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Background: Isolated limb infusion and perfusion (ILI/ILP) has been a mainstay treatment for unresectable melanoma in‐transit metastases (ITM), but increased use of immune checkpoint inhibitors (ICI) and intralesional therapy (talimogene laherparepvec [TVEC]) introduced several different management options. This study compares first‐line ILI/ILP, ICI, and TVEC. Methods: Retrospective review from 12 international institutions included patients treated from 1990 to 2022 with first‐line ILI/ILP, ICI, or TVEC for unresectable melanoma ITM. Results: A total of 551 patients were treated, with ILI/ILP (n = 356), ICI (n = 125), and TVEC (n = 70) with median follow‐up of 5.5 years. Tumor burden was highest with ILI/ILP and lowest with TVEC (p =.002). Breslow thickness was lowest with TVEC (p =.007). TVEC was mostly used in stage IIIB disease versus IIIC for ILI/ILP and ICI (p =.01). Using ICI as the reference category, TVEC had the highest odds of a complete response (CR) (odds ratio, 1.96; p =.029) and a longer local progression‐free survival (PFS) (hazard ratio [HR], 0.40; p =.003). ILI/ILP had shorter local PFS (HR, 1.72; p =.012), PFS (HR, 1.79; p <.001), distant metastasis‐free survival (DMFS) (HR, 1.75; p =.014), overall survival (HR, 1.82; p =.009), and melanoma‐specific survival (HR, 2.29; p =.004). Stage IIIB disease had longer DMFS (HR, 0.24; p <.001) compared to IIIC/D. Conclusions: TVEC as first‐line therapy for unresectable melanoma ITM was associated with superior CR rates and local PFS. Notably, TVEC was used in patients with a lower Breslow thickness, disease stage, and tumor burden. Therefore, when compared to ILI/ILP and ICI, TVEC should be considered as first‐line therapy for unresectable stage IIIB melanoma ITM with minimal tumor burden and lower Breslow thickness. Optimal first‐line therapy for unresectable melanoma in‐transit metastases has not been established, and options include isolated limb infusion/perfusion, immune checkpoint inhibitors, and intralesional therapies. In this comparison between these first‐line treatment modalities, intralesional therapy was associated with superior complete response rates and local progression‐free survival, but it was used in patients with lower tumor burden and disease stage; therefore, intralesional therapy can be considered as first‐line therapy for unresectable stage IIIB melanoma in‐transit metastases with minimal tumor burden and lower Breslow thickness. [ABSTRACT FROM AUTHOR]

Background: Isolated limb perfusion (ILP) is a regional cancer treatment in which high-dose chemotherapy is administered in an isolated extremity. The main side effect is regional toxicity, which occasionally leads to nerve damage. Measuring neuroaxonal biomarkers, might be a method predicting such complications. Therefore, the primary aim of the study is to investigate if neuronal biomarkers are measurable and alters in an isolated extremity during ILP. Secondly, if postoperative regional toxicity, alterations in sensitivity, and/or muscle strength are correlated to the biomarker levels. Methods: Eighteen scheduled ILP-patients were included in the study. Glial fibrillary acidic protein (GFAP), neurofilament light (NfL), and tau concentrations were measured in plasma sampled preoperatively, at the start and end of the ILP, on days 3 and 30, using ultrasensitive Single molecule array (Simoa) technology. The patients were assessed by a physiotherapist pre- and postoperatively. Results: At ILP end, significantly higher NfL and tau levels were measured in the extremity than in the corresponding systemic circulation (NfL; 17 vs 6 ng/L, p <.01, tau; 1.8 vs 0.6 ng/L, p <.01), and the extremity levels were significantly increased at ILP end (NfL; 66 ± 37%, p <.001, tau; 75 ± 45%, p =.001). On days 3 and 30, significantly increased NfL and GFAP levels were measured systemically (NfL day 3: 69 ± 30%, p <.001; day 30: 76 ± 26%, p <.001; GFAP day 3: 33 ± 22%, p <.002; day 30: 33 ± 23%, p ≤.004). Finally, no significant correlations were found between regional toxicity or between postoperative muscle or sensitivity decrease and biomarker release. Conclusion: During ILP, NfL and tau levels increased significantly. No obvious correlations were observed between biomarker release and regional toxicity or decreased muscle strength or sensitivity, although large-scale studies are warranted. [ABSTRACT FROM AUTHOR]

Simple Summary: In-transit metastases (ITM) are a challenging aspect of advanced melanoma, traditionally treated with surgery. However, recent advances in systemic therapies, such as immune checkpoint inhibitors and targeted treatments, have significantly improved patient outcomes. These modern therapies are now often preferred over surgery alone. This article reviews the benefits of combining systemic and locoregional treatments, highlighting their potential to enhance survival and quality of life for patients with ITM. By integrating these approaches, we aim to provide a comprehensive strategy for optimizing melanoma treatment outcomes. In-transit metastases (ITM) in melanoma present a significant therapeutic challenge due to their advanced stage and complex clinical nature. From traditional management with surgical resection, ITM treatment has evolved with the advent of systemic therapies such as immune checkpoint inhibitors and targeted therapies, which have markedly improved survival outcomes. This study aims to review and highlight the efficacy of both systemic and locoregional treatment approaches for ITM. Methods include a comprehensive review of clinical studies examining the impact of treatments like immune checkpoint inhibitors, targeted therapies, Isolated Limb Perfusion, and electrochemotherapy. The results indicate that combining systemic therapies with locoregional treatments enhances both local disease control and overall survival rates. The introduction of modern immunotherapies has not diminished the effectiveness of locoregional therapies but rather improved patient outcomes when used in conjunction. The conclusions emphasize that a multidisciplinary approach integrating systemic and locoregional therapies offers a promising strategy for optimizing the management of ITM in melanoma patients. This integrated treatment model not only improves survival rates but also enhances the quality of life for patients, suggesting a shift in standard care practices toward more comprehensive therapeutic regimens. [ABSTRACT FROM AUTHOR]

