Hyperthermic isolated limb perfusion with tumour necrosis factor and melphalan as treatment of locally advanced or recurrent soft tissue sarcomas of the extremities.

Hyperthermic isolated limb perfusion (HILP) with various chemotherapeutic agents has been used for the local treatment of high-grade soft tissue sarcomas (STS) of the extremities, but in most cases with a disappointing result. Most regimens should certainly not be considered superior to surgery plus radiotherapy. Although the majority of extremity STS can be resected locally, some have a very large size and are in close proximity to bones, nerves or blood vessels.

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.

S 16924 ((R)-2-[1-[2-(2,3-dihydro-benzo[1,4] dioxin-5-Yloxy)-ethyl]-pyrrolidin-3yl]-1-(4-fluoro-phenyl)-ethanone), a novel, potential antipsychotic with marked serotonin (5-HT)1A agonist properties: I. Receptorial and neurochemical profile in comparison with clozapine and haloperidol.

S 16924 showed a pattern of interaction at multiple (>20) native, rodent and cloned, human (h) monoaminergic receptors similar to that of clozapine and different to that of haloperidol. Notably, like clozapine, the affinity of S 16924 for hD2 and hD3 receptors was modest, and it showed 5-fold higher affinity for hD4 receptors. At each of these sites, using a [35S]GTPgammaS binding procedure, S 16924, clozapine and haloperidol behaved as antagonists.

Induction of burst firing in ventral tegmental area dopaminergic neurons by activation of serotonin (5-HT)1A receptors: WAY 100,635-reversible actions of the highly selective ligands, flesinoxan and S 15535.

This study examined the influence of the highly selective 5-HT1A receptor ligands, flesinoxan, S 15535, and WAY 100,635, upon the electrical activity of dopaminergic neurons in the ventral tegmental area (VTA), as compared to serotonergic neurons in the dorsal raphe nucleus (DRN) of anesthetized rats. Flesinoxan, a high-efficacy agonist at both pre- and postsynaptic 5-HT1A receptors, dose-dependently (inhibitory dose (ID)50 = 19.5 microg/kg, i.

Pulse treatment of human vascular endothelial cells with high doses of tumor necrosis factor and interferon-gamma results in simultaneous synergistic and reversible effects on proliferation and morphology.

Regional administration of high doses of tumor necrosis factor (TNF), interferon gamma (IFNgamma) and melphalan to patients with advanced cancers of the limbs, results in rapid and specific tumor necrosis, while the normal adjacent tissues remain unaffected. The tumor vasculature is selectively destroyed by this treatment, and neovascular endothelial cells appear to be an early and specific target of TNF and IFNgamma. To further understand some of the cellular events underlying these in vivo effects, we have investigated the response of human macro- and microvascular endothelial cells in vitro, after exposure to high doses of TNF and IFNgamma (up to 40 x 10(3) U/ml each).

Ten-year results of a strategy combining three cycles of ABVD and high-dose extended irradiation for treating Hodgkin's disease at advanced stages.

Background: The treatment of Hodgkin's disease (HD) at advanced stages relies mainly upon multi-agent chemotherapies (CT), while the role of radiation therapy has not been definitely identified. The aim of this report is to analyze the 10-year results of a prospective study including 133 patients with HD clinical stages (CS) IIIA to IVB treated by three monthly courses of ABVD (adriamycin, bleomycin, vinblastin, and dacarbazine) followed by high-dose subtotal or total lymphoid irradiation [(S)TLI].

Patients And Methods: From 1 October 1981 to 30 September 1988, 133 adult patients with HD CS IIIA (45), IIIB (33), IVA (seven) and IVB (48) were entered in the non-randomized multicentric prospective trial POF81/34.

Hyperthermic isolated limb perfusion for the treatment of soft tissue sarcomas.

Hyperthermic isolated limb perfusion (HILP) with various chemotherapeutic agents has been used for the local treatment of high-grade soft tissue sarcomas (STS) of the extremities, but in most cases, with a disappointing result. Most such regimens certainly should not be considered superior to surgery plus radiotherapy. Although the majority of extremity STS can be resected locally, some are very large and are in close proximity to bone, nerve or blood vessels.

Isolated limb perfusion in primary and recurrent melanoma: indications and results.

