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e23539 Background: Induction isolated limb perfusion (ILP) followed by limb-sparing resection or extended resection are frequently used limb salvation strategies (LSS) in locally advanced extremity soft tissue sarcoma (eSTS) to prevent amputation. However little is known about the long term health-related quality of life (HRQoL) in these patients. The aim of this study was to compare long-term patient reported outcomes (PROs) such as HRQoL after ILP compared to extended resection or amputation. Methods: Patients treated with an ILP, extended resection, or amputation were selected from the respondents of a multi-institutional cross-sectional cohort survivorship study (SURVSARC) conducted 2-10 years after diagnosis among sarcoma survivors registered in the Netherlands Cancer Registry (NCR). Extended resection was defined as resection for stage III eSTS, details regarding amputation levels other than upper or lower extremity are unknown. Used PROs were the EORTC QLQ-C30, Cancer worry scale (CWS), the Hospital Anxiety and Depression Scale (HADS), and the Toronto Extremity Salvage Score (TESS). Results: We identified 96 eSTS survivors and assigned them into four groups: ILP (N = 20), extended resection (N = 48), primary amputation (N = 20), and amputation after ILP (N = 8). While there were no differences in PROs between ILP and extended resections, results showed better functioning and functionality after these two LSS groups versus the amputation groups. The amputation groups scored significantly lower on the EORTC QLQ-C30 physical functioning scale (p < 0.001, 62.7 and 65.7 versus 78.0 and 84.1) and role functioning scale (p = 0.038, 67.5 and 52.8 versus 79.2 and 80.9), which both account for a difference with ‘medium’ clinical relevance. Also for the TESS, the scores were significantly lower for the amputation groups compared to the LSS groups (upper extremity p = 0.007 with 68.9 and 71.6 versus 93.3 and 91.1; lower extremity p < 0.001 with 72.2 and 50.9 versus 84.5 and 85.5). There were no significant differences on cancer worry, anxiety and depression were found between all groups. Conclusions: Based on this survivorship study, HRQoL in eSTS survivors treated with ILP followed by limb-sparing resection is not inferior to extended resections, however it is superior in maintenance of physical functioning and functionality compared to an amputation.[Table: see text]

It perdormed the literature data analysis on the criteria and methods for assessing the clinical efficacy of the isolated limb perfusion method in the treatment of soft tissue sarcoma. It is noted that the use of isolated limb perfusion is a rather effective method providing local control of the tumor process in locally advanced forms of soft tissue sarcoma. It has been demonstrated that the use of such a neoadjuvant treatment regimen allows administration of the drug with the achievement of high local concentrations of chemotherapeutic drugs with a relatively low incidence of systemic side effects. Criteria for tumor response to therapy, in particular RECIST (Response Evaluation Criteria In Solid Tumors), Choi criteria, adapted for magnetic resonance imaging, are presented. It is noted that a number of studies have studied the possibility of using positron emission tomography with fluorodeoxyglucose labeled with 18F (18F-FDG) to assess the response to treatment in sarcomas. At the same time, it was shown that the results of studying the metabolic response are superior in accuracy to the method of assessment using the RECIST criteria and the assessment performed by the dynamics of the tumor tissue volume has significant potential in assessing the response to isolated limb perfusion in patients with soft tissue sarcoma. The importance of a one-time assessment of positron emission tomography with 18F-FDG parameters and Magnetic Resonance Imaging for soft tissue sarcoma is confirmed by the results of a combined analysis that takes into account both morphological characteristics and quantitative metabolic parameters of the tumor. The high potential of the combined assessment of metabolic and volume-morphological parameters obtained using these methods was demonstrated; it was noted that the combination of positron emission tomography data with 18F-FDG and Magnetic Resonance Imaging enhances the reliability and efficiency of planning and monitoring of soft tissue sarcoma treatment using the isolated limb perfusion method.

Hyperthermic-isolated limb perfusion (HILP) is an established modality of treatment for patients with advanced malignant melanoma of the limb in which diseased limb is infused with high concentration of chemotherapeutic agent. There is a lack of literature addressing its perioperative implications. We present a case and discuss the need for multipronged approach, team effort, and invasive hemodynamic and metabolic monitoring.

Isolated limb perfusion (ILP) is a method for treating unresectable lesions of limbs in patients with melanoma or sarcoma by using high doses of tumor necrosis factor alpha and melphalan. This high doses can result in high systemic toxicity if there is a drug leak from the isolated circulation of the limb to the systemic. This makes it imperative to monitor the leakage rate (F(%)) during the infusion, currently performed with radiotracers. The objective of this work was to develop a leakage monitoring protocol as accurate as possible to ensure safe ILP. Material and method We built a phantom with three compartments (body, limb and precordial area) and a high sensitivity collimator fitted to a portable gamma camera. We simulate ILP with scheduled leaks every 10 min from 1% to 9% (theorical F(%)). We mesured F(%) using two equation: one is the proposed in the literature and another corrected by decay of the radioisotope. We test the optimal radiopharmaceutical doses to minimize the detector dead time error and compare F(%) mesured by both equations regarding the theoretical F(%). The leakage monitoring protocol was used in 17 ILP of 16 patients and an analysis of the recorded data was performed. Results We found significant differences between F(%) mesured using the first equation and theoretical F(%), obtaining results very adjusted to the theorical after applying the decay correction. Conclusions the decay correction of the radioisotope is a simple manner to carry out the procedure more safely, reducing the error in the calculation of F(%).

Introduction Hyperthermic Ιsolated Limb Perfusion using melphalan and TNFα (TM-HILP) is a regional chemotherapy method for advanced melanoma. Purpose To explore the feasibility of the study of Circulating Melanoma Cells (CMCs) in the context of acute physiological changes induced by TM-HILP and their association with oncological outcomes. Methods The study included 20 patients undergoing TM-HILP for unresectable in-transit melanoma of the limbs, stage III(B/C/D). CMCs in the peripheral blood were analyzed at 5-time points from the preoperative day until day 7 from surgery using the following biomarkers: MITF, Tyrosinase mRNA, Melan-A and S100b, through quantitative RT-PCR. Results No CMCs according to Tyrosinase and Melan-A biomarkers were found in any sample. Friedman test showed significant alterations perioperatively for MITF (p

Introduction The management of locally advanced extremity soft tissue sarcomas, particularly in terms of a limb salvage strategy, represents a challenge, especially in recurrent tumors. In the context of a patient-tailored multimodal therapy, hyperthermic isolated limb perfusion (ILP) is a promising limb-saving treatment option. We report the outcome of patients with primarily irresectable and locally recurrent soft tissue sarcoma (STS) treated by ILP. Patients and methods Data about patient demographics, clinical und histopathological characteristics, tumor response, morbidity and oncological outcome of all patients with STS, who underwent an ILP at our institution in a 10-year period, were retrospectively detected and analyzed. Results The cohort comprised 30 patients. Two patients were treated with ILP for palliative tumor control, 13 patients because of a local recurrent soft tissue sarcoma (rSTS) and 15 patients because of primarily unresectable soft tissue sarcoma (puSTS). 25 of the 28 patients with curative intention received surgery after ILP (11 pts with rSTS and 14 pts with puSTS). Histopathologically we observed complete response in 6 patients (24%) and partial responses in 19 patients (76%) with a significant better remission in patients with puSTS (p = 0,043). Limb salvage rate was 75%. Mean follow-up was 69 months [range 13–142 months]. Seven (7/11; 64%) patients with rSTS and one (1/14; 7%) patient with puSTS developed local recurrence after ILP and surgery, whereas eight (8/13; 62%) rSTS patients and seven (7/15; 47%) puSTS patients developed distant metastasis. During follow-up, eight patients (28.5%) died of disease (5/13; 38%) rSTS and 3/15 (20%) puSTS. ILP in the group of previously irradiated sarcoma patients (n = 13) resulted in a limb salvage rate of 69% and was not associated in an increased risk for adverse events. Discussion ILP for advanced extremity STS is a treatment option for both puSTS and rSTS resulting in good local control and should be considered in multimodal management. ILP is also a good option for patients after radiation history.

