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Many patients with tumors confined to the liver are not amenable for surgical resection, and an increasing number of these patients are treated by local ablation methods. Isolated hepatic perfusion is another treatment option especially suitable for patients with multiple or bulky primary or metastatic tumors. and can mediate clinical regression of advanced liver metastases. Experience with IHP is still limited to a few centers in the world because of its technical difficulties, surgery-related morbidity, and unproven efficacy. IHP remains an experimental modality restricted to specialized units dedicated to treating this difficult group of patients. Experimental animal IHP models have led us to explore new ways of improving efficacy, reducing technical difficulties, and minimizing regional and systemic toxicity. Future research should be directed to the identification of suitable biological or chemotherapeutic agents, defining clinical indications, and development of technical modifications to make it more generally applicable.

Purpose: A high-dose-rate intraoperative radiotherapy (HDR-IORT) technique for rectum cancer was developed and the technique, local failure, and survival were analyzed., Methods and Materials: After the exclusion of metastatic patients, 37 patients were treated with external beam RT, surgery, and HDR-IORT between 1997 and 2000. Primary locally advanced rectum cancer was found in 18 patients and recurrent disease in 19. HDR-IORT was only administered if the resection margins were < or =2 mm. The flexible intraoperative template is a 5-mm-thick pad with 1-cm-spaced parallel catheters. Clips were placed during surgery to define the target area. A dose of 10 Gy was prescribed at a 1 cm depth from the template surface and calculated using standard plans. After treatment, the dose at the clips was calculated using the reconstructed template geometry and the actual treatment dwell times. The median follow-up of surviving patients was 3 years. No patients were lost to follow-up., Results: Overall, 12 patients (32%) had local recurrence, 5 (14%) of which were in the HDR-IORT field. The 3-year local failure rate for primary tumors and recurrent tumors was 19% and 52%, respectively (p = 0.0042). The 3-year local failure rate was 37% for negative margins and 26% for positive margins (p = 0.51). A high mean dose at the clip (17.3 Gy) was found. The overall survival was significantly different for primary vs. recurrent tumors, stage, and grade., Conclusion: Because of the HDR technique, a high dose at the clips was found, with good local control. More out-of-field than in-field failures were seen. The local failure rate was significantly different for primary vs. recurrent disease.

Isolated limb perfusion with melphalan is the treatment of choice for multiple (small) melanoma-in-transit metastases. The use of tumour necrosis factor alpha (TNFalpha) in isolated limb perfusion is successful for treatment of locally advanced limb soft-tissue sarcomas and other large tumours; this approach can avoid the need for amputation. TNFalpha was approved in Europe after a multicentre trial in patients with locally advanced soft-tissue sarcomas, deemed unresectable by an independent review committee; the response rate to isolated limb perfusion with TNFalpha plus melphalan was 76% and the limb was saved in 71% of patients. Moreover, the trial showed the efficacy of isolated limb perfusion of TNFalpha and melphalan against various other limb-threatening tumours such as skin cancers and drug-resistant bony sarcomas. Laboratory models of isolated limb perfusion have helped to elucidate mechanisms of action and to develop new treatment modalities. They have identified TNFalpha-mediated vasculotoxic effects on the tumour vasculature and have shown that addition of TNFalpha to the perfusate results in an increase of three to six times in uptake of melphalan or doxorubicin by tumours. New vasoactive drugs and new mechanisms of action are being discovered. Moreover, isolated limb perfusion is an effective modality for gene therapy mediated by an adenoviral vector. Various clinical phase I-II studies can be expected in the next few years.

Background: Surgery is rarely undertaken for metastatic melanoma in the spleen. To identify indications for surgical treatment, results after splenectomy for metastatic melanoma were analyzed., Study Design: A retrospective study in which all patients at the Sydney Melanoma Unit recorded as having splenic metastases between January 1990 and May 2001 were identified. For those who underwent surgery, indications for splenectomy, operative complications, and outcomes were documented., Results: Splenectomy was performed in 15 patients, and 98 patients were treated conservatively. Indications for surgery were rupture of the spleen (n = 1), discomfort or pain (n = 7), and the spleen as an apparently solitary site of metastasis (n = 7). All seven symptomatic patients were free of pain after recovery from surgery. Postoperative morbidity occurred in two patients (14%) but there was no mortality. Median overall survival after splenectomy was 11 months, with a survival of 23 months for the subgroup of patients treated for a solitary lesion. Two patients who underwent splenectomy were disease free after more than 2 years of followup. Median overall survival of the conservatively treated patients was 4 months, which was statistically shorter than median survival of the patients who underwent splenectomy (p = 0.02)., Conclusions: Splenectomy can provide good palliation for symptomatic patients with melanoma metastases in the spleen. A selected group of patients with solitary splenic metastases can achieve longterm disease-free survival after splenectomy.

Isolated limb perfusion with Melphalan is the best treatment option to control symptomatic multiple small in-transit metastases. When lesions are bulky, Isolated Limb Perfusion (ILP) with Tumor Necrosis Factor (TNF) + Melphalan is superior as in soft tissue sarcoma. TNF changes the pathophysiology, greatly enhances the uptake of Melphalan and destructs selectively the vasculature of large tumors. To date, ILP is not indicated in an adjuvant setting.

