Jan P. Deroose

Long-Term Results of Tumor Necrosis Factor α– and Melphalan-Based Isolated Limb Perfusion in Locally Advanced Extremity Soft Tissue Sarcomas

PURPOSE Because there is no survival benefit of amputation for extremity soft tissue sarcomas (STSs), limb-sparing surgery has become the gold standard. Tumor size reduction by induction therapy to render nonresectable tumors resectable or facilitate function-preserving surgery can be achieved by tumor necrosis factor α (TNF) -based and melphalan-based isolated limb perfusion (TM-ILP). This study reports the long-term results of 231 TM-ILPs for locally advanced extremity STS. PATIENTS AND METHODS We analyzed 231 TM-ILPs in 208 consecutive patients (1991 to 2005), who were all candidates for functional or anatomic amputation for locally advanced extremity STS. All patients had a potential follow-up of up to 5 years. TM-ILP was performed under mild hyperthermic conditions with 1 to 4 mg of TNF and 10 to 13 mg/L of limb-volume melphalan. Almost all patients (85%) had intermediate- or high-grade tumors. RESULTS The overall response rate (ORR) was 71% (complete response, 18%; partial response, 53%). Multifocal sarcomas had a significantly better ORR of 83% (P = .008). The local recurrence rate was 30% (n = 70); local recurrence rates were highest for multifocal tumors (54%; P = .001) and after previous radiotherapy (54%; P < .001). Five-year overall survival rate was 42%. Survival was poorest in patients with large tumors (P = .01) and with leiomyosarcomas (P < .001). Limb salvage rate was 81%. CONCLUSION We demonstrated that TM-ILP results in a limb salvage rate of 81% in patients with locally advanced extremity STS who would otherwise have undergone amputation. Whenever an amputation is deemed necessary to obtain local control of an extremity STS, TM-ILP should be considered.

Local and intralesional therapy of in-transit melanoma metastases.

Regional relapse of melanoma may occur as satellite or in‐transit metastases proximal to the primary tumor in the direction of the lymph flow. The management of in‐transit metastases is challenging because the efficacy of treatment is largely dictated by the biological behavior of the patients melanoma. This review examines local treatment modalities. J. Surg. Oncol. 2011; 104:391–396.

Long-term outcome of isolated limb perfusion with tumour necrosis factor-α for patients with melanoma in-transit metastases.

The use of tumour necrosis factor (TNF) α in isolated limb perfusion (ILP) for in‐transit melanoma metastasis is not uniformly accepted. This article reports the long‐term results of adding TNF‐α to standard melphalan‐based ILP (TM‐ILP) for treatment of melanoma in‐transit metastases.

Hepatic steatosis is not always a contraindication for cadaveric liver transplantation

BACKGROUND Macrovesicular steatosis is assumed to be an important risk factor for early allograft dysfunction (EAD) after orthotopic liver transplantation (OLT). AIM To evaluate the impact of steatosis in combination with other risk factors on the outcome of OLT. METHODS The degree of steatosis was analysed in 165 consecutive OLTs and was classified by histological examination as non (M0), mild (<30%, M1), moderate (30-60%, M2) or severe steatosis (>60%, M3). Recipients were analysed for EAD. RESULTS EAD was observed in 28% of patients with M0, 26% with M1, 53% with M2 and 73% with M3 (P < 0.001). Patients with EAD had a significantly shorter graft survival after liver transplantation (P = 0.005) but did not correlate with survival. In multivariate regression analysis, the grade of steatosis, donating after cardiocirculatory death (DCD) grafts and duration of cold ischaemia time were significantly associated with EAD (P < 0.001, P = 0.01 and P = 0.001, respectively). CONCLUSION Livers with severe (M3) steatosis from DCD donors, combined with a prolonged CIT have a high risk for developing EAD which is correlated with shorter graft survival. Therefore M3 livers should only be considered for OLT in selected recipients without the presence of additional risk factors.

Isolated limb perfusion for melanoma in-transit metastases: developments in recent years and the role of tumor necrosis factor alpha.

Purpose of review The treatment of in-transit metastasis of melanoma remains challenging and is essentially dictated by the biological behavior of melanoma. When lesions are large or numerous, isolated limb perfusion (ILP) is an attractive treatment modality. In this review an overview of literature on treatment options of melanoma in-transit metastases will be discussed. Recent findings Most recent studies report on tumor necrosis factor (TNF) and melphalan based ILP (TM-ILP) series or mixed series of TM-ILP and melphalan only based ILP (M-ILP). After TM-ILP complete response rates of 70% (range 44–90%) have been reported, while for M-ILP this is lower with complete response rates of 54% (range 40–76%). The only randomized trial comparing TM-ILP and M-ILP revealed no clear benefit of TNF at 3 months, but improved outcome at 6 months and in patients with bulky disease. Reports on isolated limb infusion (ILI) with melphalan and actinimycin D indicate lower response rates, but similar local control rates as M-ILP at lower cost. Summary ILP is an attractive treatment option in melanoma patients with multiple in-transit metastases. In our opinion TM-ILP is superior to M-ILP as it achieves higher response rates, especially in patients with bulky disease. When lesions are small and in the distal two-thirds of the leg only, ILI is a valuable alternative.