Purpose: To evaluate and compare the clinical utility of simultaneously obtained quantitative 18F-fluorodeoxyglucose positron-emission-tomography (18F-FDG PET) and diffusion-weighted imaging (DWI) datasets for the prediction of histopathological therapy response of soft tissue sarcomas (STS) under neoadjuvant isolated limb perfusion (ILP). Methods: A total of 37 patients with confirmation of a STS of the extremities underwent an 18F-FDG PET/magnetic resonance imaging (MRI) examination before (1st scan) and after (2nd scan) ILP with melphalan and TNF-α. For each patient, the maximum tumor size, metabolic activity (standardized uptake values, SUV) and diffusion-restriction (apparent diffusion restriction values, ADC) were determined in pre- and posttherapeutic examinations and percentage changes during treatment were calculated. A Mann-Whitney U test was used and receiver operating characteristic (ROC) analysis was performed to compare the results of the different quantitative parameters to predict histopathological therapy response. Results from histopathological analysis after subsequent tumor resection served as reference standard and patients were defined as responders/non-responders based on the grading scale by Salzer-Kuntschik. Results: Histopathological analysis categorized 22 (59%) patients as therapy responders (Grade I-III) and 15 (41%) patients as non-responders (Grade IV-VI). Tumors in the responder group showed a mean reduction in size of -9.7% and metabolic activity (SUVpeak: -51.9%; SUVmean: -43.8%) as well as an increase of the ADC values (ADCmin: +29.4% and ADCmean: +32.8%) under treatment. Percentage changes in the non-responder group amounted to: tumor size -6.2%; SUVpeak: -17.3%; SUVmean: -13.9%; ADCmin: +15.3% and ADCmean: +14.6%. Changes of the SUVs and ADCmean values between responders and non-responders were significantly different ( 0.05). The corresponding AUCs were 0.63 (tumor size), 0.87 (SUVpeak), 0.82 (SUVmean), 0.63 (ADCmin), 0.84 (ADCmean) and 0.89 (ratio: ADCmean/SUVpeak), respectively. Conclusion:18F-FDG PET and MR-derived quantitative imaging parameters (SUVs and ADCmean) and their combination reveal a good performance for the prediction of histopathological therapy response of STS under neoadjuvant ILP. Therefore, integrated PET/MRI could serve as a valuable tool for pretherapeutic assessment as well as monitoring of neoadjuvant treatment strategies of STS.

OBJETIVO describir la experiencia inicial en Colombia en el manejo del melanoma de extremidad con perfusion aislada y comparar la respuesta de los subtipos histologicos mas frecuentes en Colombia con la literatura. MATERIALES Y METODOS estudio descriptivo, retrospectivo de una serie de pacientes con diagnostico de melanoma con metastasis en transito tratados con perfusion aislada de extremidad, seleccionados entre 2007 y 2016. Las variables cualitativas se analizaron con frecuencias absolutas y relativas. Las cuantitativas con medidas de tendencia central y dispersion. RESULTADOS 11 pacientes fueron tratados con perfusion aislada de extremidad. Hubo respuesta parcial en siete pacientes (63,6%), enfermedad estable en dos pacientes (18,2%) y progresion en dos pacientes (18,2%). Despues del tratamiento, cinco pacientes (45,5%) presentaron complicaciones menores. CONCLUSIONES la perfusion aislada sigue siendo importante para el tratamiento del melanoma localmente avanzado con el fin de mejorar la calidad de vida de los pacientes. La respuesta puede cambiar segun el tipo clinico de melanoma, siendo menor, segun este estudio, en pacientes con melanoma lentiginoso acral y nodular, aunque por el bajo poder, esto no se puede concluir. OBJECTIVE to describe the initial experience in Colombia of locally advanced melanoma treated by isolated limb perfusion and compare the response rate of our melanoma subtypes with the literature. METHODS descriptive, retrospective study of a series of patients selected between 2007 and 2016. Qualitative variables were analyzed with proportions and frequencies, and quantitative variable with central tendency measures and measures of dispersion. RESULTS 11 patients were treated by isolated limb perfusion. After the treatment, seven patients (63.6%) had partial response, two patients (18.2%) had stable disease and two patients (18.2%) had disease progression. Five patients (45.5%) had mild complications. CONCLUSIONS Isolated limb perfusion is still an important treatment strategy for locally advanced melanoma, with the goal of improving the patient quality of life. The response can change according to the type of melanoma, and could be smaller in patients with acral lentiginous and nodular melanoma, although we cannot make this conclusion with this type of study because it has low power and lack of a comparison group.

Simple Summary Melanoma still represents a major challenge for health systems around the world. A classical treatment for patients with a high tumor burden or rapidly recurrent in-transit metastases is isolated limb perfusion (ILP) therapy instead of locoregional surgical resection, or when the latter is no longer feasible. In this era of modern systemic treatments for melanoma, it still remains interesting to analyze the role of management approaches for locoregionally-advanced disease, such as isolated limb perfusion (ILP). With this purpose, we conducted a systematic review updating the available literature on ILP for malignant melanomas. The main objectives of this review were to focus on the effectiveness and safety of ILP. In conclusion, ILP, with its low incidence of regional and systemic toxicity, is a valuable palliative treatment not only for patients with disease confined to a limb, but also for patients with a metastatic melanoma with a bulky or symptomatic disease, in order to improve their quality of life. Abstract Background. Isolated limb perfusion (ILP) is a locoregional procedure indicated by the unresectable melanoma of the limbs. Its complexity and highly demanding multidisciplinary approach means that it is a technique only implemented in a few referral centers around the globe. This report aims to examine its potential role in the era of targeted therapies and immunotherapy by conducting a systematic review of the literature on ILP. Methods. PubMed, Embase and Cochrane Library were searched. The eligibility criteria included publications from 2000–2020 providing valid data o effectiveness, survival or toxicity. Studies in which the perfusion methodology was not clearly described, letters to the editor, non-systematic reviews and studies that applied outdated clinical guidelines were excluded. To rule out studies of a low methodological quality and assess the risk of bias, the following aspects were also required: a detailed description of the applied ILP regimen, the clinical context, follow-up periods, analyzed clinical endpoints, and the number of analyzed ILPs. The disagreements were resolved by consensus. The results are presented in tables and figures. Results. Twenty-seven studies including 2637 ILPs were selected. The median overall response rate was 85%, with a median complete response rate of 58.5%. The median overall survival was 38 months, with a 5-year overall survival of 35%. The toxicity was generally mild according to Wieberdink toxicity criteria. Discussion. ILP still offer a high efficacy in selected patients. The main limitation of our review is the heterogeneity and age of most of the articles, as well as the absence of clinical trials comparing ILP with other procedures, making it difficult to transfer its results to the current era. Conclusions. ILP is still an effective and safe procedure for selected patients with unresectable melanoma of the limbs. In the era of targeted therapies and immunotherapy, ILP remains an acceptable and reasonable palliative treatment alternative, especially to avoid limb amputations. The ongoing clinical trials combining systemic therapies and ILP will provide more valuable information in the future to clarify the potential synergism of both strategies.

