for the treatment of intermediate-stage HCC in patients with cirrhosis. Methods: Two hundred and twelve patients (185 males and 27 females; mean age, 67 years) with Child-Pugh A or B liver cirrhosis and large and/or multinodular, unresectable HCC were randomized to receive DEB-TACE (DC Bead; Biocompatibles, UK) uploaded with doxorubicin or conventional TACE with doxorubicin, lipiodol, and gelatin sponge particles. Randomization was stratified according to Child Pugh status (A or B), performance status (ECOG 0 or 1), bilobar disease (yes or no) and prior curative treatment (yes or no). Tumor response at 6 months was the primary study endpoint. An independent, blinded review of magnetic resonance imaging studies was conducted to assess tumor response according to amended RECIST criteria. Results: DEB-TACE with doxorubicin showed a higher rate of complete response, objective response and disease control compared with conventional TACE (27% vs 22%; 52% vs 44%; and 63% vs 52%, respectively; p>0.05). Patients with Child Pugh B, ECOG 1, bilobar disease and recurrence following curative treatment showed a significant increase in objective response (p=0.038) compared to the control. There was a marked reduction in serious liver toxicity in patients treated with DEB-TACE. The rate of doxorubicin related side effects was significantly lower (p=0.0001) in the DEB-TACE group compared with the conventional TACE group. Conclusions: DEB-TACE with doxorubicin is safe and effective in the treatment of intermediate-stage HCC and may offer benefit to patients with more advanced disease.

Autologous keratinocyte suspension in platelet concentrate accelerates and enhances wound healing : a prospective randomized clinical trial on skin graft donor sites

La cicatrisation cutanée requiert de nombreux mécanismes et un nombre toujours croissant de molécules participant à ces réactions sont identifiées. La compréhension de cette cinétique et des différents facteurs impliqués dans ce processus permet d'accélérer la guérison des plaies. Certains facteurs de croissance (PDGF, FGF, EGF) ont déjà été utilisés localement sur des plaies mais leurs effets relatés sont inconsistants et contradictoires, probablement en raison de l'absence de cinétique ou de concentration physiologique. Les plaquettes jouent un rôle fondamental dans la cicatrisation cutanée, principalement par la formation du clou plaquettaire et le relargage de divers facteurs de croissance et de cytokines. De même, les kératinocytes ont un rôle similaire dans l'épithélialisation des plaies. Ainsi, l'apport de plaquettes et de kératinocytes sur une plaie pourrait accélérer sa cicatrisation. L'étude rapportée ici tente de vérifier si une solution de kératinocytes autologues en suspension dans un concentré plaquettaire ou un concentré plaquettaire seul pourrait stimuler la cicatrisation cutanée. Pour ce faire, nous avons comparé trois groupes de 15 patients bénéficiant, sur une prise de greffe de profondeur similaire, d'un traitement standard fait de pansement simple, d'un concentré plaquettaire seul ou de kératinocytes autologues suspendus dans un concentré plaquettaire. Sur ces plaies, la durée de cicatrisation ainsi que la douleur au cours de la guérison ont été étudiés. Nos résultats montrent une réduction significative de la durée de cicatrisation dans le groupe traité avec un concentré plaquettaire, passant de 13.9 +/- 0.5 à 7.2 +/- 0.2 jours. Cet effet est encore plus marqué dans le groupe traité avec des kératinocytes en suspension dans un concentré plaquettaire passant de 13.9 +/- 0.5 à 5.7 +/- 0.2 jours. De même, la douleur évaluée au cinquième jour montre une nette diminution dans les deux groupes traités avec des cellules. En conclusion, notre travail montre que l'application de plaquettes autologues ou de kératinocytes en suspension dans un concentré plaquettaire permet d'accélérer la cicatrisation cutanée et de diminuer les douleurs, sans aucun effet indésirable constaté. Notre étude montre également qu'un concentré plaquettaire peut être utilisé comme vecteur pour une suspension de kératinocytes. L'identification de la cinétique d'apparition et de la concentration de chacun des facteurs de croissance lors de la cicatrisation cutanée permettrait dans le futur d'analyser plus finement et de traiter physiologiquement des plaies chroniques.

Risk assessment of recurrence in sporadic retinoblastoma using a molecular-based algorithm