Isolated limb perfusion (ILP) is a regional chemotherapy technique used in the treatment of locally advanced or unresectable extremity soft tissue sarcoma (ESTS) or malignant melanoma (MM) of the limbs. It allows for high concentrations of chemotherapeutic agents to be perfused in the limb while minimising the risk of systemic side-effects. While the technique has been utilized for decades, the role of ILP has evolved as other treatment strategies have become available. Current indications for ILP in sarcoma include induction in unresectable ESTS to allow for future definitive limb preservation procedures as well as definitive treatment of unresectable, multifocal ESTS. In MM, ILP is typically used in unresectable in-transit melanoma, and rarely as an alternative to amputation in bulky, symptomatic extremity disease. This review seeks to summarise the current evidence base and indications for ILP as well as present some technical insights from a high-volume United Kingdom (UK) unit. [ABSTRACT FROM AUTHOR]

Patients with cutaneous melanoma can develop in-transit metastases (ITM), most often localized to limbs. For patients with uveal melanoma that develop metastatic disease, the overall majority develop isolated liver metastases. For these types of metastases, regional cancer therapies have evolved as effective treatments. Isolated limb perfusion (ILP), isolated limb infusion (ILI), isolated hepatic perfusion (IHP) and percutaneous hepatic perfusion (PHP) achieve a high local concentration of chemotherapy with minimal systemic exposure. This review discusses the mechanism and available literature on locoregional treatment modalities in the era of modern immunotherapy. [ABSTRACT FROM AUTHOR]

Background: Isolated limb hyperthermic-antiblastic perfusion (ILP) was the most effective local treatment for advanced in-transit melanoma, but the advent of modern effective immunotherapy (IT), such as immune checkpoint inhibitors, has changed the treatment landscape. Methods: This study evaluated the role of the association between ILP and IT in the treatment of locally advanced unresectable melanoma, particularly in relation to modern systemic therapies. We analyzed 187 consecutive patients who were treated with ILP (melphalan or melphalan associated with TNF-alpha) for advanced melanoma at the Veneto Institute of Oncology of Padua (Italy) and the Padua University Hospital (Italy) between June 1989 and September 2021. Overall survival (OS), disease-specific survival (DSS), local disease-free survival (local DFS) and distant disease-free survival (distant DFS) were evaluated. Local toxicity was classified according to the Wieberdink scale and surgical complications according to the Clavien–Dindo classification. Response to locoregional therapy was evaluated during follow-up according to the RECIST 1.1 criteria (Response Evaluation Criteria in Solid Tumor). Results: A total of 99 patients were treated with ILP and 88 with IT + ILP. The overall response rate was 67% in both groups. At 36 months, OS was 43% in the ILP group and 61% in the ILP + IT group (p = 0.02); DSS was 43% in the ILP group and 64% in the ILP + IT group (p = 0.02); local DFS was the 37% in ILP group and 53% in the ILP + IT group (p = 0.04); and distant DFS was 33% in the ILP group and 35% in the ILP + IT group (p = 0.40). Adjusting for age and lymph node involvement, receiving ILP + IT was associated with improved OS (p = 0.01) and DSS (p = 0.007) but not local DFS (p = 0.13) and distant DFS (p = 0.21). Conclusions: Our findings confirm the synergy between ILP and IT. ILP remains a valuable loco-regional treatment option in the era of effective systemic treatments. Further studies are needed to establish the optimal combination of loco-regional and systemic treatments and address the best timing of this combination to obtain the highest local response rate. [ABSTRACT FROM AUTHOR]

Isolated limb perfusion (ILP) involves the local administration of high doses of anticancer drugs into a limb affected by unresectable locally advanced tumors (with special regard to in-transit melanoma metastases), minimizing systemic side effects. Tumor response to anticancer drugs may depend on the expression of apoptosis-related genes, such as SURVIVIN and MDM2. This retrospective cohort study investigated the association between tumor SURVIVIN and MDM2 expression levels and treatment response or clinical outcomes in patients undergoing ILP for in-transit melanoma metastases. The study cohort consisted of 62 patients with in-transit metastases who underwent ILP with tumor necrosis factor (TNF) and melphalan. Tissue samples were taken from the in-transit metastases, and RNA was extracted for gene expression analysis. Patients' response to treatment was assessed using clinical and radiological criteria two months after ILP, and disease response was classified as complete, partial, or stable/progressive disease. Disease-free survival (DFS) and overall survival (OS) were also analyzed. Expression of SURVIVIN and/or MDM2 was observed in 48% of patients; in these cases, complete response to ILP occurred in 40% of cases, with the overall response rate (complete + partial) being 85%. Patients with expression of MDM2 alone had a lower complete response rate (28%), while patients with expression of SURVIVIN alone had a higher complete response rate (50%). The combined expression of MDM2 and SURVIVIN resulted in a complete response rate of 30%. Patients without expression (of SURVIVIN or MDM2) had the highest complete response rate (58%). Survival analysis showed that high MDM2 expression was independently associated with a lower probability of a complete response to ILP. In addition, patients with MDM2 expression were three times more likely to have an incomplete response to ILP. This study highlights the importance of considering SURVIVIN and MDM2 expression in patients undergoing ILP for in-transit cutaneous melanoma metastases. High MDM2 expression was found to be an independent factor associated with a reduced likelihood of achieving a complete response to ILP, suggesting potential mechanisms of chemoresistance. These data support further research to explore the role of already available targeted therapies (i.e., MDM2 inhibitors) in improving tumor response to ILP in patients with in-transit melanoma metastases. [ABSTRACT FROM AUTHOR]

