R.J. van Ginkel

Therapeutic groin dissection for melanoma: Risk factors for short term morbidity

AIMS Ilio-inguinal lymph node dissection for stage III melanoma is often complicated by wound healing disturbances. A retrospective study was performed to investigate the wound healing disturbances after therapeutic ilio-inguinal lymph node dissection. PATIENTS AND METHODS Between 1989 and 2007, 139 consecutive patients, 73 females (53%) and 66 males (47%), median age 55 (range 20-86) years underwent a therapeutic ilio-inguinal lymph node dissection. Data were recorded on early complications: haematoma, wound infection, wound necrosis and seroma. Univariate and multivariate logistic regression analyses were used to evaluate the influence of a wide range of variables on postoperative complications. RESULTS Seventy-two patients had one or more early wound complications (49.7%). These complications comprised haematoma (n=3, 2.1%), wound infection (n=30, 20.7%), wound necrosis (n=25, 17.5%) and seroma (n=31, 21.8%). Wound infections were significantly more common in patients with a body mass index (BMI) of >25 (p=0.019). Wound necrosis developed significantly more often if the Bohler Braun splint was not used postoperatively (p=0.002). The occurrence of one or more early complications was significantly associated with the non-use of a Bohler Braun splint (p=0.026) and age of >55 years (p=0.015). CONCLUSIONS High BMI was significantly correlated with the occurrence of wound infections. Bed with of the hip and knee in flexion using a Bohler splint improved wound healing after therapeutic ilio-inguinal lymph node dissection.

Dermatofibrosarcoma protuberans : Recurrence is related to the adequacy of surgical margins

INTRODUCTION The aim of the study was to investigate the results of surgical treatment in primary and recurrent dermatofibrosarcoma protuberans (DFSP), with respect to local tumor control. PATIENTS AND METHODS Thirty-eight patients were treated between 1971 and 2005 at the University Medical Center Groningen (UMCG). Thirty patients presented with primary disease (79%) and 8 patients with locally recurrent disease (21%). The treatment consisted of surgical resection and in case of marginal or positive resection margins (R1 resection) adjuvant radiotherapy. RESULTS Adequate surgical margins as a single modality was associated with 100% local control in all primary DFSPs. Two patients whose resection specimens had microscopically positive resection margins had withdrawn from adjuvant radiotherapy and developed local recurrence (LF rate 7%). Two of the 8 patients referred with a local recurrence developed a second recurrence (LF rate 25%); one of these patients developed distant disease and ultimately died of systemic disease. None of the five patients with DFSP-FS developed LF after treatment at the UMCG. After a median follow-up of 89 (12-271) months, the 10-year disease-free survival was 85% and the 10-year disease specific survival was 100%. CONCLUSION After wide surgical resection of a DFSP or DFSP-FS, or an R1 resection combined with adjuvant radiotherapy the risk of local recurrence is extremely low.

Hyperthermic isolated limb perfusion with tumour necrosis factor-alpha and melphalan as palliative limb-saving treatment in patients with locally advanced soft-tissue sarcomas of the extremities with regional or distant metastases. Is it worthwhile?

Abstract The management of locally advanced soft-tissue sarcomas (STS) of the extremities in patients who present with regional and/or distant metastases at the time of diagnosis remains an unsolved problem. The recently introduced hyperthermic isolated limb perfusion (HILP) with tumour necrosis factor (TNF)-α and melphalan has been shown to be an effective limb-saving treatment modality, but is it feasible to use this approach with palliative intent? Nine patients, five men and four women, mean age 41 (range 21–75) years with locally advanced extremity STS and regional (n = 3) or distant (n = 6) metastases at the time of diagnosis, underwent a palliative HILP with TNF-α and melphalan. Resection of the residual tumour mass was performed, if possible, 6–8 weeks after HILP. Treatment-related morbidity, local recurrences and the limb salvage rate were scored during follow-up. The median follow-up period was 9 (range 3–39) months (seven deaths, but six were due to metastatic disease). Treatment-related morbidity was seen after 3 of the 10 perfusions performed (30%) and consisted of superficial wound infections (n = 2), blow out of the external iliac artery followed by an iliac thrombosis (n = 1). Two patients showed local recurrences after HILP followed by resection of the residual tumour mass, and one patient showed local progression after two perfusions without resection. Limb salvage was achieved in 8 patients (89%). Therefore, HILP with TNF-α and melphalan for locally advanced extremity STS in patients with disseminated disease is feasible. The local management of locally advanced extremity STS should be the same whether the intent is curative or palliative, as the local control improves the quality of life.