Le rétinoblastome (Rb) est une tumeur provenant des cellules rétiniennes progénitrices des photorécepteurs. C'est la tumeur pédiatrique maligne la plus fréquente avec une incidence par naissance évaluée entre 1/15Ό00 et 1/20Ό00. Les enfants atteints de Rb sont diagnostiqué dans leur grande majorité avant l'âge de 4 ans, soit le temps nécessaire à la différentiation et à la maturation des photorécepteurs et donc à la disparition de la cellule d'origine du Rb. La survie du patient, la sauvegarde oculaire et le pronostic visuel restent excellents pour autant que le traitement ne soit pas différé. Dans sa variante non héréditaire (60%) le Rb est toujours unilatéral et sporadique. Le Rb héréditaire de transmission dominante autosomique (40%), se décline sous toutes les formes, familiale (10%) ou sporadique (30%), que l'atteinte soit unilatérale ou bilatérale. La majorité des mutations causales sont uniques et distribuées de façon aléatoire sur la totalité du gène RB1 sans région prédisposante. La détection de ces mutations est couteuse et chronophage, tout en présentant un taux de détection relativement bas; surtout dans les cas de Rb sporadiques unilatéraux. Dans le but d'identifier les patients présentant un risque réel de développer un Rb, et de réduire le nombre d'examens sous narcose requis pour le dépistage de la maladie chez les sujets à risque, nous avons développé une stratégie sensible, rapide, efficace et peu couteuse basée sur une analyse de l'haplotype intragénique. Cet algorithme prend en compte a) la perte d'hétérozygotie intratumorale du gène RB1, b) l'origine paternelle préférentielle des nouvelles mutations germinales et c) un risque a priori dérivé des données empiriques de Vogel. Pendant la période allant de janvier 1994 à décembre 2006, nous avons comparé l'apparition de nouveau Rb parmi la fratrie et la descendance de patient atteints au nombre de nouveaux cas attendus calculé par notre algorithme. 134 familles ont été étudiées. L'analyse moléculaire a été effectuée chez 570 personnes dont 99 patients âgés de moins de 4 ans et donc à risque de développer un Rb. Parmi cette cohorte, nous avons observé l'apparition d'un cas de Rb, alors que les risques cumulés a posteriori calculé par notre algorithme prédisait l'apparition de 1.77 nouveau cas. Dans cette étude, nous avons pu valider notre algorithme prédisant la récurrence de Rb chez les parents de 1er degré de patients atteints. Cet outil devrait grandement faciliter le conseil génétique ainsi que le suivi des patients à risque de développer un Rb, surtout dans les cas ou le séquençage direct du gène RB1 n'est pas disponible ou est resté non informatif. - Purpose: Most RBI mutations are unique and distributed throughout the RBI gene. Their detection can be time-consuming and the yield especially low in cases of conservatively-treated sporadic unilateral retinoblas-toma (Rb) patients. In order to identify patients with true risk of developing Rb, and to reduce the number of unnecessary examinations under anesthesia in all other cases, we developed a universal sensitive, efficient and cost-effective strategy based on intragenic haplotype analysis. Methods: This algorithm allows the calculation of the a posteriori risk of developing Rb and takes into account (a) RBI loss of heterozygosity in tumors, (b) preferential paternal origin of new germline mutations, (c) a priori risk derived from empirical data by Vogel, and (d) disease penetrance of 90% in most cases. We report the occurrence of Rb in first degree relatives of patients with sporadic Rb who visited the Jules Gonin Eye Hospital, Lausanne, Switzerland, from January 1994 to December 2006 compared to expected new cases of Rb using our algorithm. Results: A total of 134 families with sporadic Rb were enrolled; testing was performed in 570 individuals and 99 patients younger than 4 years old were identified. We observed one new case of Rb. Using our algorithm, the cumulated total a posteriori risk of recurrence was 1.77. Conclusions: This is the first time that linkage analysis has been validated to monitor the risk of recurrence in sporadic Rb. This should be a useful tool in genetic counseling, especially when direct RBI screening for mutations leaves a negative result or is unavailable.

Prophylactic isolated limb perfusion for localized, high-risk limb melanoma: results of a multicenter randomized phase III trial. European Organization for Research and Treatment of Cancer Malignant Melanoma Cooperative Group Protocol 18832, the World Health Organization Melanoma Program Trial 15, and the North American Perfusion Group Southwest Oncology Group-8593.

PURPOSE: Patients with primary cutaneous melanoma > or = 1.5 mm in thickness are at high risk of having regional micrometastases at the time of initial surgical treatment. A phase III international study was designed to evaluate whether prophylactic isolated limb perfusion (ILP) could prevent regional recurrence and influence survival. PATIENTS AND METHODS: A total of 832 assessable patients from 16 centers entered the study; 412 were randomized to wide excision (WE) only and 420 to WE plus ILP with melphalan and mild hyperthermia. Median age was 50 years, 68% of patients were female, 79% of melanomas were located on a lower limb, and 47% had a thickness > or = 3 mm. RESULTS: Median follow-up duration is 6.4 years. There was a trend for a longer disease-free interval (DFI) after ILP. The difference was significant for patients who did not undergo elective lymph node dissection (ELND). The impact of ILP was clearly on the occurrence-as first site of progression - of in-transit metastases (ITM), which were reduced from 6.6% to 3.3%, and of regional lymph node (RLN) metastases, with a reduction from 16.7% to 12.6%. There was no benefit from ILP in terms of time to distant metastasis or survival. Side effects were higher after ILP, but transient in most patients. There were two amputations for limb toxicity after ILP. CONCLUSION: Prophylactic ILP with melphalan cannot be recommended as an adjunct to standard surgery in high-risk primary limb melanoma.