Isolated limb perfusion with TNF-alpha and melphalan for distal parts of the limb in soft tissue sarcoma patients.

Approximately 10% of soft tissue sarcomas (STS) occur in the most distal parts of the extremities. The standard therapy is local excision with adjuvant radiotherapy, but achieving wide resection margins might be difficult in the distal parts of the limb. Tumor necrosis factor‐alpha (TNF) and melphalan‐based isolated limb perfusion (TM‐ILP) is effective in locally advanced STS of the extremities. We report the results of TM‐ILP for STS in the most distal parts of the limb.

Isolated limb perfusion using tumour necrosis factor α and melphalan in patients with advanced aggressive fibromatosis

Aggressive fibromatoses (desmoid tumours) may be locally aggressive, but do not metastasize. Although a conservative approach is advocated for most patients, pain and functional impairment are indications for active treatment. Tumour necrosis factor (TNF) α and melphalan‐based isolated limb perfusion (TM‐ILP) is a limb‐saving treatment modality for soft tissue tumours. This study reports the results of TM‐ILP treatment in patients with aggressive fibromatosis.

Treatment modifications in tumour necrosis factor-α (TNF)-based isolated limb perfusion in patients with advanced extremity soft tissue sarcomas

BACKGROUND Tumour necrosis factor-α (TNF) and melphalan based isolated limb perfusion (TM-ILP) is an attractive treatment option for advanced extremity soft tissue sarcomas (STS). This study reports on a 20-year single centre experience and discusses the evolution and changes in methodology since the introduction of TNF in ILP. PATIENTS AND METHODS We performed 306 TM-ILPs in 275 patients with extremity STS. All patients were candidates for amputation or mutilating surgery in order to achieve local control. Clinical response evaluation consisted of clinical examination and magnetic resonance imaging. To evaluate the importance of TNF-dose, treatment results of two periods (1991-2003 high dose (3-4 mg) TNF; 2003-2012 reduced dose (1-2mg) TNF) were compared. RESULTS During the study period, more femoral perfusions were done instead of iliac perfusions. Reduction of TNF dose and reduction of total ILP time did not lead to different clinical response rates (70% and 69% for periods 1 and 2 respectively) or different local recurrence rates, but was associated with less local toxicity (23% and 14% for periods 1 and 2 respectively). Hospital stay was significantly reduced during the study period. There was an improved pathological response in the high dose TNF group without consequences for clinical outcome. CONCLUSION TM-ILP remains a very effective treatment modality for limb threatening extremity STS. Moreover, reduction of dose and the growing experience in ILP led to less local toxicity and shorter hospital stay.

Repeated isolated limb perfusion in melanoma patients with recurrent in-transit metastases.

In-transit metastases of melanoma occur in 5–8% of all melanoma patients. In case of extensive locoregional disease, Tumor necrosis factor-&agr; and melphalan-based isolated limb perfusion (TM-ILP) had proven to yield excellent local control. Here, we report on repeat TM-ILP for locoregional recurrence after isolated limb perfusion. Between 1991 and 2013, 37 consecutive repeat TM-ILPs were analyzed in 32 different patients. Three patients underwent a third TM-ILP. During a median follow-up of 20 months after repeat TM-ILP, the overall response rate was 86%. Complete response (CR) was recorded after 24 TM-ILPs (65%). CR after first TM-ILP was a strong predictor for successful repeat TM-ILP in terms of clinical response and local recurrence. Local toxicity was mild (70% Wieberdink I–II). The local recurrence rate was 59%. Five-year overall survival was 35%. Repeat TM-ILP is a safe treatment modality in melanoma patients with recurrent in-transit metastases of melanoma. Those with a CR after first TM-ILP benefit the most from repeat TM-ILP.

Isolated limb perfusion for unresectable extremity cutaneous squamous cell carcinoma; an effective limb saving strategy

BackgroundA small minority of patients present with locally advanced cutaneous Squamous Cell Carcinoma (cSCC). The aim of this study was to evaluate the effectiveness of Tumour necrosis factor α (TNF) and melphalan based isolated limb perfusion (TM-ILP) as a limb saving strategy for locally advanced extremity cSCC.MethodsA retrospective search from prospectively maintained databases, at two tertiary referral centers, was performed to identify patients treated with TM-ILP for locally advanced cSSC of an extremity between 2000 and 2015.ResultsA total of 30 patients treated with TM-ILP for cSCC were identified, with a median age of 71 years (36–92) and 50% female. Response could not be evaluated in 3 patients. After a median follow up of 25 months, the overall response rate was 81% (n = 22), with 16 patients having a complete response (CR, 59%). A total of 7 patients developed local recurrence, with a median time to recurrence of 9 months (Interquartile Range 7–10). Progressive disease was observed in 5 patients (19%). Limb salvage rate was 80%. The overall 2-year survival was 67%.ConclusionsTM-ILP should be considered as an option in patients with locally advanced cSCC in specialised centers, resulting in a high limb salvage rate.