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Malignant melanoma patients with metastatic disease confined to the limbs or liver may be treated with hyperthermic isolated regional perfusion with a chemotherapeutic agent, most commonly melphalan. This procedure enables much higher tissue concentrations of the chemotherapeutic agent compared with systemic administration. Isolated limb perfusion (ILP) is approved for treatment of cutaneous metastatic melanoma, while the efficacy of isolated hepatic perfusion (IHP) is under evaluation for the treatment of liver metastases from uveal melanoma. Following ILP and IHP tumours often gradually decrease in size during a period of several months, which might be explained by a treatment-induced immunological anti-tumour response. This thesis aimed at investigating the potential role of the immune system for treatment response to ILP and IHP utilising in vivo analyses of patient material and mice models and in vitro cell cultures. As reported in Paper I and Paper II, patients who harboured a high fraction of activated and antigen-specific T cells in blood prior to ILP were more likely to achieve a complete disappearance of tumours following ILP. Furthermore, the in vitro and in vivo assays showed that melphalan exposure enhanced the activation of T cells and increased the numbers of intermediate and non-classical monocytes. This may be due to the melphalan-induced upregulation of immune-related stress markers on melanoma cells, which in turn stimulated immune cells. In Paper III it was reported that high levels of interferon-stimulated gene products in patient blood, including CXCL10, CCL2 and PD-L2, were predictive of a favourable treatment response to ILP, and that the receptors of these ligands increased on immune cells following treatment. Paper IV describes different T cell immune profiles in blood between uveal melanoma patients and healthy controls, and showed that melanoma patients harboured a lower frequency of CD8+ T cells and more regulatory T cells. Uveal melanoma patients achieved a longer progression-free survival following IHP if they harboured a high fraction of activated T cells in blood. In conclusion, the findings presented in this thesis point towards a role of the immune system for treatment responses following both ILP and IHP, suggesting that it may be beneficial to combine isolated regional perfusion with immunotherapy.

Patients with primary irresectable, locally advanced soft tissue sarcomas of the limbs form a challenging group for the treating physician. Multimodality treatment is necessary to guarantee optimal limb salvage and survival rates. Since the introduction of isolated limb perfusion in the late fifties, several treatment regimens have been proposed. Isolated perfusion with melphalan and TNF-alpha, as part of a multimodality treatment, is regarded as the current best treatment option today. Ongoing studies are investigating potential benefit of other doses, new chemotherapeutic agents and new techniques in perfusion and radiotherapy. This article provides a historical overview of published literature and insight in upcoming treatment techniques. (C) 2012 Elsevier Ltd. All rights reserved.

Patients with primary irresectable, locally advanced soft tissue sarcomas of the limbs form a challenging group for the treating physician. Multimodality treatment is necessary to guarantee optimal limb salvage and survival rates. Since the introduction of isolated limb perfusion in the late fifties, several treatment regimens have been proposed. Isolated perfusion with melphalan and TNF-alpha, as part of a multimodality treatment, is regarded as the current best treatment option today. Ongoing studies are investigating potential benefit of other doses, new chemotherapeutic agents and new techniques in perfusion and radiotherapy. This article provides a historical overview of published literature and insight in upcoming treatment techniques. (C) 2012 Elsevier Ltd. All rights reserved.

Background and Objectives: Dose reduction and shortening of duration of perfusion in isolated limb perfusion with TNF-alpha and Melphalan (TMILP) are associated with less systemic toxicity and seem to be safe and effective on short-term. However, data on long-term patient outcome are scarce.Methods: From 1991 to 2008, 102 TM-ILPs were performed in 98 patients for a locally advanced soft tissue sarcoma of the extremity. Perfusions were categorized in three groups: (A) high dose and long duration (n = 59), (B) high dose and short duration (n 16), and (C) low dose and short duration (n = 27). Long-term local control rates and (limb)-survival were evaluated.Results: Limb salvage rates were in group A 76.3%, B 62.5%, and C 85.2% (P = 0.2). With a median follow up of 76 (range 4-203) months, 50 patients were still alive (51%). Disease-specific 5-year survival was not different between the three groups: A 55.4%, B 52.5%, and C 57.3% (P = 0.9). There was no difference in local recurrence-free 5-year survival (adjusted P = 0.1) and distant metastases-free survival (P = 0.9).Conclusions: Dose reduction and shorter duration of TM-ILP seem to be safe and effective regarding long-term patient outcome, as 5-year local control rates and (limb)-survival are not compromised. J. Surg. Oncol. 2011;103:648-655. (C) 2011 Wiley-Liss, Inc.