In advanced melanoma of the limbs with in-transit metastasis, melphalan with isolated limb perfusion (M-ILP) produces around 50% complete remissions (CR). The combination of melphalan with tumour necrosis factor-alpha (TNFalpha) and interferon-gamma (IFNgamma) in isolated limb perfusion (TIM-ILP) gives around 80% CR. A prospective randomised phase II study compared 32 patients who received TIM-ILP with 32 patients who received TM-ILP (without IFNgamma).

Evidence for the involvement of endothelial cell integrin alphaVbeta3 in the disruption of the tumor vasculature induced by TNF and IFN-gamma.

Administration of tumor necrosis factor (TNF) and gamma interferon (IFN-gamma) to melanoma patients causes selective disruption of the tumor vasculature but the mechanism of this disruption is unknown. Here we report that exposure of human endothelial cells to TNF and IFN-gamma results in a reduced activation of integrin alphaVbeta3, an adhesion receptor that plays a key role in tumor angiogenesis, leading to a decreased alphaVbeta3-dependent endothelial cell adhesion and survival. Detachment and apoptosis of angiogenic endothelial cells was demonstrated in vivo in melanoma metastases of patients treated with TNF and IFN-gamma.

Systemic release of soluble TNF receptors after high-dose TNF in isolated limb perfusion.

Isolated limb perfusion (ILP) with high dose tumour necrosis factor (TNF), interferon gamma and melphalan (TIM) is an efficient treatment for patients with regionally advanced melanoma and sarcoma. In 44 patients, we determined the kinetics of soluble TNF receptors (sTNF-RI and RII) plasma concentrations, and correlated them with systemic TNF and interleukin 6 (IL-6) levels and shock. Seven patients treated conventionally by ILP without cytokine served as controls.

Principles and guidelines for surgeons: management of cutaneous malignant melanoma. European Society of Surgical Oncology Brussels.

This article outlines and discusses the principles of the guidelines for the management of malignant melanoma by surgeons. The guidelines are based, in large part, on the consensus of the Dutch Melanoma Working Party that was revised in 1997. The article reflects internationally accepted treatment principles that have arisen both from critical assessment of existing evidence and data, and from the outcome of randomized studies.

Recombinant interleukin-2-based treatments for advanced melanoma: the experience of the European Organization for Research and Treatment of Cancer Melanoma Cooperative Group.

Purpose: This article reviews the currently available data on phase II and III trials regarding the efficacy of recombinant interleukin-2 (rIL-2)-based regimens in the treatment of stage IV melanoma, and discusses the rationale and outcome of past and currently ongoing rIL-2-based chemo-immunotherapy phase III trials conducted by the European Organization for Research and Treatment of Cancer Melanoma Cooperative Group.

Patients And Methods: In the first EORTC-MCG phase III trial, stage IV melanoma patients were stratified on the basis of serum lactate dehydrogenase levels and tumor burden and randomized to receive rIL-2 (decrescendo regimen) plus interferon-alpha (IFN-alpha) plus or minus cisplatin. In the second trial, which is still ongoing, patients are being randomized to receive dacarbazine plus cisplatin plus IFN-alpha plus or minus rIL-2.

Isolation limb perfusion with tumor necrosis factor alpha and chemotherapy for advanced extremity soft tissue sarcomas.

The unique property of high dose recombinant tumor necrosis factor alpha (rTNF alpha) is to activate and selectively destroy the tumor-associated microvasculature. For the systemic application of rTNF alpha it has been shown that the maximum tolerated dose (MTD) is 10 times less than the effective dose in animals. The main toxicity corresponds to systemic inflammatory response syndrome with a decrease in vascular resistance and hypotension.

Lack of antitumour activity of human recombinant tumour necrosis factor-alpha, alone or in combination with melphalan in a nude mouse human melanoma xenograft system.

The most promising developments in the field of isolated limb perfusion have centred around the use of the recombinant cytokine tumour necrosis factor-alpha (rTNF-alpha) in combination with melphalan. While the results of clinical trials are impressive, the exact antitumour mechanisms of rTNF-alpha and its role in combination with melphalan remain unclear. Our aim was to study the antitumour activity of human rTNF-alpha with or without the combination of melphalan in a nude mouse human melanoma xenograft system.

Cell differentiation and cell-cycle alterations by tyrosine kinase inhibitors in human melanoma cells.