Background: Isolated limb perfusion (ILP) for soft tissue sarcomas (STS) is usually performed with tumor necrosis factor alpha (TNF-α) and melphalan. ILP regularly leads to a total blood loss (BLt) of 1.5–2 L/patient. Blood inflow from the central blood circulation to the limb is influenced by unstable pressure gradients and pain reactions after the administration of melphalan. With perioperative regional anesthesia (RA), pain levels can be reduced, and the pressure gradient stabilized resulting in a reduced BLt. The aim of this study was to compare the BLt with and without RA in patients with ILP during circulation of drugs. Methods: Patients were treated according to the following protocol: After the establishment of limb circulation, ILP was started with the administration of TNF-α. Half the dose of melphalan was given as a bolus after 30 min, and the remaining dose was continuously administered in the following 30 min. The extremity was washed out after 90 min. ILP with perioperative RA (supraclavicular plexus block/peridural catheter) was performed prospectively in 17 patients and compared to a matched retrospective control group of 17 patients without RA. BLt was documented and perioperative anesthesiological data were analyzed for response rates after the application of melphalan (RaM). Results: BLt and RaM tended to be lower for the intervention group with RA if compared to the control group without RA in all analyses. The trend of lower BLt and RaM in ILP with RA was more pronounced for the upper extremity compared to the lower extremity. Results were not statistically significant. Conclusion: These findings indicate that the use of RA can help to stabilize hemodynamic anesthetic management and reduce the BLt in ILP, especially during perfusion of the upper extremities. [ABSTRACT FROM AUTHOR]

Background: Isolated limb perfusion (ILP) is a regional surgical treatment for localized metastatic disease. High doses of chemotherapeutic agents are administered within an extracorporeal circulated isolated extremity, treating the metastasis, while systemic toxicity is avoided. To our knowledge, indexed oxygen supply/demand relationship during ILP has not previously been described. Our aim was to measure and describe oxygen metabolism, specifically oxygen delivery, consumption, and extraction, in an isolated leg/arm during ILP. Also investigate whether invasive oxygenation measurement during ILP correlates and can be used interchangeable with the non-invasive method, near infrared spectroscopy (NIRS). Methods: Data from 40 patients scheduled for ILP were included. At six time points blood samples were drawn during the procedure. DO2, VO2, and O2ER were calculated according to standard formulas. NIRS and hemodynamics were recorded every 10 min. Results: For all observations, the mean of DO2 was 190±59 ml/min/m2, VO2 was 35±8 ml/min/m2, and O2ER was 21±8%. VO2 was significantly higher in legs compared to arms (38±8 vs. 29±7 ml/min/m2, p=0.02). Repeated measures showed a significant decrease in DO2 in legs (209±65 to 180±66 ml/min/m2, p=<0.01) and in arms (252±72 to 150±57 ml/min/m2, p=<0.01). Significant increase in O2ER in arms was also found (p=0.03). Significant correlation was detected between NIRS and venous extremity oxygen saturation (SveO2) (rrm=0.568, p=<. 001, 95% CI 0.397–0.701). When comparing SveO2 and NIRS using a Bland–Altman analysis, the mean difference (bias) was 8.26±13.03 (p=<. 001) and the limit of agreement was − 17.28–33.09, with an error of 32.5%. Conclusion: DO2 above 170 ml/min/m2 during ILP kept O2ER below 30% for all observations. NIRS correlates significant to SveO2; however, the two methods do not agree sufficiently to work interchangeable. Clinical Trial Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT04460053 and NCT03073304. [ABSTRACT FROM AUTHOR]

Abstract 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.

Prior to the advent of effective systemic therapy for melanoma, isolated limb perfusion (ILP) was the most effective local treatment for advanced in-transit melanoma (ITM). However, many patients who are now treated by ILP will have received prior immunotherapy. We sought to compare response rates to ILP in patients who had previously received immunotherapy compared to immunotherapy naive patients. All patients who underwent ILP for ITM between January 2015 and July 2020 for melanoma were identified retrospectively from two tertiary institutions. Surgical morbidity and oncologic outcomes were compared between immunotherapy naive and immunotherapy pre-treated patients. 97 perfusions were performed for melanoma. Of those, 18 patients had undergone prior immunotherapy. There were no differences in clinicopathological characteristics or perioperative outcomes between cohorts. Surgical morbidity and local toxicity were similar between both cohorts. Patients who underwent immunotherapy prior to ILP had significantly decreased complete response (CR) rates compared with immunotherapy-naïve (6% vs 47%, p = 0.0018) and a significantly decreased overall survival (OS) and distant progression free survival (DPFS) (p = 0.0031 and p = 0.0006 respectively). There was no difference in overall response (OR), partial response (PR), stable disease (SD), progressive disease (PD) and local progression free survival (LPFS) between cohorts. Oncological outcomes and complete response rates are worse in patients who have received immunotherapy prior to ILP compared with immunotherapy naïve patients. Despite this, ILP is still a valuable second line treatment for local control in patients who have multiple, bulky and/or recurrent ITM post immunotherapy. [ABSTRACT FROM AUTHOR]

Purpose of Review: The purpose of this study is to discuss the current knowledge and future perspectives regarding the treatment options for in-transit metastases (ITM), along with the optimal algorithms for patients presenting with this adverse manifestation of melanoma. Recent Findings: In addition to procedures historically accepted for the management of ITM, encompassing surgery and regional techniques, novel medications in the form of immune checkpoint inhibitors (ICI) and targeted therapies now represent standard options, allowing for the possibility of combined approaches, with an expanding role of systemic therapies. Summary: Melanoma in-transit metastases consist of intralymphatic neoplastic implants distributed between the primary site and the regional nodal basin, within the subepidermal and dermal lymphatics. Distinct risk factors may influence the development of ITM, and the clinical presentation can be highly heterogeneous, enhancing the complexity of the management of ITM. Surgical resection, when feasible, continues to represent a standard approach for patients with curative intent. Patients with extensive or unresectable disease may also benefit from regional approaches that include isolated limb perfusion or infusion, electrochemotherapy, and a wide variety of intralesional therapies. Over the past decade, regimens with ICI and BRAF/MEK inhibitors dramatically expanded the benefit of systemic treatments for patients with melanoma, both in the adjuvant setting and for those with advanced disease, and the combination of these modalities with regional treatments, as well as neoadjuvant approaches, may represent the future for the treatment of patients with ITM. [ABSTRACT FROM AUTHOR]