The biological behavior of melanoma is unpredictable. Three to five per cent of melanoma patients will develop in-transit lesions and the median time to recurrence ranges between 13-16 months. At the time of recurrence the risk of occult nodal metastasis, with clinically negative regional lymph nodes, is as high as 50%. The risk of in-transit lesions depends on the tumor biology and not on the surgical approach to the regional lymph nodes. The high incidence of in-transit lesions at the lower limb may be caused by the gravity and delayed lymphatic drainage. The treatment of limited disease is local excision, laser ablation, cryosurgery, while multiple in-transit lesions or bulky disease located in a limb can be successfully treated with regional chemotherapy, a therapeutic isolated limb perfusion or infusion with melphalan or a combination of melphalan and tumor necrosis factor (TNF) alpha. If local regional treatment or systemic dacarbazine based systemic treatment fails, novel systemic treatment strategies with vaccines, antibodies and gene therapy are currently investigated.

Item does not contain fulltext BACKGROUND: The aim of this study was to investigate the long-term limb salvage rate and overall survival after isolated limb perfusion (ILP) with tumor necrosis factor alpha and melphalan for locally advanced soft tissue sarcoma (STS). METHODS: From 1991 to 2003, 73 patients (36 men, 37 women, median age 54 [range 14-80] years) with biopsy-proven STS underwent 77 perfusions followed by delayed surgical resection, with or without adjuvant radiation. Limb salvage and overall survival curves were calculated by the Kaplan-Meier method. RESULTS: A total of 21 amputations (28%) were performed. Overall 1, 5, and 10 years' limb salvage was 80.1% +/- 4.8%, 68.2% +/- 6.5%, and 60.6% +/- 9.2%, respectively. We found that the risk of amputation was linked to three time periods. The first was within a year after perfusion, mainly as a result of massive necrosis of the tumor and overlying skin, resulting in soft tissue deficit or recurrent disease (n = 17). The second was within 5 years, with two amputations performed for late local recurrence. The third occurred 10 years after perfusion, with two amputations performed for critical leg ischemia. Another two patients developed a pathological fracture of the femur due to radiation osteonecrosis. These four patients received adjuvant radiotherapy. Overall, 1, 5, and 10 years' survival was 82.9% +/- 9.2%, 58.7% +/- 13.1%, and 42.5% +/- 18.2%, respectively. CONCLUSIONS: ILP treatment with tumor necrosis factor alpha and melphalan followed by delayed surgical resection and adjuvant radiation treatment is an effective limb salvage treatment regimen for locally advanced STS. However, we observed late morbidity, with two amputations performed for critical leg ischemia and two pathological fractures of the femur in patients receiving adjuvant radiotherapy.

Background: Hyperthermic isolated limb perfusion (HILP) with tumor necrosis factor alpha (TNF-alpha), interferon gamma, and melphalan has proved to be useful in the treatment of recurrent malignant melanoma and of locally advanced soft tissue sarcomas of the extremities.Objective: To determine whether this modality is also effective in the treatment of locally advanced nonmelanoma skin tumors of the extremities.Patients and Methods: Fifteen patients with locally advanced primary, recurrent, or metastatic skin tumors of the extremities (12 with squamous cell carcinoma and 3 with Merkel cell carcinoma) underwent HILP with TNF-alpha, interferon gamma, and melphalan. Six tumors were localized in the upper extremity (40%), and 9 in the lower extremity (60%). Treatment-related complications, limb salvage rate, local recurrence, and regional and distant metastases were scored during a median follow-up of 20 months.Results: After HILP, 9 patients (60%) Showed a complete response (with histopathological confirmation). Four patients (27%) showed a partial response (with histopathological confirmation in 1 patient), and 2 patients (13%) showed no change (with histopathological confirmation in 1 patient and with clinical evidence in 1 patient). Two patients (13%) showed treatment-related complications. The limb salvage was achieved in 12 patients (80%), and the local recurrences developed in 4 patients (27%). During follow-up, regional lymph node metastases were observed in 2 patients (13%) and distant metastases in 2 patients (13%).Conclusion: Based on our results, HILP with TNF-alpha, interferon gamma, and melphalan should be considered as a limb-saving treatment modality in patients with locally advanced nonmelanoma skin tumors of the extremities who would otherwise be candidates for ablative surgery.