Although many solid tumors use the lymphatic system to metastasize, there are few treatment options that directly target cancer present in the lymphatic system, and those that do are highly invasive, uncomfortable, and/or have limitations. In this review we provide a brief overview of lymphatic function and anatomy, discusses changes that befall the lymphatics in cancer and the mechanisms by which these changes occur, and highlight limitations of lymphatic drug delivery. We then go on to summarize relevant techniques and new research for targeting cancer populations in the lymphatics and enhancing drug delivery intralymphatically, including intralymphatic injections, isolated limb perfusion, passive nano drug delivery systems, and actively targeted nanomedicine.

Our purpose was to assess the diagnostic potential of simultaneously acquired 18F-FDG PET and MRI data sets for therapy response assessment of isolated limb perfusion (ILP) in patients with soft-tissue sarcomas (STS). Methods: In total, 45 patients with histopathologically verified STS were prospectively enrolled for an integrated 18F-FDG PET/MRI examination before and after ILP. Therapy response was assessed based on different MRI- and PET-derived morphologic (RECIST and the MR-adapted Choi criteria) and metabolic (PERCIST) criteria. In addition, a regression model was used combining relative changes in quantitative variables to predict treatment response under ILP. Histopathologic results after subsequent tumor resection served as the reference standard, and patients were categorized as responders or nonresponders on the basis of the 6-stage regression scale by Salzer-Kuntschik. Results: Histopathologic analysis categorized 27 patients as responders (grades I-III) and 18 patients as nonresponders (grades IV-VI). Calculated sensitivity, specificity, positive and negative predictive values, and diagnostic accuracy were 22%, 89%, 75%, 43%, and 49% for RECIST; 70%, 44%, 66%, 50%, and 60% for the Choi criteria; and 85%, 78%, 85%, 78%, and 82% for PERCIST. Receiver-operating-characteristic analysis revealed an area under the curve (AUC) of 0.56 for RECIST, 0.57 for the Choi criteria, and 0.82 for PERCIST. The combined regression model revealed higher values (AUC, 0.90) than for the stand-alone analysis, however, differences to metabolic parameters did not reach significance (P value: 0.067). Conclusion: Our study demonstrates the superiority of 18F-FDG PET over MRI data sets for response assessment of STS under neoadjuvant ILP. In a clinical setting, MRI delivers valuable information for presurgical assessment. Therefore, combining 18F-FDG PET and MRI data may enable more reliable treatment planning and therapy monitoring of STS.

Background In-transit metastasis is considered a locoregional disease in cutaneous melanoma (CM) patients. Isolated limb perfusion (ILP) is among the treatment options in selected cases. The aim of this study was to determine the success of pre- and post-perfusion mSIS values in predicting the potential complications and the prognosis of the disease by investigating the early and long-term results of mSIS values calculated before and after ILP in CM cases with in-transit metastases. Materials and methods Patients who underwent ILP within the period from 2014 to 2020 in our department were retrospectively scanned. A total of 20 patients were found to undergo ILP. The scores obtained from modified inflammation score (mSIS) were formulated according to albumin (Alb) and lymphocyte to monocyte ratio (LMR) scores. Results The mean follow-up time was 20.47 months. Complications requiring surgical intervention developed in three patients. According to the Wieberdink local toxicity classification, the majority (70%) of the patients were found to be grade II. Based on pre-perfusion mSIS values, 8 patients were classified as mSIS 0 while six patients were classified as mSIS 1 and 2. Based on post-perfusion mSIS values, 14 patients and one patient were classified as mSIS 2 (70%) and mSIS 0, respectively. Accordingly, univariate analysis showed that mSIS 1 and mSIS 2 were negative prognostic factors for mean survival in the pre-perfusion period (HR 0.162, 95% CI 0.036–0.729; p = 0.018 and HR: 0.223, 95% CI 0.049–1.019; p = 0.053) whereas albumin (Alb) and lymphocyte to monocyte ratio (LMR) were not independent prognostic factors for mean survival. Conclusion The mSIS values calculated in the pre-perfusion period can give an opinion about the OS of the patients whereas post-perfusion mSIS values may predict potential surgical complications and local toxicities.

Isolated limb perfusion (ILP) is widely accepted as treatment for recurrent melanoma limited to the limbs. The use of ILP has decreased in recent years with the introduction of potentially effective new systemic therapies. We evaluated retrospectively if ILP still may be a treatment option in locally advanced melanoma. In Finland, ILP is centralized to the Comprehensive Cancer Center of Helsinki University Hospital. We included all ILP patients treated at our hospital between 2007 and 2018. Clinical factors and treatment outcomes were retrospectively evaluated. Altogether 60 patients received ILP. Toxicity was mostly transient. The overall response rate was 77% with 35% complete responses and 42% partial responses. The median progression-free survival (PFS) was 6.1 months (range 0.6-116.5 months) and the median melanoma-specific survival (MSS) was 29.9 months (range 3.5-138.7 months). Patients with CR had superior median PFS (19.7 months, range 2.5-116.5 vs. 4.5 months, range 0.6-39.7 months, P = 0.00003) and median MSS (median MSS not reached vs. 25.9 months, range 3.5-98.7 months, P = 0.0005) compared to other responders. Younger patients (

Simple Summary In this study, we assessed the potential of simultaneously acquired 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) and magnetic resonance imaging-derived quantitative imaging parameters to predict the tumor grade, metastatic status, and response to neoadjuvant therapy of primary soft-tissue sarcomas of the extremities. Based on the results of the present study, quantifications of the 18F-FDG PET uptake provide useful prognostic data for the evaluation of histopathological response to neoadjuvant treatment as well as the aggressiveness of high-risk sarcomas, whereas no correlation between the different outcome variables and the results for tumor size and diffusion-weighted imaging-derived apparent diffusion coefficient values was found. Accordingly, measurements of the metabolic activity of primary and untreated soft-tissue sarcomas could non-invasively deliver relevant information, that may be used for treatment planning and risk-stratification of sarcoma patients in a pretherapeutic setting. Abstract Background: To evaluate the potential of simultaneously acquired 18F-FDG PET- and MR-derived quantitative imaging data sets of primary soft-tissue sarcomas for the prediction of neoadjuvant treatment response, the metastatic status and tumor grade. Methods: A total of 52 patients with a high-risk soft-tissue sarcoma underwent a 18F-FDG PET/MR examination within one week before the start of neoadjuvant treatment. For each patient, the maximum tumor size, metabolic activity (SUVs), and diffusion-restriction (ADC values) of the tumor manifestations were determined. A Mann–Whitney-U test was used, and ROC analysis was performed to evaluate the potential to predict histopathological treatment response, the metastatic status or tumor grade. The results from the histopathological analysis served as reference standard. Results: Soft-tissue sarcomas with a histopathological treatment response revealed a significantly higher metabolic activity than tumors in the non-responder group. In addition, grade 3 tumors showed a significant higher 18F-FDG uptake than grade 2 tumors. Furthermore, no significant correlation between the different outcome variables and tumor size or calculated ADC-values could be identified. Conclusion: Measurements of the metabolic activity of primary and untreated soft-tissue sarcomas could non-invasively deliver relevant information that may be used for treatment planning and risk-stratification of high-risk sarcoma patients in a pretherapeutic setting.