The aim of this study was to compare long-term patient reported outcomes (PROs) in patients with locally advanced extremity soft tissue sarcoma (eSTS) after isolated limb perfusion followed by resection (IR), compared to extended resection (ER), primary amputation (A) or secondary amputation after IR (IR-A). Patients were selected from the respondents of a multi-institutional cross-sectional cohort survivorship study (SURVSARC) conducted among sarcoma survivors registered in the Netherlands Cancer Registry (NCR), 2–10 years after diagnosis. Used PROs were the EORTC QLQ-C30, the Cancer worry scale (CWS), the Hospital Anxiety and Depression Scale (HADS), and the Toronto Extremity Salvage Score (TESS). We identified 97 eSTS survivors: IR = 20, ER = 49, A = 20, IR-A = 8. While there were no differences in PROs between IR and ER, results showed better functioning and functionality in both groups versus the amputation groups. The amputation groups scored significantly lower on physical functioning (A = 62.7, IR-A = 65.7 versus IR = 78.0, ER = 82.7, p = 0.001) and role functioning (A = 67.5, IR-A = 52.8 versus IR = 79.2, ER = 80.6, p = 0.039), both EORTC QLQ-C30 scales. Also for the TESS, the scores were significantly lower for the amputation groups compared to the limb sparing groups (upper extremity p = 0.007 with A = 68.9, IR-A = 71.6 versus IR = 93.3, ER = 91.1; lower extremity p < 0.001 with A = 72.2, IR-A50.9 versus IR = 84.5 and ER = 85.5). There were no significant differences between the groups on cancer worry, anxiety and depression. HRQoL in eSTS survivors treated with IR or ER is equal; for maintenance of physical functioning and functionality IR and ER outperform an amputation. [ABSTRACT FROM AUTHOR]

Local recurrence (LR) is one of the main pitfalls in surgery for extremities soft tissue sarcoma (eSTS). Achieving clear histopathological margins is the most important factor to reduce the risk of LR, but the ability to do so depends on not only surgical technique but also the interplay between tumor biology, anatomical location and surgical approach. The balance between postoperative morbidity and oncological benefits in reducing the risk of LR needs to be considered. This review will cover which etiological factors for the development of eSTS lead to an increased risk of LR and discuss histological subtypes that have a high risk of LR and which surgical and neoadjuvant therapeutic strategies can minimize the risk of LR. The traditional view that surgical radicality always results in low rates of LR, while marginality alone always leads to high rates of relapse, is outdated. In the modern era of surgical oncology, limb salvage and high-level function after resectional surgery are the key surgical goals. The best results are achieved by combining effective neoadjuvant treatments with planned bespoke oncological operations that consider the biological and anatomical factors of each individual sarcoma. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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.

Background: Isolated limb perfusion (ILP) is a treatment option for malignancies localized to an extremity and is performed by surgical isolation of the limb which is connected to an extracorporeal circulation system. A high concentration of a chemotherapeutic agent is perfused through the limb, while systemic toxicity is avoided. Currently, the use of packed red blood cells in the priming solution is the norm during ILP. The aim of this study was to investigate the possibility to replace an erythrocyte-based prime solution with a crystalloid-based prime solution while maintaining the regional metabolic oxygen demand during ILP. Methods: In a single-center, randomized controlled, non-blinded, non-inferiority clinical trial, 21 patients scheduled for treatment with ILP were included and randomized 1:1 to either an erythrocyte-based prime solution (control) or a crystalloid-based prime solution (intervention). Results: There was a significant difference in lactate level (mmol/L) during the perfusion between the intervention group and the control group (1.6 ± 0.4 vs. 3.6 ± 0.7, p = .001). No significant differences in oxygen extraction (%) (22 ± 11 vs. 14 ± 4, p = .06), oxygen delivery (ml/min) (90 ± 49 vs. 108 ± 38, p = .39), oxygen consumption (ml/min) (14 ± 2 vs. 14 ± 5, p = .85), regional central venous saturation (%) (83 ± 10 vs. 91 ± 4, p = .07) or INVOS (%) (76 ± 14 vs. 81 ± 11, p = .42) were found between the intervention group and the control group. Conclusion: This study showed no significant improvement with the addition of packed red blood cells into the prime solution in ensuring the metabolic oxygen demand in the treated extremity during ILP, and we, therefore, recommend that a crystalloid-based prime solution should be used.

La perfusión de miembro aislado (PMA) es un método para el tratamiento de extremidades con lesiones irresecables de pacientes con melanoma o sarcoma. Se usan altas dosis de factor de necrosis tumoral α y melfalán, que pueden provocar toxicidad sistémica severa en caso de fuga del fármaco desde la circulación aislada de la extremidad a la sistémica. Esto hace imperativo monitorizar el porcentaje de fuga (F[%]) durante la perfusión, actualmente realizado con radiotrazadores. El objetivo de este trabajo fue elaborar un protocolo de monitorización de fuga lo más exacto posible que garantizara una PMA segura. Construimos un fantoma con 3 compartimentos (cuerpo, extremidad y área precordial) y un colimador de alta sensibilidad adaptable a una gammacámara portátil. Simulamos PMA con fugas programadas cada 10 min del 1 al 9% (F[%] teóricos). Medimos estos F(%) mediante 2 ecuaciones: una propuesta en la literatura y otra corregida por decaimiento del radioisótopo. Testamos las dosis de radiofármaco óptimas para minimizar el error por tiempo muerto del detector y comparamos los F(%) medidos según las 2 ecuaciones con los F(%) teóricos. El protocolo de monitorización de fuga se utilizó en 17 PMA de 16 pacientes y se analizaron los datos registrados. Encontramos diferencias significativas entre los F(%) medidos con la primera ecuación y los F(%) teóricos, con unos resultados muy ajustados a los teóricos al aplicar la corrección por decaimiento. La corrección por decaimiento del radioisótopo es una manera simple de realizar el procedimiento de forma más segura y de disminuir el error en el cálculo de F(%). 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. These 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. We built a phantom with 3 compartments (body, limb and precordial area) and a high sensitivity collimator fitted to a portable gammacamera. We simulate ILP with scheduled leaks every 10 minutes from 1% to 9% (theorical F[%]). We mesured F(%) using 2 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. 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. 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(%). [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. [ABSTRACT FROM AUTHOR]