Purpose: Hyperthermic isolated limb perfusion (HILP) with tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), and melphalan is associated with a dramatic antitumor effect in locally advanced extremity soft-tissue sarcomas (STS). The aim of this study was to demonstrate the feasibility and efficacy of adjuvant radiotherapy after HILP with TNF-alpha, IFN-gamma, and melphalan and delayed surgical resection.Methods and Materials: Between 1991 and 1995, 34 patients-16 males and 18 females, median age 50 (range 18-80) years-underwent HILP for locally advanced extremity STS. Resection of the residual tumor mass was performed in most patients after 6-8 weeks. Fifteen patients with histopathological viable tumor after resection received adjuvent 60-70 Gy external beam radiotherapy (EBRT) (44%, HILP + EBRT group). Nineteen patients received HILP without adjuvent EBRT (56%, HILP-only group). Five patients in the HILP-only group had also distant metastases (15%) and received HILP as a palliative treatment. Treatment morbidity, local recurrences, and regional and distant metastases ere scored.Results: During a median follow-up of 34 months (range 8-54), Limb salvage was achieved in 29 patients (85%): 14 patients after HILP + EBRT and 15 patients after HILP only. None of the patients from the HILP + EBRT group developed local recurrences; however, five patients from the HILP-only did (26%) (p Conclusion: Adjuvent EBRT after HILP with TNF-alpha, IFN-gamma, and melphalan and delayed tumor resection of locally advanced extremity STS is feasible and may increase local tumor control without increasing treatment morbidity. (C) 1998 Elsevier Science Inc.

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. In these cases, amputation is the only means of resecting the tumour. A new combination of drugs used in the set-up of HILP with tumour necrosis factor-alpha and melphalan has emerged as a very promising option for the limb-saving management of locally advanced STS. In recent studies, complete response rates of approximately 30% and partial remission rates of 50% have been achieved, while the overall limb-salvage rate is more than 80%. (C) 1998 Wiley-Liss, Inc.

Background: Hyperthermic isolated limb perfusion (HILP) with tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), and melphalan is associated with a dramatic anti-tumor effect in which the neo-vascularization of the tumor is supposed to be the major target, The aim of the present study was to correlate the angiographic findings with the pathological response in patients undergoing HILP for locally advanced soft-tissue sarcoma,Patients and Methods: Twenty-five patients, 14 male and 11 female, mean age 47 years (range 18-80) were studied. Angiographies were performed before and a median period of 7 weeks (range 4-14 weeks) after HILP. Eight weeks after perfusion, the residual tumor mass was resected and pathologically examined, The changes in tumor vascularization after treatment were scored and compared with the pathological response,Results: All baseline angiograms showed a hypervascular tumor. After HILP, a normal angiography result (NA) was observed in 18 patients (72%) and an abnormal angiography result (AA) was observed in seven patients (28%). All patients with an NA showed a pathologically complete response (pCR) or a pathological partial response with >90% necrosis of the tumor, Of seven patients with an AA, pathological examination showed a PCR in one patient, 10-50% viable tumor volume in four patients, and no pathological response after perfusion in two patients. A good correlation was seen between angiographic and pathological classification (p Conclusion: An angiography performed after hyperthermic isolated limb perfusion with TNF-alpha and melphalan provides a good indication, regardless of whether a good pathological response is expected.

The value of hyperthermic isolated limb perfusion (HILP),vith cisplatin in the management of locally advanced soft tissue sarcomas or metastatic bone sarcoma was studied, Four patients mere treated with HILP under mild hyperthermia (39-40 degrees C) with 20-30 mg cisplatin/l perfused limb volume, Toxicity in the perfused limbs was moderate, and the erythema and oedema that occurred resolved spontaneously within 7-14 days as did the slight motor and sensory neuropathy over a longer period of time. Clinically, a reduction of pain was observed in all patients, Two weeks after perfusion, tumour biopsies were taken to evaluate tumour response, Two patients showed a pathological complete response, one patient showed >90% necrosis and one patient showed no response. Currently patients are treated with tumour necrosis factor and melphalan as perfusion agents. The above-mentioned results make the combination of tumour necrosis factor with cisplatin in the isolated limb perfusion setting an interesting option.