Background and objectives Locoregional metastases are typical biological manifestations of advanced malignant melanomas. Treatment with hyperthermic isolated limb perfusion (HILP) should be considered in affected patients. In the present study, we have analyzed the results of HILPs performed in our department. Patients and methods Eighty patients with locoregional metastases of the extremities received HILP at the Department of Surgery between January 2007 and December 2016. The mean follow-up was 38 months. Results The study included 50 men and 30 women (mean age: 63 years). The median time between melanoma diagnosis and HILP was 25 months (range: 1–219 months). HILP was performed in curative (n = 45) and palliative (n = 35) intention. Seventy-five patients received a drug combination of melphalan/dactinomycin and five patients received a drug combination of melphalan/tumor necrosis factor-alpha. Remission rates were determined in 72 of 80 patients (90%) as follows: partial response n = 28, complete response n = 25, no response n = 19. Of the 25 patients with complete response, 13 patients developed a new tumor manifestation during follow-up (locoregional recurrences n = 4; distant metastases n = 3; both n = 6). The median overall survival rate was 33 months. Tumor stage influenced the survival rate significantly (p = 0.001). Patients with complete response showed a significantly better overall survival than patients with partial or no response (p = 0.016). Conclusion HILP is an effective therapeutic option in patients with locoregional metastases. This procedure carries a certain risk of side effects and adverse events but overall results in good response rates. Therefore, HILP should be offered to selected patients based on an individual discussion, considering their health status and oncological prognosis.

For locally advanced soft tissue sarcomas and metastases from melanoma located in the extremities, mutilating surgery or amputation may be necessary to achieve local control. Isolated limb perfusion with high-dose chemotherapy may represent an alternative to amputation for this patient group.

Background. Isolated limb perfusion (ILP) is a locoregional procedure indicated by the unresectable melanoma of the limbs. Its complexity and highly demanding multidisciplinary approach means that it is a technique only implemented in a few referral centers around the globe. This report aims to examine its potential role in the era of targeted therapies and immunotherapy by conducting a systematic review of the literature on ILP. Methods. PubMed, Embase and Cochrane Library were searched. The eligibility criteria included publications from 2000–2020 providing valid data o effectiveness, survival or toxicity. Studies in which the perfusion methodology was not clearly described, letters to the editor, non-systematic reviews and studies that applied outdated clinical guidelines were excluded. To rule out studies of a low methodological quality and assess the risk of bias, the following aspects were also required: a detailed description of the applied ILP regimen, the clinical context, follow-up periods, analyzed clinical endpoints, and the number of analyzed ILPs. The disagreements were resolved by consensus. The results are presented in tables and figures. Results. Twenty-seven studies including 2637 ILPs were selected. The median overall response rate was 85%, with a median complete response rate of 58.5%. The median overall survival was 38 months, with a 5-year overall survival of 35%. The toxicity was generally mild according to Wieberdink toxicity criteria. Discussion. ILP still offer a high efficacy in selected patients. The main limitation of our review is the heterogeneity and age of most of the articles, as well as the absence of clinical trials comparing ILP with other procedures, making it difficult to transfer its results to the current era. Conclusions. ILP is still an effective and safe procedure for selected patients with unresectable melanoma of the limbs. In the era of targeted therapies and immunotherapy, ILP remains an acceptable and reasonable palliative treatment alternative, especially to avoid limb amputations. The ongoing clinical trials combining systemic therapies and ILP will provide more valuable information in the future to clarify the potential synergism of both strategies.

Nonmelanoma skin cancer (NMSC) is more prevalent than all the other cancers combined together. The most common regions affected by skin cancer are the head and neck, but there is a large proportion of the cases located on the limbs. They could be bulky, very extensive and/or located in specialized regions like the hands or near to a joint. Most of those cases should be amputated, with several compromises of the function and a negative impact on the patients' quality of life. Isolated limb perfusion is a proven alternative to limb salvage on soft tissue sarcomas, but there are just a few reports about its application on non-melanoma skin cancer. The aim of the article is to describe the outcomes and prove the benefits and effectiveness to avoid limb amputation when using isolated limb perfusion on locally advanced non-melanoma skin cancer. We present clinical, retrospective study as a case series report. The study includes four patients with locally advanced non-melanoma skin cancer in the limb - three cases with squamous cell carcinoma (SCC), and one patient with Merkel cell carcinoma (MCC) who underwent to tumor necrosis factor-alpha (TNFα) and melphalan based isolated perfusion of the limb (TM-ILP). Toxicity, clinical response, and limb salvage were described. Patients were treated in the oncological surgical department in a referral hospital in Mexico. The limb salvage rate was achieved in 75%. All patients had a favorable response to TM-ILP. Complete response of the tumor was noted on two (50%) of the patients (one with histopathological confirmation), the other 50% had a partial response to the TM-ILP. No serious toxicity related to TM-ILP was observed. One patient (25%) developed regional lymph involvement six months after perfusion. Lymphadenectomy was performed, and the patient subsequently has a six-year disease-free survival. In conclusion, TM-ILP could be an effective, reliable, and safe therapy on limb salvage in selected patients with non-melanoma skin cancer who are not adequate surgical candidates.

INTRODUCTION: Kaposi sarcoma (KS) is a rare soft tissue sarcoma. In case of locally advanced disease, mutilating surgery such as amputations or major reconstructive procedures are sometimes inevitable. The aim of this study was to evaluate the effectiveness of isolated limb perfusion (ILP) in patients with locally advanced KS of the extremities.MATERIAL AND METHODS: All patients who underwent ILP for KS between 1996 and 2018 at Erasmus MC, Rotterdam were identified. Clinical data was obtained from either a prospectively maintained database or retrospective assessment of patient files.RESULTS: A total of 14 primary ILP's were performed in 11 patients. Median follow-up from primary ILP was 30 months (range, 5-98). The overall response rate of primary ILP was 100%, with a complete response (CR) rate of 50%. Only minimal local toxicity (Wieberdink I-III) was observed. Local progressive disease occurred after eight primary ILP's (57%) with a median local progression free survival (PFS) of 18 months (95% confidence interval [CI]: 7.0-28.9). Subsequently, four (46%) patients received a total of 5 recurrent ILP's. After the recurrent ILP on the same leg, the overall response rate was 75% and a CR-rate of 50%. One patient needed amputation post-operatively resulting in a limb salvage rate of 91%. One (9%) patient developed metastases four months after ILP.CONCLUSIONS: ILP is a highly effective treatment modality with very limited morbidity rates for patients with locally advanced KS of the extremity. ILP should be considered as a treatment modality for locally advanced KS of the extremities.

Background: Isolated limb perfusion (ILP) is a treatment option for unresectable in-transit melanoma metastases of the extremities. Approximately two-thirds of the patients have a complete response, and known predictive factors mainly regard tumor burden. In an attempt to identify subgroups with higher response rates, we retrospectively analyzed the predictive value of the BRAF V600E/K mutation for response at our institution. Methods: Between January 2012 and December 2017, 98 consecutive patients underwent first-time ILP with melphalan for melanoma in-transit metastases and were included in the study. Data was retrieved from our prospectively kept database. Tumor burden was assessed preoperatively as number of lesions and largest tumor diameter. BRAF status was determined according to clinical routine. Response rates were classified according to WHO criteria. Results: Of the 98 patients included in the analysis, 32 patients had a BRAF V600E/K mutation (33%) and 66 patients were BRAF wild type (wt). There was no difference in age, sex or tumor burden between the groups. Comparing response between BRAF V600E/K mutation and BRAF wt, the overall response rate was 69% vs. 77% (p=.36) and the complete response rate was 47% vs. 52% (p=.67). There was no difference in survival, with a median survival of 47 months. Conclusion: In this consecutive series of patients, BRAF V600E/K mutation was not found to be a significant factor for response or survival following ILP.