Abstract Background Isolated limb perfusion with TNF-alpha and melphalan (TM-ILP) in combination with complete tumor resection is an effective treatment option for non-resectable soft-tissue sarcoma of the extremities, with limb salvage rates greater than 80%. The aim of this study was to assess quality of life (QoL) after TM-ILP, also with regard to long-term survival. Methods We retrospectively examined 27 patients who had primarily non-resectable soft-tissue sarcoma of the leg and who had undergone TM-ILP and complete tumor resection (with limb-sparing intent) during their follow-up examinations using the Quality of Life Questionnaire (QLQ-C30) and the German Short Musculoskeletal Function Assessment (SMFA-D). The results from the QLQ-C30 were compared to the reference values for the general population, to the “all cancer patients” reference values (both reference values published by the European Organization for Research and Treatment of Cancer (EORTC)), and to the reference values of a historical amputation group from the literature. The results of the SMFA were compared with those from a reference group of healthy individuals. Results Surprisingly, we found that the global health status/QoL in the TM-ILP group was not significantly different from the general population or from patients with amputation, but it was higher than that of patients with cancer in general. Concerning the SMFA, we did find functional impairments in patients after TM-ILP compared to the reference group. With regard to long-term survival, we found no time-dependent deterioration in QoL for longer time intervals after treatment. Conclusions These results support the use of TM-ILP in limb-sparing multimodal therapy settings from a quality-of-life perspective, but they also encourage further research on this matter.

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.

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. [ABSTRACT FROM AUTHOR]

Background: Limb-sparing surgery in locally advanced soft tissue sarcomas (LA STS) is challenging. The aim of this study is to evaluate upfront isolated limb perfusion (ILP) in untreated patients with LA STS. Methods: All consecutive patients with LA STS of the limbs deemed borderline or unresectable and treated with upfront ILP as induction treatment between 2003 and 2016 were included. Demographic, clinical and long-term characteristics were obtained and retrospectively analyzed. Results: 41 patients (pts), with a median age of 51 years [range 21–76], were identified (lower limb 68%, upper limb 32%). Liposarcoma and undifferentiated pleomorphic sarcoma were the most common subtypes (27% and 22%, respectively). Acute toxicities, using Wieberdink classification, were grade II (35 pts, 85%), grade III (2 pts, 5%) and no grade IV–V. Local control rate was 98%. 32 pts had limb-sparing surgery (78%). 1 pt had an early amputation due to progressive disease after ILP. 8 pts were not operated (four had RT alone, one had distant metastases, two had a complete response and one died 3 months after ILP of a pulmonary embolism). 36 pts (84%) received postoperative RT. After a median follow-up of 43 months, 18 pts (47%) relapsed. Median disease-free survival (DFS) was 6.7 years. The median overall survival (OS) was not reached. The 1-year, 5-year and 10-year DFS and OS rates were, respectively, 75%, 50% and 45%, and 90%, 63% and 55%. Conclusion: Upfront ILP is an efficient and well-tolerated limb-sparing procedure in borderline or unresectable LA STS without hampering OS. [ABSTRACT FROM AUTHOR]

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.

The goals of treatment for soft tissue sarcoma (STS) of the extremities are local tumor control, preservation of limb function and reduction of the risk of distant metastasis. The standard treatment for STS of the limbs is wide local excision with histologically negative margins and, in the majority of cases, adjuvant radiotherapy. In the case of locally advanced tumors, this might not be feasible, especially when the tumor is located at the periphery of the limb, or tumor infiltration, encasement or fixation of motor nerves, major vessels or bones has occurred, in which case, amputation may be necessary. The aim of neoadjuvant treatment is to minimize the need for amputation or surgery that leads to major functional impairment with an acceptable level of toxicity and without a negative impact on survival. This is a comprehensive review of the various neoadjuvant treatment strategies applied in an attempt to salvage the limb and to preserve its function in patients with locally advanced STS. Systemic chemotherapy with regional hyperthermia and isolated limb infusion (ILI) are promising. Novel treatment option such as, isolated limb perfusion (ILP) with tumor necrosis factor-α (TNF-α) and melphalan appears to be the most effective neoadjuvant treatment modality for these cases. ILP provides the highest likelihood of local tumor eradication with preservation of the limb and its function for patients with limb-threatening locally advanced STS. Approximately one quarter of the patients experience complete pathological response and half of the patients a partial response, together resulting in limb salvage in three quarters of the patients. Because of the high pathological response rates, the high limb salvage rate, the improved surgical margins after ILP with TNF-α and melphalan, and its low toxicity, the indications for performing this treatment should be evaluated for primary and recurrent tumors when infiltration, encasement and/or fixation of motor nerves, major vessels, or bones are present. When ILP is indicated, the limited availability of the technique, which is provided at present by only one center in Greece, should not be a reason to withhold from a patient the opportunity of salvage of the limb and its function. [ABSTRACT FROM AUTHOR]

Objective: 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). Methods: 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. Results: 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. Conclusions: MI-ILP is feasible and gives the same treatment characteristics as open ILP, but with the advantage of a minimally invasive vascular access. [ABSTRACT FROM AUTHOR]

