Flavia Brunstein

One hundred consecutive isolated limb perfusions with TNF-alpha and melphalan in melanoma patients with multiple in-transit metastases

Objective:The aim of this study is to describe the experience with 100 TNF-based ILP for locally advanced melanoma and to determine prognostic factors for response, time to local progression, and survival. Methods:One hundred TNF-based ILPs were performed between 1991 and 2003 in 87 patients for whom local control by surgery of in-transit melanoma metastases was impossible. In total, 62 iliac, 33 femoral, and 5 axillary ILPs were performed in mild hyperthermic conditions with 2 to 4 mg of TNF and 10 to 13 mg of melphalan per liter of limb volume. Results:Overall response was 95%, with 69% complete response, 26% partial response, and 5% no change. Complete response rate differed significantly for patients with IIIA disease versus IIIAB and IV. Local and systemic toxicity was mild to moderate in almost all cases, with no treatment-related death and one treatment-related amputation. Five-year overall survival was 32%; local progression occurred in 55% after a median of 16 months. In complete response patients, 5-year survival was 42% with local progression in 52% at a median of 22 months. Response rate and survival were significantly influenced by stage of disease; (local progression free) survival was influenced by response rate. Conclusions:TNF-based ILP results in excellent response rates in this patient population with unfavorable characteristics. Response on ILP predicts outcome in patients and reflects aggressiveness of the tumor.

A clinical, prospective, randomized, double-blind trial comparing skin whitening complex with hydroquinone vs. placebo in the treatment of melasma.

Objectives To compare, in a double‐blind, randomized, prospective study, the clinical improvement of hyperpigmentation in 30 patients with melasma using hydroquinone or skin whitening complex topically on one side of the face vs. a placebo cream on the other. The study was performed during the period November 2000 to March 2001 at the Federal University of São Paulo, Escola Paulista de Medicina.

Synergistic antitumor response of interleukin 2 with melphalan in isolated limb perfusion in soft tissue sarcoma-bearing rats.

The cytokine interleukin 2 (IL-2) is a mediator of immune cell activation with some antitumor activity, mainly in renal cell cancer and melanoma. We have previously shown that tumor necrosis factor (TNF)-alpha has strong synergistic antitumor activity in combination with chemotherapeutics in the isolated limb perfusion (ILP) setting based on a TNF-mediated enhanced tumor-selective uptake of the chemotherapeutic drug followed by a selective destruction of the tumor vasculature. IL-2 can cause vascular leakage and edema and for this reason we examined the antitumor activity of a combined treatment with IL-2 and melphalan in our well-established ILP in soft tissue sarcoma-bearing rats (BN175). ILP with either IL-2 or melphalan alone has no antitumor effect, but the combination of IL-2 and melphalan resulted in a strong synergistic tumor response, without any local or systemic toxicity. IL-2 enhanced significantly melphalan uptake in tumor tissue. No signs of significant vascular damage were detected to account for this observation, although the tumor sections of the IL-2- and IL-2 plus melphalan-treated animals revealed scattered extravasation of erythrocytes compared with the untreated animals. Clear differences were seen in the localization of ED-1 cells, with an even distribution in the sham, IL-2 and melphalan treatments, whereas in the IL-2 plus melphalan-treated tumors clustered ED-1 cells were found. Additionally, increased levels of TNF mRNA were found in tumors treated with IL-2 and IL-2 plus melphalan. These observations indicate a potentially important role for macrophages in the IL-2-based perfusion. The results in our study indicate that the novel combination of IL-2 and melphalan in ILP has synergistic antitumor activity and may be an alternative for ILP with TNF and melphalan.

V-Y ADVANCEMENT FLAP FOR THE RECONSTRUCTION OF PARTIAL AND FULL THICKNESS DEFECTS OF THE UPPER LIP

We analysed the records of 25 patients who had their upper lips reconstructed after resection of a tumour. All the repairs were done with triangular cutaneous and musculocutaneous flaps with a skin island with V-Y advancement, and a subcutaneous or muscular pedicle with or without mucosa. The choice of flap was based on the width of the defect after the tumour had been resected. A subcutaneous pedicled flap was used in 14 patients; a musculocutaneous flap not including the mucosa in 5, and including the mucosa in 6. This flap can be used to repair upper lip defects of any thickness. The procedure is quite safe from a circulatory point of view and the flap has the advantage of requiring only one procedure. It is aesthetically satisfactory in most patients and maintains the good function and sensitivity of the lip.

Histamine combined with melphalan in isolated limb perfusion for the treatment of locally advanced soft tissue sarcomas: preclinical studies in rats

PURPOSE To evaluate the potential benefit of histamine combined with melphalan in the isolated limb perfusion (ILP) as an alternative to TNF-alfa and melphalan combination, for the treatment of irresectable soft tissue sarcomas of the limbs in Brown Norway (BN) rats. METHODS 20 BN rats had small fragments of syngeneic BN-175 fibrosarcoma inserted on the right hind limb. In 7-10 days the tumor reached a median diameter of 12-15 mm and they were randomly divided in four groups (sham, melphalan, histamine and escalating doses of histamine combined to melphalan) being submitted to experimental ILP for 30 minutes. Tumors were measured daily with a caliper and the volume was calculated. RESULTS Response curves showed a significant effect of the combination of histamine 200 mg/mL with melphalan, with 66% overall response, including 33% complete responses (p< 0.01). There were no systemic collateral effects and locally only mild temporary edema was observed for some animals treated with histamine. CONCLUSION Histamine combined with melphalan had a promising effect in the ILP warranting future studies to better explore the mechanism of action as well as its potential use in organ perfusion.