Soft tissue sarcomas constitute 1% of adult malignant tumors. They are a heterogeneous group of more than 50 different histologic types. Isolated limb perfusion is an established treatment strategy for locally advanced sarcomas. Since its adoption for sarcomas in 1992, after the addition of TNFα, few modifications have been done and although indications for the procedure are essentially the same across centers, technical details vary widely. The procedures mainly involves a 60 minutes perfusion with melphalan and TNFα under mild hyperthermia, achieving a limb preservation rate of 72 to 96%; with an overall response rates from 72 to 82.5% and an acceptable toxicity according to the Wieberdink scale. The local failure rate is 27% after a median follow up of 14 to 31 months compared to 40% of distant recurrences after a follow up of 12 to 22 months. Currently there is no consensus regarding the benefit of ILP per histotype, and the value of addition of radiotherapy or systemic treatment. Further developments towards individualized treatments will provide a better understanding of the population that can derive maximum benefit of ILP with the least morbidity.

Jim Umbricht (1930-1964) was a Major League baseball pitcher for the Pittsburgh Pirates and Houston Astros (formerly Houston Colt .45s). In 1963, he was diagnosed with stage III malignant melanoma which presented with a right leg pigmented skin lesion and right groin lymphadenopathy. Umbricht was treated at MD Anderson Cancer Center and Tumor Institute in Houston with the relatively new therapeutic modality of isolated limb perfusion. He was able to resume pitching 2 months after the surgery and played the remainder of the baseball season. Unfortunately, he died of metastatic disease on April 8, 1964. This contribution highlights Umbricht's medical care back in 1963 compared with current treatment options for advanced-stage malignant melanoma. Jim Umbricht's courageous story increased public awareness of malignant melanoma and can still inspire us to educate the public about this deadly form of skin cancer.

Systemic toxicities have severely limited the clinical application of tumor necrosis factor (TNF) as an anticancer agent. Activity‐on‐Target cytokines (AcTakines) are a novel class of immunocytokines with improved therapeutic index. A TNF‐based AcTakine targeted to CD13 enables selective activation of the tumor neovasculature without any detectable toxicity in vivo. Upregulation of adhesion markers supports enhanced T‐cell infiltration leading to control or elimination of solid tumors by, respectively, CAR T cells or a combination therapy with CD8‐targeted type I interferon AcTakine. Co‐treatment with a CD13‐targeted type II interferon AcTakine leads to very rapid destruction of the tumor neovasculature and complete regression of large, established tumors. As no tumor markers are needed, safe and efficacious elimination of a broad range of tumor types becomes feasible., TNF and IFN‐γ are cytokines with great anticancer potential but with limited clinical application due to side‐effects. In the present study, the tumor endothelium is identified as target cell for their antitumor activity and new biologics that allow their safe targeting are developed.

Background Ossifying fibromyxoid tumor (OFMT) is a rare soft tissue neoplasm of uncertain lineage and intermediate biological potential. It is more common in middle-aged men, usually arising from the deep tissues of the extremities. It is now established that it is a translocation related tumor, most often marked by translocation of PHF1 gene. Surgery is the mainstay of treatment and proves usually curative, although, in rarer cases the disease shows malignant features and tendency to recur both locally and at distant sites. In such cases, no standard treatment exists. Case presentation We report on a case of malignant advanced OFMT of the hand with lung metastases responding to isolated limb perfusion with human recombinant tumor necrosis factor and melphalan and chemotherapy with epirubicin and ifosfamide. Conclusions To our knowledge, this is the first report of activity of soft tissue sarcoma-oriented chemotherapy in advanced OFMT.

The aim of the present study was to investigate the incidence of organ dysfunction, and to describe the clinical characteristics and intensive care unit (ICU) outcomes of critically ill cancer patients who were admitted to an oncological ICU during the isolated limb perfusion post-operative period. The present study was an observational investigation of 42 critically ill cancer patients who were admitted to the ICU of the Instituto Nacional de Cancerología, during the isolated limb perfusion post-operative period, between July 2010 and February 2016. The mean age of the patients was 45.7±16.9 years, and 45.2% (19 cases) were female. Soft tissue sarcoma was the most common pre-operative diagnosis (38.1%), and the mean duration of surgery was 267.6±50.1 min. Furthermore, a mean blood loss volume of 732.3±526.1 ml during the procedure was recorded, and the patients received a mean volume of 3.88±1.28 l crystalloid fluid during the surgical procedure, subsequently requiring an additional 2.95±6.28 l on the first post-operative day. The incidence of organ dysfunction was 90.5% and was most frequently noted in the respiratory (81%), hepatic (33%), hematologic (31%) and renal (11.9%) systems. No patients succumbed to the disease during the ICU and hospital stay. Nevertheless

In transit metastases (ITM) from extremity or trunk melanomas are subcutaneous or cutaneous lymphatic deposits of melanoma cells, distant from the primary site but not reaching the draining nodal basin. Superficial ITM metastases develop in 5-10% of melanoma patients and are thought to be caused by cells spreading along lymphatics; ITM appear biologically different from distant cutaneous metastases, these probably due to a haematogenous dissemination. The diagnosis is usually clinical and by patients, but patients need to be adequately educated in the recognition of this clinical situation. Ultrasound or more sophisticated instrumental devices may be required if the disease develops more deeply in the soft tissues. According to AJCC 2009 staging classification, ITM are included in stages IIIb and IIIc, which are considered local advanced disease with quite poor 5-year survival rates and outcomes of 24-54% at 5 years.2 Loco-regional recurrence is in fact an important risk factor for distant metastatic disease, either synchronous or metachronous. Therapy for this pattern of recurrence is less standardised then in most other clinical situations and options vary based on the volume and site of the disease. Definitive surgical resection remains the preferred therapeutic approach. However, when surgery cannot be performed with a reasonable cosmetic and functional outcome, other options must be utilized.3-6 Treatment options are classified as local, regional or systemic. The choice of therapy depends on the number of lesions, their anatomic location, whether or not these are dermal or subcutaneous, the size and the presence or absence of extra-regional disease.

Data on isolated limb perfusion (ILP) in elderly melanoma patients are scarce. We aimed to evaluate the efficacy and safety of ILP in our institutional cohort of melanoma patients. We performed retrospective analysis of stage IIIB/C melanoma patients who underwent ILP for melanoma in-transit metastases (ITMs) in our institution between 2000 and 2016. Normothermic ILP was performed with either melphalan or melphalan and tumor necrosis factor. Baseline and treatment characteristics, locoregional progression-free survival (LPFS) and melanoma-specific survival (MSS) were assessed and prognostic factors for response, recurrence, and survival were analyzed using univariable and multivariable analysis. Overall, 91 patients were included in this study. Based on the median age of 70 years, we split patients into younger and elderly groups. No differences in response rates were observed between age groups, with an overall response rate of 81% and complete response (CR) rate of 47%. LPFS did not differ between age groups, and median LPFS was 16 months for patients with a CR. Median MSS was 38 months and differed between younger (45 months) and elderly patients (18 months). Toxicity was generally mild and did not differ between age groups. Two patients (2.2%) suffered Wieberdink IV toxicity, while no patients required amputation because of severe toxicity. CR was prognostic for improved LPFS and MSS, while patients >70 years of age and patients with stage IIIC disease had a higher risk of melanoma-specific death. Because of its safety profile and high CR rates, ILP is a viable option for patients with bulky or multiple melanoma ITMs, including elderly (>70 years of age) patients.