Background and Objectives: Dose reduction and shortening of duration of perfusion in isolated limb perfusion with TNF-alpha and Melphalan (TMILP) are associated with less systemic toxicity and seem to be safe and effective on short-term. However, data on long-term patient outcome are scarce. Methods: From 1991 to 2008, 102 TM-ILPs were performed in 98 patients for a locally advanced soft tissue sarcoma of the extremity. Perfusions were categorized in three groups: (A) high dose and long duration (n = 59), (B) high dose and short duration (n 16), and (C) low dose and short duration (n = 27). Long-term local control rates and (limb)-survival were evaluated. Results: Limb salvage rates were in group A 76.3%, B 62.5%, and C 85.2% (P = 0.2). With a median follow up of 76 (range 4-203) months, 50 patients were still alive (51%). Disease-specific 5-year survival was not different between the three groups: A 55.4%, B 52.5%, and C 57.3% (P = 0.9). There was no difference in local recurrence-free 5-year survival (adjusted P = 0.1) and distant metastases-free survival (P = 0.9). Conclusions: Dose reduction and shorter duration of TM-ILP seem to be safe and effective regarding long-term patient outcome, as 5-year local control rates and (limb)-survival are not compromised. J. Surg. Oncol. 2011;103:648-655. (C) 2011 Wiley-Liss, Inc.

Background. Hyperthermic isolated limb perfusion (HILP) has been shown to be effective for locoregional metastases or local recurrent disease. Locoregional recurrences after previous HILP is an unsolved problem.Methods. HILP with cisplatin, 20-30 mg/l perfused limb volume, was performed in seven patients with recurrent melanoma (five with Stage IIIA and two with Stage IIIAB) after previous HILP with melphalan with or without dactinomycin. A cisplatin perfusion without local excision was performed in four patients; this treatment resulted in two complete responses and one partial response. In three patients, a cisplatin perfusion was performed with local excision of the in-transit metastases.Results. During a median follow-up of 20 months (range, 10-25 months), in five (83%) patients the tumor recurred locally after a median period of 5 months (range, 3-11 months). No systemic toxicity was observed. Local toxicity consisted of postperfusion edema and neurotoxicity in all patients. The edema resolved within 2 weeks, which was in contrast to persistent neurotoxicity. A severe motor-sensory neuropathy was observed in three (43%) patients and mild sensory neuropathy in four (57%) patients.Conclusions. The severe neurotoxicity and the high local recurrence rate do not justify the use of HILP with cisplatin for recurrent melanoma after previous HILP with melphalan with or without dactinomycin.

For more than 50 years, the technique of extremity perfusion has been explored in the limb salvage treatment of local, recurrent, and multifocal sarcomas. The "discovery" of tumor necrosis factor-or. in combination with melphalan was a real breakthrough in the treatment of primarily irresectable extremity sarcomas. Development of new treatment strategies in extremity perfusion, better perfusion or infusion equipment, and modifying the technique and the use of molecular imaging technology might further improve limb salvage rates and decrease local failures in the future and provide more insight into the tumor biology of sarcoma.

Background: Hyperthermic isolated limb perfusion (HILP) with tumor necrosis factor alpha (TNF-alpha), interferon gamma, and melphalan has proved to be useful in the treatment of recurrent malignant melanoma and of locally advanced soft tissue sarcomas of the extremities. Objective: To determine whether this modality is also effective in the treatment of locally advanced nonmelanoma skin tumors of the extremities. Patients and Methods: Fifteen patients with locally advanced primary, recurrent, or metastatic skin tumors of the extremities (12 with squamous cell carcinoma and 3 with Merkel cell carcinoma) underwent HILP with TNF-alpha, interferon gamma, and melphalan. Six tumors were localized in the upper extremity (40%), and 9 in the lower extremity (60%). Treatment-related complications, limb salvage rate, local recurrence, and regional and distant metastases were scored during a median follow-up of 20 months. Results: After HILP, 9 patients (60%) Showed a complete response (with histopathological confirmation). Four patients (27%) showed a partial response (with histopathological confirmation in 1 patient), and 2 patients (13%) showed no change (with histopathological confirmation in 1 patient and with clinical evidence in 1 patient). Two patients (13%) showed treatment-related complications. The limb salvage was achieved in 12 patients (80%), and the local recurrences developed in 4 patients (27%). During follow-up, regional lymph node metastases were observed in 2 patients (13%) and distant metastases in 2 patients (13%). Conclusion: Based on our results, HILP with TNF-alpha, interferon gamma, and melphalan should be considered as a limb-saving treatment modality in patients with locally advanced nonmelanoma skin tumors of the extremities who would otherwise be candidates for ablative surgery.