Value of continuous leakage monitoring with radioactive iodine-131-labeled human serum albumin during hyperthermic isolated limb perfusion with tumor necrosis factor-alpha and melphalan.

BackgroundThe aim of this study was to analyze the value of continuous leakage monitoring with radioactive iodine-131-labeled human serum albumin (RISA) in patients treated with hyper-thermic isolated limb perfusion with tumor necrosis factor-α (TNFα) and melphalan.MethodsForty-eight patients with melanoma (n=14) or soft tissue sarcoma (n=34) of an extremity underwent 51 perfusions. Perfusion was performed at the iliac level in 22 cases, at the popliteal level in 16 cases, at the femoral level in 7 cases, and at the axillary level in 6 cases. Leakage rates and perfusion circuit and systemic levels of TNFα, interleukin-6, and C-reactive protein were determined, as were systemic hematological and metabolic profiles and tumor response.ResultsThe mean isotopically measured leakage was 2.9%. Systemic leakage was ≤2% in 28 perfusions and >2% in 23 perfusions. The correlation between the maximal monitored leakage and maximal systemic TNFα levels was. 7114. The area under the curve for TNFα in the perfusion circuit, indicating the exposure of the perfused limb to TNFα, was 18.7% lower in the >2% leakage group. No significant differences in tumor response were found between groups. The area under the curve for systemic TNFα, indicating the exposure of the patient to TNFα, was 18.1 times higher in the >2% leakage group, resulting in a significant decrease in leukocyte and platelet count, hyperbilirubinemia, hypocholesterolemia, and proteinemia. No beneficial effect of the systemically leaked TNF and melphalan was seen on the occurrence of distant metastasis during follow-up. There was a significant difference between perfusions performed at the iliac and femoral levels compared with leakage values at the popliteal level.ConclusionsA good correlation between RISA leakage measurement and TNFα exposure during and after hyperthermic isolated limb perfusion with TNFα and melphalan was demonstrated. RISA leakage measurement serves as a good guide for the effectiveness of isolation during perfusion. If leakage exceeds the 2% limit during perfusion, less exposure of the tumor-bearing limb to TNFα, increased exposure of the patient systemic circulation to TNFα, and more systemic side effects can be expected.

Effects of hyperthermic isolated limb perfusion with tumor necrosis factor-alpha and melphalan on pulmonary function assessments.

High doses of tumor necrosis factor-alpha (TNF) seem to be effective in the treatment of solid tumors in the extremities. By applying current intensive care technology, systemic administration of high doses of TNF levels might be feasible for the treatment of cancer in other localizations. To establish the early and late effects of high systemic TNF levels on the lungs, we determined lung function parameters in 12 patients before and after hyperthermic isolated limb perfusion (HILP) with TNF and melphalan. Because of leakage during perfusion, mean maximum systemic TNF levels of 60.0 ng/ml (range, 0.3-356 ng/ml) were obtained. Significant alterations in the vital capacity (VC), the capillary blood volume (Vc), the diffusing capacity of the alveolocapillary membrane (Dm), and the transfer capacity of the lungs for carbon monoxide per unit alveolar volume (KCO) were observed 1 week after HILP. Eight weeks after HILP, they returned to pretreatment value. Alterations in lung functions were not related to the maximum systemic TNF level. In conclusion, disturbances in pulmonary functions are observed in patients after HILP with TNF and melphalan. These disturbances, which are probably partly caused by high systemic TNF levels, are reversible and would not preclude administration of systemic TNF in high doses.