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Background This novel study compared the use of tumor necrosis factor (TNF)-alpha and melphalan-based isolated limb perfusion (TM-ILP) to the standard treatment of locally recurrent soft tissue extremity sarcoma. The aim was to assess whether TM-ILP positively influences the recurrence-free survival of locally recurrent high-grade soft tissue sarcoma (STS) of the extremities. Methods We retrospectively analyzed our clinical database for patients with STS. Variables were analyzed using chi-square test or Mann-Whitney rank-sum test. Furthermore, Kaplan-Meier survival plots were calculated and a proportional hazard regression model was developed. Results Out of 448 patients with extraabdominal STS treated between August 2012 and December 2015, 52 cases involving 47 patients had locally recurrent STS. Twenty-eight of these patients were treated with TM-ILP prior to surgical resection (TM-ILP-group), and 24 were treated with standard therapy (without TM-ILP). The 3-year recurrence-free survival for the TM-ILP-group was estimated at 75% (95% confidence interval (CI), 71.5–78.5). Local recurrence-free survival in the standard group was significantly lower (LRFS: 43.4%, 95% CI 38.7–48.1, p = 0.026). Multivariable analysis revealed resection with negative margins, lower number of previous recurrences, and TM-ILP as positive predictors for recurrence-free survival. Conclusions TM-ILP and consecutive resection of residual tumor with negative resection margins significantly improves local recurrence-free survival for patients with a first local recurrence of high-grade STS in the extremities.

Melanoma is an aggressive cutaneous malignancy that can recur in the form of in-transit lesions. In-transit disease can present challenges for both physician and patient, particularly when unresectable and bulky. Multiple new therapeutic modalities have been introduced in recent time, but regional chemotherapy for extremity in-transit disease in the form of hyperthermic isolated limb perfusion and isolated limb infusion are useful tools in achieving disease response, improving survival in those that do not recur distantly, and helping to salvage limbs in cases where amputation is the only other treatment alternative. This chapter serves to cover the modern literature that guides current clinic practice using these modalities. While both are effective treatments, isolated limb infusion has gained momentum with increasing use due to its simplicity and similar disease response rates. With the introduction of new systemic agents, further research will need to look into the best ways that regional chemotherapy can be utilized within the scheme of a multimodality treatment plan for patients with in-transit extremity disease.

Pri rakavih bolnikih z melanomom ali sarkomom, omejenim na en ud, se kot alternativa amputaciji ali drugim operacijam izvaja kirurški poseg, imenovan izolirana perfuzija udov. Pacientovo okončino pri tem priklopijo na izoliran krvni obtok in vanj dodajo tekočino, ki med drugim vsebuje radioaktivno snov ter visoke odmerke zdravil. Med posegom je potrebno ves čas spremljati, da uhajanje tekočine iz izolirane okončine v preostali del telesa ne preseže dovoljene meje, saj bi v nasprotnem primeru to predstavljajo nevarnost za pacienta. V magistrski nalogi je predstavljen prototip prenosnega scintilacijskega detektorja za merjenje radioaktivnosti, ki se uporablja za zaznavanje uhajanja. Detektor je v grobem sestavljen iz scintilatorja, fotopomnoževalke, večkanalnega analizatorja in grafičnega uporabniškega vmesnika. Kot večkanalni analizator smo uporabili FPGA vezje na razvojni plošči Red Pitaya. Motiv za delo je sestaviti detektor, ki je majhen in lahko prenosen in bi v prihodnosti lahko zamenjal obstoječ detektor na Onkološki kliniki UKC Ljubljana. Isolated limb perfusion is a surgical procedure used for treating cancer patients with melanoma or sarcoma isolated to a single limb. It is used as an alternative to limb amputation or other mutilating operations. Patient’s limb is disconnected from systemic bloodstream and connected to its own isolated one in which radioactive tracer and high dosage of medication are injected. During procedure, constant monitoring of fluid leakage from isolated limb to systemic bloodstream is important for patient’s safety. In case leakage exceeds safe threshold, the procedure is stopped. Thesis addresses a portable prototype scintillation detector for measuring radioactivity which indirectly measures leakage during isolated limb perfusion. Detector is based on scintillator, photomultiplier, multichannel analyzer and graphic user interface. Multichannel analyzer is made with FPGA circuit on Red Pitaya development board. The main motive for work was to build a small and portable detector which could in future replace the one that is currently used at the Institute of Oncology in Ljubljana.

Background: Sarcoma treatment is a complex and multidisciplinary process. Little is known about the actual status of sarcoma care in Germany. Objectives: We evaluated: (1) on an institutional level, which physician diagnosed and treated sarcomas; (2) whether guidelines and tumor board recommendations were routinely implemented; and (c) access to which diagnosis and treatment options was regarded as problematic. We also examined factors that were associated with access problems. Methods: A cross-sectional online survey was employed among German sarcoma physicians between June 2017 and February 2018 with convenience sampling. Results: Two hundred fourteen physicians participated; 46% were oncologists and 27% surgeons, 38% worked in hospitals of maximum care, 34% were office based and 27% worked in other hospitals, 68% of all of the physicians consulted established guidelines, and 93% presented their patients in multidisciplinary tumor boards. The most common access problems were: isolated limb perfusion (39%), deep-wave hyperthermia (33%), and FDG-PET (27%), and 42% reported no access problems at all. Those physicians who treat more than 100 patients per year reported “no access problems” more frequently compared to centers with lower patient numbers (vs. 0–10 patients, OR 0.14; 95% CI 0.03–0.61; vs. 11–100 patients, OR 0.21; 95% CI 0.06–0.73). Conclusions: Access to multidisciplinary tumor boards seems to be largely guaranteed in the participants of our survey. The use of guidelines could be further implemented and expanded. The number of treated patients appears to be a significant factor to avoid access problems to treatment options.

Background: Cutaneous melanoma is a malignancy with an increasing incidence worldwide, especially in northern Europe. The aim of this thesis is to scrutinize the results achieved by traditional surgery and the opportunities offered by translational research for the more advanced stages of the disease. Paper I analysed outcomes of sentinel node biopsy (SNB) performed on 769 con-secutive patients with cutaneous melanoma. Breslow thickness was the only pre-dictive factor for a positive SN. The 5-year melanoma specific survival (MSS) was 81% and in multivariate analysis the negative prognostic factors for survival were SN-status, followed by Breslow thickness and ulceration. Paper II reported on 290 consecutive patients who underwent 380 isolated limb perfusion (ILP), of which 90 were re-ILPs. The results between the 1st, the 2nd and the 3-5th were compared. Patients with a complete response at the first treat-ment were likely to have the same response at re-ILP without any increase in the risk for local toxicity or complications. Paper III BRAF mutational status as a predictive factor for response was studied in 98 patients who underwent ILP. In this consecutive series, 32 patients had a BRAF V600E/K mutation and 66 patients were BRAF wild type, and no significant correlation for response or survival was found. Paper IV was a translational study based on patient-derived xenograft models including 21 cutaneous melanoma biopsies transplanted into either NOG or IL-2 transgenic NOG (hIL2-NOG) mice. It was shown that the models reliably could be used to predict the effect of tumour-infiltrating lymphocytes against the tumours. Conclusions: The surgical approach and therapies for patients with cutaneous melanoma are becoming more targeted and personalized. A specialised multidisci-plinary approach can improve the understanding of the disease, support the deci-sion-making process towards the most advantageous treatment options for each individual patient at a specific time.

Hyperthermic isolated limb perfusion (ILP) with high-dose melphalan is a treatment option for melanoma patients with metastasis confined to limbs (in-transit metastasis). The therapy entails a complete response (CR) rate of 50–70%. Cellular immunity is proposed to impact on the clinical efficacy of ILP, but the detailed aspects of ILP-induced immune activation remain to be explored. For this study, we explored the potential role of interferon-stimulated gene (ISG) products, including CXCL10, CCL2, PD-L2 and IFN-γ along with expression of their cognate receptors CXCR3, CCR4, CCR5 and PD-1 on lymphocytes, for the clinical efficacy of ILP. Patients with high serum levels of CXCL10, CCL2, PD-L2 and IFN-γ were more likely to achieve CR after ILP. Additionally, the expression of CXCR3, CCR4 and CCR5 on T cells and/or natural killer (NK) cells was enhanced by ILP. Peripheral blood mononuclear cells (PBMCs) secreted high levels of CXCL10, CCL2 and IFN-γ in response to co-culture with melphalan-exposed melanoma cells in vitro. Activated T cells migrated toward supernatants from these co-cultures. Furthermore, melphalan-exposed melanoma cells triggered upregulation of CXCR3, CCR4, CCR5 and PD-1 on co-cultured T cells and/or NK cells. Our results suggest that constituents released from melphalan-exposed melanoma cells stimulate the ISG axis with ensuing formation of chemokines and upregulation of chemokine receptor expression on anti-neoplastic immune cells, which may contribute in ILP-induced tumor regression.