Purpose: Hyperthermic isolated limb perfusion (HILP) with tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), and melphalan is associated with a dramatic antitumor effect in locally advanced extremity soft-tissue sarcomas (STS). The aim of this study was to demonstrate the feasibility and efficacy of adjuvant radiotherapy after HILP with TNF-alpha, IFN-gamma, and melphalan and delayed surgical resection. Methods and Materials: Between 1991 and 1995, 34 patients-16 males and 18 females, median age 50 (range 18-80) years-underwent HILP for locally advanced extremity STS. Resection of the residual tumor mass was performed in most patients after 6-8 weeks. Fifteen patients with histopathological viable tumor after resection received adjuvent 60-70 Gy external beam radiotherapy (EBRT) (44%, HILP + EBRT group). Nineteen patients received HILP without adjuvent EBRT (56%, HILP-only group). Five patients in the HILP-only group had also distant metastases (15%) and received HILP as a palliative treatment. Treatment morbidity, local recurrences, and regional and distant metastases ere scored. Results: During a median follow-up of 34 months (range 8-54), Limb salvage was achieved in 29 patients (85%): 14 patients after HILP + EBRT and 15 patients after HILP only. None of the patients from the HILP + EBRT group developed local recurrences; however, five patients from the HILP-only did (26%) (p

Background: Hyperthermic isolated limb perfusion (HILP) with tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), and melphalan is associated with a dramatic anti-tumor effect in which the neo-vascularization of the tumor is supposed to be the major target, The aim of the present study was to correlate the angiographic findings with the pathological response in patients undergoing HILP for locally advanced soft-tissue sarcoma, Patients and Methods: Twenty-five patients, 14 male and 11 female, mean age 47 years (range 18-80) were studied. Angiographies were performed before and a median period of 7 weeks (range 4-14 weeks) after HILP. Eight weeks after perfusion, the residual tumor mass was resected and pathologically examined, The changes in tumor vascularization after treatment were scored and compared with the pathological response, Results: All baseline angiograms showed a hypervascular tumor. After HILP, a normal angiography result (NA) was observed in 18 patients (72%) and an abnormal angiography result (AA) was observed in seven patients (28%). All patients with an NA showed a pathologically complete response (pCR) or a pathological partial response with >90% necrosis of the tumor, Of seven patients with an AA, pathological examination showed a PCR in one patient, 10-50% viable tumor volume in four patients, and no pathological response after perfusion in two patients. A good correlation was seen between angiographic and pathological classification (p

The value of hyperthermic isolated limb perfusion (HILP),vith cisplatin in the management of locally advanced soft tissue sarcomas or metastatic bone sarcoma was studied, Four patients mere treated with HILP under mild hyperthermia (39-40 degrees C) with 20-30 mg cisplatin/l perfused limb volume, Toxicity in the perfused limbs was moderate, and the erythema and oedema that occurred resolved spontaneously within 7-14 days as did the slight motor and sensory neuropathy over a longer period of time. Clinically, a reduction of pain was observed in all patients, Two weeks after perfusion, tumour biopsies were taken to evaluate tumour response, Two patients showed a pathological complete response, one patient showed >90% necrosis and one patient showed no response. Currently patients are treated with tumour necrosis factor and melphalan as perfusion agents. The above-mentioned results make the combination of tumour necrosis factor with cisplatin in the isolated limb perfusion setting an interesting option.

Background. Hyperthermic isolated limb perfusion (HILP) has been shown to be effective for locoregional metastases or local recurrent disease. Locoregional recurrences after previous HILP is an unsolved problem. Methods. HILP with cisplatin, 20-30 mg/l perfused limb volume, was performed in seven patients with recurrent melanoma (five with Stage IIIA and two with Stage IIIAB) after previous HILP with melphalan with or without dactinomycin. A cisplatin perfusion without local excision was performed in four patients; this treatment resulted in two complete responses and one partial response. In three patients, a cisplatin perfusion was performed with local excision of the in-transit metastases. Results. During a median follow-up of 20 months (range, 10-25 months), in five (83%) patients the tumor recurred locally after a median period of 5 months (range, 3-11 months). No systemic toxicity was observed. Local toxicity consisted of postperfusion edema and neurotoxicity in all patients. The edema resolved within 2 weeks, which was in contrast to persistent neurotoxicity. A severe motor-sensory neuropathy was observed in three (43%) patients and mild sensory neuropathy in four (57%) patients. Conclusions. The severe neurotoxicity and the high local recurrence rate do not justify the use of HILP with cisplatin for recurrent melanoma after previous HILP with melphalan with or without dactinomycin.