Background Isolated limb perfusion (ILP) is a well-established treatment for patients with advanced extremity malignancies unsuitable for limb-conserving surgery. However, little is known about the outcomes of this treatment in elderly patients. We sought to determine the effects of age on the tolerability and efficacy of ILP for advanced extremity malignancy. Patients and methods Patients undergoing ILP at our institution between January 2005 and January 2018 were identified from a prospectively maintained database. Patients were stratified by pathology (melanoma, soft-tissue sarcoma, other) and age (<75 years and ≥75 years). Outcomes of interest were perioperative morbidity and mortality, locoregional toxicities, response rates and oncological outcomes. Results During the study period, a total of 189 perfusions were attempted. Successful perfusions were performed in 179 patients, giving a technical success rate of 94.7%. No difference in perfusion success rates, severe locoregional toxicity and perioperative morbidity or mortality was noted between those aged <75 years and ≥75 years. The overall response rate in melanoma was 82.4%, and no difference in response rates or oncological outcomes between age groups was noted in these patients. The overall response rate in soft-tissue sarcoma was 63.5%, with no difference in response rates noted between age groups. However, patients aged <75 years with soft-tissue sarcoma had prolonged local recurrence-free survival compared with older patients (13 versus 6 months), possibly due to the prevalence of chemosensitive subtypes in the younger age group. Conclusion ILP is an effective treatment for advanced extremity malignancies in the elderly, with comparable response rates and toxicities to younger patients. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the response rates of different extremity soft-tissue sarcoma subtypes (eSTS) after isolated limb perfusion (ILP), based on an international multi-centre study. The retrospective cohort comprised eSTS patients from 17 specialised ILP centres that underwent melphalan-based ILP, with or without recombinant human tumour necrosis factor (rhTNFα) (TM-ILP and M-ILP, respectively). Response was measured on imaging (magnetic resonance imaging) and/or clinical response, for which M-ILPs were excluded. A total of 1109 eSTS patients were included. The three most common histological subtypes were undifferentiated pleomorphic sarcoma (17%, n = 184), synovial sarcoma (16%, n = 175) and myxofibrosarcoma (8%, n = 87). rhTNFα was used in 93% (TM-ILP) and resulted in a significantly better overall response rate (ORR, p = 0.031) and complete responses (CR, p < 0.001) in comparison to M-ILP, without significant differences among histological subgroups. The ORR of TM-ILP was 68%, including 17% CR. Also, 80% showed progressive disease. Significantly higher response rates were shown for Kaposi sarcoma (KS) with 42% CR and 96% ORR (both p < 0.001), and significantly higher CR rates for angiosarcoma (AS, 45%, p < 0.001) and clear cell sarcoma (CCS, 31%, p = 0.049). ILP was followed by resection ≤ 6 months in 80% of the patients. The overall limb salvage rate was 88%, without significant differences among histological subgroups, but was significantly higher for ILP responders compared to non-responders (93% versus 76%, p < 0.001). ILP resulted in high response and LRS among all eSTS subtypes, however, with significant differences between subtypes with most promising results for KS, AS and CCS. • ILP shows high response rates with an ORR of 68% and a CR of 17%. • With an LSR of 88%, ILP is a valuable limb salvage treatment for patients with eSTS. • ILP is a generic eSTS treatment with responses in every subtype. [ABSTRACT FROM AUTHOR]

Complete response can be difficult to assess after isolated limb perfusion (ILP) for metastatic in-transit melanoma, especially when numerous and unresectable post-necrotic persisting pigmented lesions occur. These residual lesions are mainly seen in the more superficial and pigmented types of metastatic disease and correspond to the residual melanophage granuloma that persists after tumor tissues undergo complete necrosis. Reflectance confocal microscopy (RCM) is a non-invasive technique that allows the exploration of the superficial dermis. Here, we present the case of a patient in whom numerous post-ILP limb residual pigmented lesions were explored using combined RCM and histological examination of sample lesions and could be characterized as non-active. This approach allowed us to avoid additional excisions.

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. [ABSTRACT FROM AUTHOR]

Background Angiosarcomas are rare and aggressive soft-tissue sarcomas. The only potential curative treatment is complete surgical excision. This study reports the outcome of isolated limb perfusion (ILP) with high-dose melphalan and tumour necrosis factor α for locally advanced angiosarcoma. Material and methods All patients who underwent an ILP for angiosarcomas between 1991 and 2016 in three tertiary referral centres were identified from prospectively maintained databases. Results A total of 39 patients were included, with a median follow-up of 18 months (interquartile range 6.1–60.8). Of these patients, 23 (58.9%) patients had a complete response (CR) after ILP, 10 (25.6%) had a partial response, 4 (10.3%) had stable disease and 2 (5.1%) patients had progressive disease immediately after ILP. A total of 22 patients developed local progression (56.4%), whereas nine (23.1%) developed distant metastases. The patients with CR had a significantly prolonged median local progression-free survival (PFS) (15.4 versus 7.3 months, p = 0.015) when compared with non-CR patients, and a trend towards better median overall survival (81.2 versus 14.5 months, p = 0.054). Six patients underwent multiple ILPs, whereby the CR rate of the first, second and third ILPs were 60%, 80% and 67%, respectively. Thirteen (33.3%) patients needed further surgical intervention, consisting of resection in eight patients (20.5%) and amputation in five patients (12.8%). Conclusion ILP is an effective treatment option for patients with locally advanced angiosarcoma in the extremities, resulting in a high number of CRs, a high limb salvage rate and prolonged local PFS. [ABSTRACT FROM AUTHOR]

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, <10% of the patients required vasopressors. Additionally, <5% of the patients required invasive mechanical ventilation. Therefore, ICU admission directly following isolated limb perfusion should not be standardized. [ABSTRACT FROM AUTHOR]

Background: Hyperthermic isolated limb perfusion (HILP) represents a limb-sparing treatment for unresectable soft tissue sarcoma (STS) of the extremities with substantial complete response rates. HILP often provides good functional limb preservation, hence a significant improvement also in terms of quality of life of the patient. Notwithstanding these clear advantages, the traditional technique is still hindered by relatively high post-operative morbidity. Method: We treated a 78-year-old female with unresectable angiosarcoma of the left leg using a new surgical approach: an entirely laparoscopic HILP. Results: No conversion from laparoscopic to "open" surgery was necessary. Since no abdominal muscle section was performed, post-operative pain was low and easily manageable; early mobilisation and early discharge were achieved. Patient developed moderate toxicity, which resolved spontaneously within 3-4 weeks, with complete return to normal daily activities after 30 d. Complete clinical response with preservation of leg function was obtained. Conclusions: We describe for the first time an entirely laparoscopic HILP. Demonstration of this technique's efficacy and safety on a large series of patients is clearly necessary but its therapeutic efficacy appears to be comparable to the standard technique. Furthermore, laparoscopic HILP has shown low post-operative morbidity: no wound complications, mild and easily manageable post-operative pain and early discharge from the hospital and early resuming of daily activities. [ABSTRACT FROM AUTHOR]