Purpose In recent years, the incidence of malignant melanoma has rapidly increased worldwide. Among patients with recurrences, approximately 5% develop in-transit metastases, which can potentially be treated with isolated limb perfusion (ILP). However, little is known about patient experiences with this treatment. A more thorough understanding might guide future research and clinical care. In this study, we aimed to describe patients’ experiences of ILP treatment. Methods This study included eight patients who participated in a semi-structed interviewed, conducted at one occasion between 3 and 11 months after their ILP treatment. The mean interview duration was 26 min. Data were analyzed using qualitative inductive content analysis according to the methods of Elo-Kyngas and Graneheim and Lundman. Results Our analysis yielded three categories, each built on two subcategories: positive experiences after ILP treatment emerged from the sub-categories reduced tumor burden and living a less restricted life; negative experiences after ILP was built on the subcategories fear of relapse and complications and side effects; and experiences of healthcare was founded on the subcategories need for correct information and being viewed as sicker then experienced. Conclusion Participants showed greater focus on the healthy parts of their lives, even when negative symptoms occurred after ILP treatment. They also described how healthcare workers focused on their illness. Based on these findings, we suggest the following means of providing good nursing care to ILP patients: give correct information, strive to reduce patients’ negative symptoms, support their daily living needs, and provide emotional support to reduce fear of recurrence.

Background and objectives Isolated limb perfusion (ILP) and infusion (ILI) are treatment modalities for unresectable melanoma in-transit metastases and extremity soft tissue sarcomas (STS). We sought to characterize the national trend in their utilization in the context of novel melanoma therapies introduced in 2011. Methods Using the National Inpatient Sample (2005-2014), patients with a primary diagnosis of limb melanoma or STS who underwent ILP/ILI were identified by diagnosis and procedure codes. Annual percent change (APC) in ILP/ILI procedures was determined. Results From 2005 through 2014, 670 and 130 ILP/ILI procedures were performed for melanoma and STS, respectively. Mean age was 64 (SD 15) years for melanoma and 59 (SD 18) years for STS. Over time, procedures for melanoma decreased with an APC of -17 (P = .019). Comparing 2005-2010 and 2011-2014, the mean number of procedures for melanoma decreased from 91 to 32 per year (P = .007). In contrast, there was no change for STS (APC 6.5, P = .39; mean 11 and 16 per year in 2005-2010 and 2011-2014, respectively, P = .46). Conclusions ILI/ILP utilization has decreased for melanoma, but not for STS. Whether trends for ILP and ILI differed could not be determined. ILP/ILI remains an important option to consider for regional disease control.

Introduction Hyperthermic isolated limb perfusion (HILP) has an established role in the management of melanoma, but its role for Merkel cell carcinoma (MCC) is less well defined. Methods Retrospective review of our institutional experience with HILP for MCC was conducted (2009–2015). Literature search was performed through 04/2015 and 10 studies met inclusion criteria. Results Four patients underwent HILP for MCC at our institution. There were no major complications and complete response was achieved in all patients. Early metastatic recurrence developed in two patients. The remaining two had no evidence of disease at last follow-up (36 months) or death (39 months). Systematic review identified an additional 12 pts that underwent HILP for MCC, for a total of 16 cases. Median age was 73 [IQR 69–78] years and 56% were men. Of the patients with reported follow-up, 12 (86%) had complete response, 1 had stable disease, and 1 partial response. Four patients developed local–regional recurrence and six distant metastases, all within 6 months. Overall median follow-up time was 15 [7–36] months. Conclusion Among a highly selective group of patients, regional perfusion for MCC is safe and has a high complete response rate. HILP is an acceptable therapeutic modality for obtaining durable loco-regional control but early distant metastatic disease remains a significant cause of mortality. J. Surg. Oncol. 2016;114:187–192. © 2016 Wiley Periodicals, Inc.

We report the case of a 31-year-old woman with left foot bones located epithelioid hemangioendothelioma. It is a rare type of vascular tumor, locally aggressive with metastatic potential. It was revealed by a chronic isolated left foot pain. Conventional imaging showed multiple osteolytic lesions of the bones, appearing aggressive. Both bone scintigraphy and F-FDG PET showed an increased uptake of these lesions and confirmed the limited extent to distal extremity of the left lower limb. Final diagnosis was given on a surgical biopsy. Patient was treated by hyperthermic chemotherapy using isolated limb perfusion.

Hyperthermic isolated limb perfusion with melphalan (M-ILP) is a treatment option for melanoma patients with metastases confined to the limbs. This study aimed at defining the role of cellular immunity for the clinical response to M-ILP in melanoma patients. It was observed that patients with enhanced cytotoxic CD8+ T cell reactivity to common antigens (HCMV/EBV/influenza virus) prior to M-ILP were more likely to achieve a complete disappearance of macroscopic tumors (complete response). Following M-ILP treatment, the proportions of CD16+ intermediate and non-classical monocytes in peripheral blood were significantly enhanced along with induction of HLA-DR on CD4+ and CD8+ T cells. For further studies of the mechanism behind melphalan-induced immune activation an in vitro model, aiming at mimicking the clinical M-ILP protocol, was established, where PBMCs were co-cultured with melanoma cells, which had been pre-exposed to melphalan under mild hyperthermia. Upon exposure to melphalan, melanoma cells showed increased expression of immune-related markers including MHC class I and Hsp70. Moreover, when the melphalan-treated melanoma cells were co-cultured with PBMCs, this triggered an increased proportion of CD33+CD14+CD16++ non-classical monocytes among the PBMCs. Furthermore, the melphalan-treated melanoma cells stimulated the expansion of CD8+ T cells in the co-cultured PBMCs. These cells produced enhanced levels of IFN-γ and granzyme B and were capable of killing melanoma cells. To further verify an immunogenic role of melphalan, mice were vaccinated with melphalan-exposed murine melanoma cells. When challenged with live melanoma cells, vaccinated mice showed reduced tumor growth and enhanced infiltration of tumor-specific T cells into tumors. We conclude that melphalan-exposed melanoma cells trigger expansion of CD16+ monocytes and activate cytotoxic T cells and that these events may contribute to the antitumoral efficacy of M-ILP.

Hyperthermic isolated limb perfusion with melphalan (M-ILP) is a treatment option for melanoma patients with metastases confined to the limbs. This study aimed at defining the role of cellular immunity for the clinical response to M-ILP in melanoma patients. It was observed that patients with enhanced cytotoxic CD8+ T cell reactivity to common antigens (HCMV/EBV/influenza virus) prior to M-ILP were more likely to achieve a complete disappearance of macroscopic tumors (complete response). Following M-ILP treatment, the proportions of CD16+ intermediate and non-classical monocytes in peripheral blood were significantly enhanced along with induction of HLA-DR on CD4+ and CD8+ T cells. For further studies of the mechanism behind melphalan-induced immune activation an in vitro model, aiming at mimicking the clinical M-ILP protocol, was established, where PBMCs were co-cultured with melanoma cells, which had been pre-exposed to melphalan under mild hyperthermia. Upon exposure to melphalan, melanoma cells showed increased expression of immune-related markers including MHC class I and Hsp70. Moreover, when the melphalan-treated melanoma cells were co-cultured with PBMCs, this triggered an increased proportion of CD33+CD14+CD16++ non-classical monocytes among the PBMCs. Furthermore, the melphalan-treated melanoma cells stimulated the expansion of CD8+ T cells in the co-cultured PBMCs. These cells produced enhanced levels of IFN-γ and granzyme B and were capable of killing melanoma cells. To further verify an immunogenic role of melphalan, mice were vaccinated with melphalan-exposed murine melanoma cells. When challenged with live melanoma cells, vaccinated mice showed reduced tumor growth and enhanced infiltration of tumor-specific T cells into tumors. We conclude that melphalan-exposed melanoma cells trigger expansion of CD16+ monocytes and activate cytotoxic T cells and that these events may contribute to the antitumoral efficacy of M-ILP.