Differentiation therapy is an attractive option for malignant melanoma, as traditional forms of chemotherapy seem to have little effect on this type of tumour. Among the several pathways for the experimental induction of differentiation of melanoma, we have focused on signal transduction mediated by protein kinases. We have examined the effects of calphostin C (a protein kinase C inhibitor), genistein and methyl 2,5-dihydroxycinnamate (tyrosine kinase inhibitors), and exogenous phosphotyrosine (an activator of protein tyrosine phosphatases) on the growth, morphology and differentiation of malignant melanomas in vitro.

Treatment of ocular melanoma metastatic to the liver by hepatic arterial chemotherapy.

Purpose: Ocular melanoma is characterized by a high rate of liver metastases and is associated with a median survival time less than 5 months. There is no standard treatment available. Treatment strategies have, without success, relied on the experience with metastatic cutaneous melanoma.

Melanoma-reactive human cytotoxic T lymphocytes derived from skin biopsies of delayed-type hypersensitivity reactions induced by injection of an autologous melanoma cell line.

The expression by melanomas of multiple antigens that are recognized by specific MHC class I-restricted CTLs has been clearly demonstrated. The goal of many immunotherapy protocols being developed is, therefore, the induction and/or augmentation of CTLs specific for such antigens. One approach has been to immunize using irradiated autologous melanoma cells.

Interactions of (+)- and (-)-8- and 7-hydroxy-2-(di-n-propylamino)tetralin at human (h)D3, hD2 and h serotonin1A receptors and their modulation of the activity of serotoninergic and dopaminergic neurones in rats.

The aminotetralins, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and 7-OH-DPAT behave as preferential agonists at serotonin (5-HT)1A and dopamine D3 and D2 receptors, respectively. In our study, we evaluated the influence of their (+)- and (-) isomers on the electrical activity of serotoninergic neurones of the dorsal raphe nucleus (DRN), which bear 5-HT1A autoreceptors, and of dopaminergic neurones of the ventral tegmental area (VTA), which possess inhibitory D3 and D2 receptors. These actions were compared to their in vitro interactions with cloned, human (h)5-HT1A, hD3 and hD2 receptors.

[Covering of a thoraco-lumbar defect by omentoplasty].

With a case of thoraco-lumbar defect, the authors discuss about different procedures to cover it. In this place, the better procedure is certainly the latissimus dorsi flap, in all combinations. The indication for omentoplasty at this spinal site should not be performed by first intention but by exclusion of other procedures, as in the case considered by the authors.

Melanoma risk and residence in sunny areas. EORTC Melanoma Co-operative Group. European Organization for Research and Treatment of Cancer.

Melanoma risk among subjects from Germany, France and Belgium who had lived for 1 year or more in sunny climates was examined in a one-to-one unmatched case-control study conducted among white subjects 20 years old or more. A total of 412 consecutive patients with melanoma diagnosed from 1 January 1991 onwards, were derived from hospital registers; 445 controls were randomly chosen in the same municipality as the cases. After adjustment for host characteristics, melanoma risk associated with residence in a sunny area was 2.

[Large abdominal wall reconstruction by free flap after recurrence of a dermatofibrosarcoma protuberans].

Based on a case of recurrence of a dermatofibrosarcoma protuberans of the abdominal wall, the authors discuss the need for initial wide resection of this type of skin tumour and the possibilities of repair of extensive full thickness defects of the abdominal wall by means of a latissimus dorsi myocutaneous free flap.

Isolated limb perfusion with tumor necrosis factor and melphalan for limb salvage in 186 patients with locally advanced soft tissue extremity sarcomas. The cumulative multicenter European experience.

Objective: The objective of the study was to achieve limb salvage in patients with locally advanced soft tissue sarcomas that can only be treated by amputation or functionally mutilating surgery by performing an isolated limb perfusion (ILP) with tumor necrosis factor (TNF) + melphalan (M) as induction biochemotherapy to obtain local control and make limb-sparing surgery possible.

Summary Background Data: To increase the number of limb-sparing resections in the treatment of locally advanced extremity soft tissue sarcoma, preoperative radiation therapy or chemotherapy or a combination of the two often are applied. The ILP with cytostatic agents alone is another option but rarely is used because of rather poor results.