Introduction:Isolated limb perfusion (ILP) is a treatment option for patients with in-transit metastases of malignant melanoma in the extremities, as well as locally advanced sarcoma. ILP allows for a delivery of high-dose chemotherapy to an isolated extremity with minimal systemic toxicity. However, local toxicity like oedema, blistering, nerve damage and compartment syndrome can occur. Myoglobin measurements have been used as a screening method to predict the most severe cases of local toxicity. The aim was to investigate if myoglobin is a predictive factor for local toxicity after ILP in patients with melanoma in-transit metastases. Methods:One hundred and ninety-three patients were treated for the first time with ILP for in-transit metastases between 2001 and 2015. Myoglobin was measured once the first hours after the perfusion (POD0), and for the first five post-operative days (POD1-5). Local toxicity was graded according to Wieberdink, and grouped in mild (I and II), moderate (III), and severe (IV and V). Wieberdink-groups were compared with myoglobin measurements, and myoglobin measurements were compared between gender, perfusion time, perfusion temperature and cannulated vessels. Results:There is no statistically significant difference in myoglobin serum levels during the first five days post perfusion between patients suffering from mild, moderate or severe local toxicity. There is no difference between toxicity groups when it comes to distribution of sex, tumour size, or tumour numbers. Conclusion:Levels of myoglobin do not predict local toxicity for patients with melanoma in-transit metastases treated with ILP when measured during the first five post-operative days. [ABSTRACT FROM PUBLISHER]

Background: Tumor necrosis factor alpha (TNF) and melphalan-based isolated limb perfusion (TM-ILP) is one of the most effective treatment modalities for unresectable soft tissue sarcoma (STS) of the extremities. Liposarcomas (LS) are a large and heterogeneous subgroup of STS with different biological behavior and prognoses. The aim of this study was to evaluate LS and the different subentities with respect to their responsiveness towards TM-ILP. Methods: We matched our ILP database with our pathology database to identify patients who received TM-ILP due to STS followed by resection of the residual tumor. We identified 126 patients who matched these inclusion criteria. In this patient group we identified 24 patients with a LS. Histopathological regression was assessed from all resection specimens and was compared between groups: LS vs. non-LS and for myxoid and non-myxoid LS subgroups. Results: There were no significant differences in the overall tumor regression comparing non-LS (median 95%, mean 77%) and LS (median 90%, mean 74%). For the subgroup analysis, a higher grade of regression after TM-ILP was found in myxoid-LS (median 95%, mean 79% ± 31.5) compared to the non-myxoid LS (median 75%, mean 72% ± 24.6). Atypical lipomatous tumors (ALT) were less responsive to TM-ILP treatment (median 40%, mean 40%). Conclusion: The histopathological response of LS toward TM-ILP is equally good compared to non-lipomatous STS. Myxoid LS seem to have a tendency towards a better response to TM-ILP compared to non-myxoid LS and ALT showed the lowest response rate in the liposarcoma subgroup. Furthermore, we found that TM-ILP seems to facilitate successful R0 resection. Due to the low number of cases in the subgroups we advocate further research on this topic. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Synovial sarcoma is a rare type of soft tissue sarcoma that occurs mostly in young adults, and it is always regarded as a high-grade tumor. Here, we report the case of a 31-year-old German Caucasian male with synovial sarcoma of the wrist who was offered amputation at his local hospital. After referral to our Reference Centre for Soft Tissue Sarcoma, the quadruple approach of isolated limb perfusion, surgical ablation, adipofascial perforator flap and radiation avoided amputation and enabled preservation of good hand function with no evidence of recurrence or metastasis after 1 year.

An 18-year old osteosarcoma patient with a huge tumor mass at the distal femur and inguinal metastases was treated with the intention to preserve the leg and additionally treat the pelvic metastases locally. Therefore we modulated the technique of isolated limb perfusion. Isolated Limb Perfusion was performed as an Extended Isolated Limb Stop-Flow Infusion (EISLI) where the pelvis was included into the perfusion bed. Balloon catheters were placed in the arterial and venous bifurcation in the pelvis. For increasing the drug concentration at the tumor site, an angiographic catheter was placed arterially with the tip right in front of the tumor region. A Stop-Flow phase before the perfusion phase was applied. After 4 cycles of EISLI the lesions in the pelvis disappeared and surgical resection of the tumor and implantation of an endoprosthesis was possible and successful. Histopathological findings showed no vital cells in the resected tumor region. Currently the patient is tumor free and does not show recurrence or pulmonal metastases for 18 months after the last induction treatment cycle. With EISLI the inclusion of the pelvis is possible during isolated limb perfusion. In addition with low total dosages EISLI enabled drug concentrations many times higher at the tumor site than possible during systemic chemotherapy or standard isolated limb perfusion. It is a technique that allows limb preservation and treatment of positive lymphnodes in the groin. Quality of life is maintained during the Regional Chemotherapy (RCT). • Isolated Limb Perfusion can be extended to the pelvic region with balloon catheters at the arterial and venous bifurcation. • Drug concentrations at a tumor can be increased by stopflow infusion. • Increased drug concentrations during 5 min stopflow phase might cause sufficient tissue drug uptake. • Extended Isolated Limb Infusion (EISLI) can be an alternative to limb amputation. [ABSTRACT FROM AUTHOR]

Surgical intervention is the mainstay treatment for soft tissue sarcomas. The significance of adjuvant and neoadjuvant therapies such as chemotherapy, radiation and isolated limb perfusion remains under controversial discussion. The goal of this review is to discuss the effects of the aforementioned treatment modalities and their timing of application on plastic surgery techniques. Furthermore, options of reconstruction in cases of complications caused by adjuvant and neoadjuvant therapies are discussed. When compared with adjuvant radiation, neoadjuvant treatment can reduce negative side effects such as fibrosis and edema, because radioderma can be removed during the subsequent surgical procedure. Furthermore, there have not been any reports of negative effects of neoadjuvant radiation on microsurgical procedures. However, the dose of neoadjuvant radiation correlates with increased risks of impaired wound healing postoperatively. Thus, a patient-specific approach to decide whether radiation should be performed adjuvant or neoadjuvant is necessary. Pre-operative irradiation should be considered in cases where functional structures are exposed after tumor resection, in order to ensure the best possible functionality. Adjuvant radiation should be considered in all other cases because of its known superior wound healing. .As for chemotherapy, no negative influence of its use adjuvant or neoadjuvant to reconstructive procedures such as local or free flaps has been reported. Lastly, small sample size studies have not shown increased risks of microsurgical failure or wound complications after isolated limb perfusion. The findings of this review suggest that the chronological order of the discussed therapeutic approaches is not a decisive factor in the surgical outcome of reconstructive procedures for soft tissue sarcoma.