Hyperthermic isolated limb perfusion with TNF and Melphalan for primarily irresectable soft tissue sarcoma; Three time periods at risk for amputation

S: PLENARY and PARALLEL SESSIONS F i g ~ 1. S ~ v i v a l b y P E T treatment iaterLt post CRT 14 Molecular Profiling Predicts Colon Cancer Survival Better Than Dukes Staging I. Yang, 2 S. Eschrich, l G. Bloom, l J. Quackenbush, 2 T.J. Yeatman.l* 1. Surgery and Interdisciplinary Oncology, H Lee Moff i t t Cancer Center, Tampa, FL; 2. The Institute for Genomic Research, Gaithersburg, MD. Introduction: Dukes staging has been the gold standard for colon cancer staging since its inception in 1932. Recently, gene expression profiles have shown promise in discriminating tumors of varying degrees of risk. We report the first prognostic classifier based on an analysis of 20 genes capable of determining survival that is significantly more accurate than Dukes staging. Methods: Seventy-two patients were selected from the Moffitt Cancer Center Tumor Bank and Registry who had been followed for > 24 months. Gene expression profiles were created using a 32,000 cDNA microarray and then subjected to Significance Analysis of Microarray (SAM) analysis to identify large sets of discriminating genes. Construction of a Support Vector Machine was then undertaken to develop a classifier capable of predicting outcome. The accuracy of this classifier was assessed by leave one out cross validation and compared to that of standard Dukes staging. Results: Hierarchical clustering and PCA identified two populations of genes distinguishing the majority of patients that had survived > 24 mo versus those that did not. These observations strongly suggested the potential for underlying gene expression information to drive a prognostic classifier. SVM analysis identified a set of approximately 20 genes whose expression discriminated good from bad survival with better accuracy than Dukes staging at a minimum of 24 mo of follow-up (82% vs 77%). Interestingly, one of the 20 genes identified by the SVM as important in survival prediction was osteopontin, a gene we previously reported to be the gene most strongly correlated with advancing tumor stage in colorectal cancer. Conclusion: We have produced the first molecular classifier capable of predicting outcome for colon cancer that exceeds the accuracy of Dukes staging, particularly in stages B and C where discrimination is critical. This classifier is based on a 20 gene set of which osteopontin, a known gene associated with colon cancer progression, plays a prominent role. 15 Hyperthermic isolated limb perfusion with TNF and Melphalan for primarily irresectable soft tissue sarcoma; three time periods at 1 , l 2 risk for amputation R. Van Ginkel, K. Thijssens, E. Pras, W. De Graaf, 2 A. Suurmeyer, 2 H. Hoekstra.I 1. Surgical Oncology, University Hospital Groningen, Groningen, Netherlands; 2. University Hospital Groningen, Groningen, Netherlands. Introduction Hyperthemic isolated limb perfusion (HILP) with tumor necrosis factor (TNF) and Melphalan is an established treatment strategy for limb saving surgery for primarily irresectable soft tissue sarcoma (STS). The aim of this study was to investigate the long term limb salvage rate and overall survival of HILP. Patients and Methods From 1992-2003, 70 patients with biopsy proven STS of variable histologic subtypes underwent 74 perfusions. HILP was performed with 4 or 3 mg TNF and 10 or 13 mg/L extremity volume for lower respectively upper extremity. Limb salvage curves and overall survival was calculated using the Kaplan-Meier method. Results A total of 17 amputations (24 %) were performed. Overall 1, 5 and 10 years limb salvage was 81.5-4.7%, 74.9_+6.8% and 65.5_+ 10.3% respectively (Fig 1). Three time episodes of amputation were observed. The first occured within the first year after perfusion due to a postperfusion reaction with massive necrosis of the tumor or renewed tumor growth after an initial good response to perfusion. Thirteen amputations were performed in this time period (1 wk-8 months). The second time period was within 5 years with 2 amputations performed for late local recurrent disease (37 and 58 months). The third episode occurred ten years after perfusion. Amputation was performed for ischemic arterial complications (110 and 125 months). No recurrent disease was found on pathological examination of the amputated specimen. Another two patients developed a pathological fracture of the femur due to osteoporosis (78 and 129 months after perfusion). All these 4 patients received post-perfusion radiotherapy. Overall 1, 5 and 10 years survival was 81.5_+5.0%, 55.3-+6.8% and 36.3-+10.3% respectively (Fig 2). Conclusions In 4 out of 5 patients with primarily irresectable STS, TNF Melphalan HILP is able to preserve the affected extremity and the development of distant metastasis is the main reason for mortality. However, we observed late morbidity with 2 pathological fractures and 2 amputations performed for ischemic arterial complications without evidence of recurrent disease. Fi ju re 1 L i m b sa l vage Figure 2 Patient survival 80 . . . . . . . ~ 80