Isolated limb perfusion (ILP) and isolated limb infusion (ILI) are treatment options for patients with locally advanced melanomas and sarcomas of the extremities. ILP potentially have higher response rates, but requires open surgery for vascular access, whereas ILI is minimally invasive and easier to perform. We now present the technical details and outcome of a new approach to ILP by a minimally invasive vascular access (MI-ILP).Six patients, five with melanoma in-transit metastases and one with squamous cell carcinoma, were included in a phase I feasibility trial. Percutaneous vascular access of the extremity vessels was performed and the inserted catheters were then connected to a perfusion system.All six treated patients underwent the procedure without the need for conversion to open surgery. The median operating time was 164 min and the median leakage rate was 0.1%. The complete response rate was 67%. Four patients (67%) had a Wieberdink grade II reaction and two patients (33%) had a grade III reaction.MI-ILP is feasible and gives the same treatment characteristics as open ILP, but with the advantage of a minimally invasive vascular access.

Background Induction chemotherapy by isolated limb perfusion (ILP) with melphalan and tumour necrosis factor-α is an effective strategy to facilitate limb-conserving surgery in locally advanced extremity sarcoma. In a comparison of cohorts matched for grade, size and surgical resectability, we compared the outcome of patients undergoing induction ILP prior to limb-conserving surgery and selective post-operative radiotherapy with patients undergoing limb-conserving surgery and routine post-operative radiotherapy. Methods Patients with primary, grade 2/3 sarcomas of the lower limbs over 10 cm in size were identified from prospectively maintained databases at 3 centres. Patients treated at a UK centre underwent limb-conserving surgery and post-operative radiotherapy (Standard cohort). Patients at two German centres underwent induction ILP, limb-conserving surgery and selective post-operative radiotherapy (ILP cohort). Results The Standard cohort comprised 80 patients and the ILP cohort 44 patients. Both cohorts were closely matched in terms of tumour size, grade, histological subtype and surgical resectability. The median age was greater in the Standard vs the ILP cohort (60.5 years vs 56 years, p = 0.033). The median size was 13 cm in both cohorts. 5-year local-recurrence (ILP 12.2%, Standard 20.1%, p = 0.375) and distant metastases-free survival rates (ILP 49.6%, Standard 46.0% p = 0.821) did not differ significantly between cohorts. Fewer patients received post-operative radiotherapy in the ILP cohort compared with the Standard cohort (27% vs 82%, p

Background: This study explores various volume of interest (VOI) delineation techniques for fluorine-18-fluorodeoxyglucose positron emission tomography with computed tomography (18F-FDG PET-CT) scans during neoadjuvant extremity soft tissue sarcoma (ESTS) treatment. Results: During neoadjuvant treatment, hyperthermic isolated limb perfusion (HILP) and preoperative external beam radiotherapy (EBRT), 11 patients underwent three 18F-FDG PET-CT scans. The first scan was made prior to the HILP, the second after the HILP but prior to the start of the EBRT, and the third prior to surgical resection. An automatically drawn VOIauto, a manually drawn VOIman, and two gradient-based semi-automatically drawn VOIs (VOIgrad and VOIgrad+) were obtained. Maximum standardized uptake value (SUVmax), SUVpeak, SUVmean, metabolically active tumor volume (MATV), and total lesion glycolysis (TLG) were calculated from each VOI. The correlation and level of agreement between VOI delineation techniques was explored. Lastly, the changes in metabolic tumor activity were related to the histopathologic response. The strongest correlation and an acceptable level of agreement was found between the VOIman and the VOIgrad+ delineation techniques. A decline (VOIman) in SUVmax, SUVpeak, SUVmean, TLG, and MATV (all p < 0.05) was found between the three scans. A > 75% decline in TLG between scan 1 and scan 3 possibly identifies histopathologic response. Conclusions: The VOIgrad+ delineation technique was identified as most reliable considering reproducibility when compared with the other VOI delineation techniques during the multimodality neoadjuvant treatment of locally advanced ESTS. A significant decline in metabolic tumor activity during the treatment was found. TLG deserves further exploration as predictor for histopathologic response after multimodality ESTS treatment.

Background and Objectives: Extensive surgery is often required for advanced soft tissue sarcoma (STS) of the limb. In the 1980s, a new approach was developed: isolated limb perfusion (ILP). This study aimed to assess incidence and impact on patient survival based on lymph node metastasis with systematic radical lymphadenectomy during ILP. Methods: Retrospective study of 57 consecutive patients treated by ILP for limb STS with simultaneous radical lymph node dissection in our tertiary referral center between 1992 and 2015. Results: Median age was 62 years (19-87) and 30 patients were male (53%). Lymph node involvement was observed in 13 patients (N1, 23%), regarded as metastatic spreading in 4 angiosarcomas, 3 epithelioid sarcomas, 2 leiomyosarcomas, 2 undifferentiated sarcomas and 2 synovial sarcomas. For the N0 patient group, median survival was 73.9 months (CI 95% 41.9-105.9) compared to 15.1 months (CI 95% 7.4-22.6) in case of metastatic lymph node ( p =0.002). The median disease-free survival was 33,0 months (CI 95% 12,5-53.5) in N0 group and 8.0 months (CI 95% 4.0-11.9) in N1 ( p =0.006). Conclusions: Lymph node metastases of STS patients selected for ILP seemed to have a negative impact on both overall and disease-free survival. Radical lymph node dissection should be included in ILP procedure.

In-transit metastases of melanoma occur in 5-8% of all melanoma patients. In case of extensive locoregional disease, Tumor necrosis factor-α 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.

Background: Isolated limb perfusion with TNF-alpha and melphalan (TM-ILP) is a highly effective treatment for locally advanced tumours of the extremities. Previous research suggests an almost immediate disintegration of the blood supply of the tumour. The aim of the present study was to verify this hypothesis using non-invasive measurements of microvascular perfusion and tissue oxygenation. Methods: A total of 11 patients were included in the study. TM-ILP was performed under mildly hyperthermic conditions (39 °C) in the extremities via proximal vascular access. Capillary-venous microvascular blood flow, haemoglobin level (Hb) and oxygen saturation (SO2) were determined using laser Doppler and white-light spectroscopy, respectively, before TM-ILP and at 30 min, 4 h, 1 day, 4 days, 1 week, 2 weeks and 6 weeks after TM-ILP from tumour and healthy muscle tissues. Results: Blood flow and Hb were mostly higher, whereas SO2 was lower, in tumour tissue compared with muscle tissue. In both tumour and muscle tissues, blood flow significantly increased immediately after TM-ILP and remained elevated for at least 2 weeks, followed by a return to the initial values 6 weeks after the procedure. Conclusion: No signs were found of early destruction of the tumour vasculature. The observations suggest that an inflammatory reaction is one of the key elements of TM-ILP.