The management of locally advanced or recurrent extremity sarcoma often necessitates multimodal therapy to preserve a limb, of which isolated limb perfusion (ILP) is a key component. However, with standard chemotherapeutic agents used in ILP, the duration of response is limited. Novel agents or treatment combinations are urgently needed to improve outcomes. Previous work in an animal model has demonstrated the efficacy of oncolytic virotherapy when delivered by ILP and, in this study, we report further improvements from combining ILP-delivered oncolytic virotherapy with radiation and surgical resection. In vitro, the combination of radiation with an oncolytic vaccinia virus (GLV-1h68) and melphalan demonstrated increased cytotoxicity in a panel of sarcoma cell lines. The effects were mediated through activation of the intrinsic apoptotic pathway. In vivo, combinations of radiation, oncolytic virotherapy and standard ILP resulted in delayed tumour growth and prolonged survival when compared with standard ILP alone. However, local disease control could only be secured when such treatment was combined with surgical resection, the timing of which was crucial in determining outcome. Combinations of oncolytic virotherapy with surgical resection and radiation have direct clinical relevance in extremity sarcoma and represent an exciting prospect for improving outcomes in this pathology. [ABSTRACT FROM AUTHOR]

The management of locally advanced extremity soft tissue sarcoma of the limbs is challenging, particularly for recurrent tumors and those adjacent to neurovascular bundles and joints. Typically, the tumors are large, below the fascia, and high-grade (T2b or stage III according to the American Joint Committee on Cancer) and thus require multimodal therapy. Treatment options must be tailored to patient and tumor characteristics. Isolated limb perfusion with recombinant human tumor necrosis factor α and melphalan (TNF-ILP) adds a therapeutic option to radiation therapy (RT) and systemic chemotherapy. Although the procedure is somewhat sophisticated to learn, it is a safe method and has been used now for almost 2 decades at more than 50 centers worldwide. TNF-ILP yields a high rate of complete or nearly complete pathologic tumor remission. In combination with surgical resection of the tumor remnant after isolated limb perfusion, the limb salvage rate is close to 90%. Often, patients can be spared adjuvant RT without long-term local tumor control rates being compromised. Nevertheless, TNF-ILP has never been compared with another treatment regimen in a randomized trial. This review summarizes the mode of action and standard application of TNF-ILP and focuses on a critical discussion of the role of TNF-ILP in the multimodal treatment of locally advanced primary and recurrent extremity sarcoma. Cancer 2016. © 2016 American Cancer Society. Cancer 2016;122:2624-2632. © 2016 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background:Isolated limb perfusion (ILP) is an established and effective treatment for advanced melanoma and soft tissue sarcomas of the extremities with a high overall response rate. The aim of this study was to describe our experience of ILP for more rare types of tumours. Methods:Patients with Merkel cell carcinoma (MCC) (n = 4), squamous cell carcinoma (SCC) (n = 2), B-cell lymphoma (n = 1), desmoid tumours (n = 3), pigmented villonodular synovitis (PVNS) (n = 1) and giant cell tumour (n = 1) were treated with ILP and analysed retrospectively. Results:The four patients with in-transit MCC had three complete responses (CR) and one partial response (PR); the two patients with SCC had one CR and one stable disease (SD); the patients with desmoid tumours had two PR and one SD. A CR was also observed for the patient with a giant cell tumour, but the patient with PVNS had a SD. The patient with cutaneous metastases of B-cell lymphoma showed a CR, however with rapid systemic progression. Local toxicity according to Wieberdink was grade II in 10 patients (83%) and grade III in two patients (17%). Conclusions:These results show that ILP can be used as a treatment option also for more rare disease entities when other treatments have failed. [ABSTRACT FROM AUTHOR]

Purpose: Histological response assessment following neoadjuvant treatment can help identify patients at a higher risk for systemic disease progression. Our goal was to evaluate whether mitotic count and the amount of viable tumour following neoadjuvant isolated limb perfusion (ILP) for primary, locally advanced, non-metastatic, high-grade extremity soft tissue sarcoma correlate with prognosis.Patients and methods: This study is a retrospective analysis of 61 patients who underwent neoadjuvant ILP followed by surgical resection with curative intent between 2001 and 2011. Non-parametric analyses were carried out with the Mann-Whitney U and the Wilcoxon signed-rank test. Survival curves were calculated with the Kaplan-Meier method and compared with the log-rank test.Results: The median follow-up was 44 months for all patients and 55 months for survivors. The amount of viable tumour after ILP had no correlation with overall (OS) (P = 0.227) or event-free (EFS) (P = 0.238) survival probability. Patients with a low mitotic count after ILP had a significantly higher OS (P < 0.001), EFS (P = 0.002) and post-relapse survival probability (P = 0.030) compared to patients with an intermediate or high mitotic count.Conclusions: The mitotic count following ILP for primary, high-grade, locally advanced, non-metastatic soft tissue sarcoma appears to significantly correlate with prognosis. If these results are validated in a prospective setting, they could provide a rationale for the design of adjuvant systemic chemotherapy trials with the goal of improving the prognosis of patients with an intermediate or high mitotic count after ILP. [ABSTRACT FROM PUBLISHER]