{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T15:08:17Z","timestamp":1790867297798,"version":"4.1.0"},"reference-count":37,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[1992,3,1]],"date-time":"1992-03-01T00:00:00Z","timestamp":699408000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["World j. surg."],"published-print":{"date-parts":[[1992,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>To increase the therapeutic efficacy of recombinant tumor necrosis factor alpha (rTNF\u03b1) and reduce the systemic side effects, a protocol was designed using isolation perfusion of the limbs with hyperthermia for in transit metastases of melanoma. A triple combination of high dose rTNF\u03b1 + recombinant interferon\u2010gamma (rIFN\u2010\u03b3) + melphalan was chosen because of a synergistic anti\u2010tumor effect of rTNF\u03b1 with rIFN\u2010\u03b3 and of rTNF\u03b1 with alkylating agents reported in the literature. Twenty\u2010nine patients of mean age 60 years (range 22\u201382 years) entered the study after informed consent and received a total of 31 isolation perfusions with the triple combination. There were 24 women and 5\u00a0men with multiple progressive<jats:italic>in transit<\/jats:italic> melanoma metastases of the lower limb (stage IIIa or IIIab). rTNF\u03b1 at the unique dose of 4\u00a0mg was injected as a bolus in the arterial line, under mild hyperthermic conditions (40 to 40.5\u00b0C) for 90\u00a0minutes. rIFN\u2010\u03b3 was given subcutaneously on days \u22122 and \u22121 and in the perfusate, with rTNF\u03b1, at the dose of 0.2\u00a0mg. Melphalan was administered in the perfusate at dose giving a concentration of 40 \u00b5g\/ml.<\/jats:p><jats:p>In all the 31 isolation perfusions performed in the triple combination protocol, in order to prevent a septic shock\u2010like syndrome which had been encountered in 2 patients treated outside this protocol for sarcoma and carcinoma, the patients received dopamine continuous infusion at 3 \u00b5g\/kg\/min from the start of isolation perfusion and for 48 hours, and only showed mild hyptension and very transient chills and temperature. Regional toxicity attributable to rTNF\u03b1 was minimal. There have been 16 patients with hematologic toxicity consisting of neutropenia (11 cases, 1 case grade 4 and 1 case grade 3) and neutropenia with thrombocytopenia (12 cases, 1 case grade 4 and 4 cases grade 2). Eighteen of 29 patients had been previously treated with melphalan in isolation perfusion (n=13) or with cisplatinum (n=2), rTNF\u03b1\u2010Melphalan (n=1), or rTNF\u03b1 alone (n=2). Median follow\u2010up has been 41 weeks. The 29 patients are evaluable: there have been 26 (90%) complete remissions (CR), 3 (10%) partial remissions (PR), and no failures. Actuarial disease\u2010free survival and total survival have been 63% and 73%, respectively, at 12\u00a0months. In all cases, softening of the nodules was obvious within 3\u00a0days after isolation perfusion and time to definite response ranged between day 6 and 22.<\/jats:p><jats:p>This interim analysis of a phase II study suggests that high dose of rTNF\u03b1 can be administered with acceptable toxicity by isolation perfusion with dopamine and hyperhydration. Tumor responses can be evidenced in all patients, with 90% CR. Furthermore, combination of rTNF\u03b1, rIFN\u2010\u03b3, and melphalan seems to achieve high efficacy with minimal toxicity, even after failure of prior therapy with melphalan alone.<\/jats:p>","DOI":"10.1007\/bf02071526","type":"journal-article","created":{"date-parts":[[2005,8,13]],"date-time":"2005-08-13T21:02:16Z","timestamp":1123966936000},"page":"234-240","source":"Crossref","is-referenced-by-count":101,"title":["In transit metastases of malignant melanoma treated by high dose rTNF\u03b1 in combination with interferon\u2010\u03b3 and melphalan in isolation perfusion"],"prefix":"10.1002","volume":"16","author":[{"given":"Danielle","family":"Li\u00e9nard","sequence":"first","affiliation":[{"name":"Laboratory of Oncology and Experimental Surgery, Melanoma and Sarcoma Clinic Department of Surgery, and Department of Anaesthesiology Jules Bordet Institute Universit\u00e9 Libre de Bruxelles Belgium"},{"name":"C.P.O.\u2010C.H.U.V. Rue du Bugnon CH\u20101011 Lausanne"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ferdy J.","family":"Lejeune","sequence":"additional","affiliation":[{"name":"Laboratory of Oncology and Experimental Surgery, Melanoma and Sarcoma Clinic Department of Surgery, and Department of Anaesthesiology Jules Bordet Institute Universit\u00e9 Libre de Bruxelles Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Ewalenko","sequence":"additional","affiliation":[{"name":"Laboratory of Oncology and Experimental Surgery, Melanoma and Sarcoma Clinic Department of Surgery, and Department of Anaesthesiology Jules Bordet Institute Universit\u00e9 Libre de Bruxelles Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[1992,3]]},"reference":[{"key":"e_1_2_1_2_1","first-page":"3990","article-title":"Human tumor xenografts treated with human TNF alone or in combination with IF","volume":"46","author":"Balkwill F.","year":"1986","journal-title":"Cancer Res."},{"key":"e_1_2_1_3_1","first-page":"4755","article-title":"Therapeutic potential of tumour necrosis factor alpha and gamma interferon in experimental human ovarian cancer","volume":"47","author":"Balkwill F.","year":"1987","journal-title":"Cancer Res."},{"key":"e_1_2_1_4_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.3764421"},{"key":"e_1_2_1_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/330662a0"},{"key":"e_1_2_1_6_1","first-page":"4057","article-title":"Phase I trial of recombinant human gamma\u2010interferon and recombinant human tumor necrosis factor in patients with advanced gastrointestinal cancer","volume":"49","author":"Abbruzzese J.","year":"1989","journal-title":"Cancer Res."},{"key":"e_1_2_1_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/0277-5379(89)90034-5"},{"key":"e_1_2_1_8_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.298.6683.1290"},{"key":"e_1_2_1_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00267953"},{"key":"e_1_2_1_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/0277-5379(89)90021-7"},{"key":"e_1_2_1_11_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.72.9.3666"},{"key":"e_1_2_1_12_1","doi-asserted-by":"publisher","DOI":"10.1097\/00000658-197010000-00018"},{"key":"e_1_2_1_13_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.138.11.4023"},{"key":"e_1_2_1_14_1","first-page":"185","volume-title":"General discussion II. 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