The efficacy of isolated limb perfusion (ILP) for 'intransit' metastases from malignant melanoma and irresectable soft tissue sarcoma has been improved considerably by the addition of tumour necrosis factor (TNF) alpha. A rat sarcoma tumour model was, therefore, developed to evaluate the effects of TNF-alpha, melphalan and the combination of these drugs in the treatment of sarcoma. In BN rats bearing the non-immunogenic BN 175 sarcoma ILPs were performed with perfusate only, TNF-alpha, melphalan alone, or in combination when tumours had grown to approximately 1.5 cm in diameter. All rats treated with sham perfusion or perfusion with 50 micrograms TNF-alpha showed progressive disease. After perfusion with 40 micrograms melphalan no change in tumour diameter was observed in any rats at 4 days. After a combined perfusion with 40 micrograms melphalan and 50 micrograms TNF-alpha complete remission was noted in 12 of 16 rats. This synergistic effect in vivo between relatively ineffective doses of TNF-alpha and melphalan was not observed in vitro.

Summary Isolated limb perfusion (ILP) with tumour necrosis factor alpha (TNF-a) and melphalan has shown impressive results in patients with irresectable soft tissue sarcomas and stage III melanoma of the extremities. The mechanisms of the reported in vivo synergistic anti-tumour effects of TNF-a and melphalan are not precisely understood. We have developed an ILP model in the rat using a non-immunogenic sarcoma in which similar in vivo synergy is observed. The aim of this present study was to analyse the morphological substrate for this synergistic response of TNF-cx in combination with melphalan to shed more light on the pathomechanisms involved. Histology of the tumours from saline-(n = 14) and melphalan-treated (n = 11) rats revealed apparently vital tumour cells in over 80% of the cross-sections. Interstitial oedema and coagulation necrosis were observed in the remaining part of the tumour. Haemorrhage was virtually absent. TNF-oa (n = 22) induced marked oedema, hyperaemia, vascular congestion, extravasation of erythrocytes and haemorrhagic necrosis (20-60% of the cross-sections). Oedema and haemorrhage suggested drastic alterations of permeability and integrity of the microvasculature. Using light and electron-microscopy, we observed that haemorrhage preceded generalised platelet aggregation. Therefore, we suggest that the observed platelet aggregation was the result of the microvascular damage rather than its initiator. Remarkably, these events hardly influenced tumour growth. However, perfusion with the combination of TNF-a and melphalan (n = 24) showed more extensive haemorrhagic necrosis (80 -90% of the cross-sections) and revealed a prolonged remission (mean 11 days) in comparison with the other groups of rats. Electron microscopical analysis revealed similar findings as described after TNF-ax alone, although the effects were more prominent at all time points after perfusion. In conclusion, our findings suggest that the enhanced anti-tumour effect after the combination of TNF-a with melphalan results from potentiation of the TNF-oa-induced vascular changes accompanied by increased vascular permeability and platelet aggregation. This may result in additive cytotoxicity or inhibition of growth of residual tumour cells.Keywords: tumour necrosis factor alpha; melphalan; isolated limb perfusion; sarcoma; platelets Isolated limb perfusion (ILP) with TNF-a and melphalan has shown impressive results in patients with irresectable soft tissue sarcomas and stage III melanoma of the extremities (Lienard et al., 1992. ILP involves isolation of the diseased limb, its connection to a heart-lung machine and the administration of a triple drug regimen at 39-40°C (mild hyperthermia) based on the reported synergism of TNF-a with melphalan and interferon-y (IFN-y) (Eggermont et al., 1993). The rationale of ILP is to improve the response rate by increasing the drug concentration while avoiding systemic toxicity. Morphological and immunohistochemical analysis of biopsies from patients after ILP suggested that the tumour mic...

Isolated limb perfusion (ILP) with TNF alpha, IFN gamma and melphalan causes impressive tumour reduction in patients with irresectable soft tissue sarcomas with a high limb salvage rate. Since this therapy could be of value in patients with progressive osteosarcoma, we performed a study in an osteosarcoma tumour model in the rat. The ROS-1 osteosarcoma was implanted s.c. in the hind leg of WAG rats. Rats were divided in four groups: rats that underwent ILP with perfusate alone, TNF alpha alone, melphalan alone or their combination. Almost all rats, treated with a sham ILP or a perfusion with 40 micrograms melphalan, showed progressive disease (PD) (6/6 and 5/6). After perfusion with 50 micrograms TNF alpha alone a varied response was observed: 2/6 PD, 2/6 no change (NC) and 2/6 a complete remission (CR). After combined perfusion: 3/6 rats had a partial remission and 3/6 a CR. The best and most consistent responses are obtained by combining TNF alpha and melphalan. The discrepancy with the in vitro sensitivity of ROS-1 indicates that indirect effects are important in this tumour model.

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Background: The novel coronavirus disease 2019 (COVID-19) is a recent viral outbreak that has rapidly spread to multiple countries worldwide. Little is known about COVID-19 infection-related complications. Case Report: We report a patient who developed spontaneous bilateral pneumothorax after a recent COVID-19 infection. To our knowledge, this is the first reported case of spontaneous bilateral pneumothorax in a patient with recent confirmed severe acute respiratory syndrome coronavirus-2 infection without any risk factors for pneumothorax and who had not received positive pressure ventilation. Why Should an Emergency Physician Be Aware of This?: There may be a possible correlation between a recent COVID-19 infection and the development of spontaneous pneumothorax. The diagnosis of spontaneous pneumothorax should be considered in any patient with known or suspected recent COVID-19 infection who presents with new acute symptoms consistent with pneumothorax or sudden clinical deterioration.