Background: Isolated limb perfusion (ILP) with tumor necrosis factor (TNF) and melphalan is highly effective in treating limb-threatening soft tissue sarcoma (STS) and other bulky tumors. Because of fear of TNF-associated toxicity, ILP with TNF is not offered to older patients in some cancer centers, although especially in older patients, every attempt to avoid an amputation that may end their independence must be considered., Methods: Out of 306 TNF-based ILPs, 50 ILPs were performed for limb salvage in 43 patients >75 years old (range, 75-91 years): 29 STS and 14 melanoma patients., Results: In the STS patients, a response rate of 76% and a limb-salvage rate of 76% were achieved; in the melanoma patients, a 100% response rate and a 93% limb-salvage rate were achieved. Local toxicity was mild. The three postoperative deaths that occurred in the total series of 306 TNF-based ILPs in Rotterdam (<1%) occurred in patients >75 years old after leakage-free perfusions and were not related to TNF but to extremely high-risk profiles in these three patients., Conclusions: Older patients should not be withheld a TNF-based ILP for limb salvage, because the procedure is safe and highly effective in these patients.

Background: Cutaneous Stewart-Treves lymphangiosarcomas represent a rare group of tumors characterized by a high grade of vascularization and by localization in an extremity with lymphedema. The multifocality and the localization makes these tumors eligible for treatment with isolated limb perfusion (ILP). ILP with tumor necrosis factor (TNF) and melphalan is a safe and highly effective procedure that can achieve limb salvage in >or=80% of all patients with nonresectable extremity soft tissue sarcoma or melanoma., Methods: In 10 patients with multifocal Stewart-Treves lymphangiosarcoma of the extremities, 16 ILPs with TNF plus melphalan were performed. All patients would have been candidates for exarticulation of the extremity., Results: We observed an 87% overall response rate (complete and partial responses); one patient had a mixed response, and one patient did not respond to the therapy. In nine perfusions (56%), a complete response was achieved, and five perfusions (31%) resulted in a partial response. Limb salvage was achieved in eight patients (80%), with a mean follow-up duration of 34.8 months (range, 3 to >or=115 months). Regional toxicity was limited and systemic toxicity minimal to moderate, with no toxic deaths., Conclusions: Multifocal Stewart-Treves lymphangiosarcomas in extremities with chronic lymphedema can be successfully treated by ILP with TNF and melphalan.

Previously we demonstrated that addition of Tumour Necrosis Factor-alpha to melphalan or doxorubicin in a so-called isolated limb perfusion results in synergistic antitumour responses of sarcomas in both animal models and patients. Yet, 20 to 30% of the treated tumours do not respond. Therefore agents that synergise with tumour necrosis factor alpha must be investigated. Actinomycin D is used in combination with melphalan in isolated limb perfusion in the treatment of patients with melanoma in-transit metastases and is well known to augment tumour cell sensitivity towards tumour necrosis factor alpha in vitro. Both agents are very toxic, which limits their systemic use. Their applicability may therefore be tested in the isolated limb perfusion setting, by which the tumours can be exposed to high concentrations in the absence of systemic exposure. To study the beneficial effect of the combination in vivo, BN-175 soft tissue sarcoma-bearing rats were perfused with various concentrations of actinomycin D and tumour necrosis factor alpha. When used alone the drugs had only little effect on the tumour. Only when actinomycin D and tumour necrosis factor alpha were combined a tumour response was achieved. However, these responses were accompanied by severe, dose limiting, local toxicity such as destruction of the muscle tissue and massive oedema. Our results show that isolated limb perfusion with actinomycin D in combination with tumour necrosis factor alpha leads to a synergistic anti-tumour response but also to idiosyncratic locoregional toxicity to the normal tissues. Actinomycin D, in combination with tumour necrosis factor alpha, should not be explored in the clinical setting because of this. The standard approach in the clinic remains isolated limb perfusion with tumour necrosis factor alpha in combination with melphalan.

Hypothesis: The natural history and clinical behavior of benign hepatic tumors during long-term follow-up may not justify primary surgical treatment., Design: Retrospective study., Setting: Tertiary referral center., Patients: Two hundred eight patients diagnosed as having a benign liver tumor between January 1, 1979, and December 31, 1999., Intervention: Seventy-four patients underwent hepatic surgery and 134 were managed conservatively by radiological follow-up., Main Outcome Measures: Symptoms and complications were assessed during management and follow-up., Results: In the surgically treated population, the liver lesion was symptomatic in 47 patients (64%) and an incidental finding in 27 (36%). The operative morbidity and mortality were 27% (20 of 74 patients) and 3% (2 of 74 patients), respectively. Overall, 28 (80%) of 35 patients with complaints were asymptomatic after surgery. During observation of the tumor in the conservatively managed group, 39 (87%) of 45 patients who presented with complaints were asymptomatic during a mean follow-up of 45 months; 6 patients had mild abdominal pain considered to be unrelated to the tumor., Conclusions: Conservative management of solid benign liver lesions such as focal nodular hyperplasia and hemangioma can be performed safely, irrespective of their size. We only advise surgery for liver lesions when there is an inability to exclude malignancy or in the case of severe complaints related to the tumor. Resection is always advocated in the case of a large hepatocellular adenoma (>5 cm) to reduce the risk of rupture and malignant degeneration.

Cytokine gene transfer using (multiple) intratumoral injections can induce tumor regression in several animal models, but this administration technique limits the use for human gene therapy. In the present studies we describe tumor growth inhibition of established limb sarcomas after a single isolated limb perfusion (ILP) with recombinant adenoviral vectors harboring the rat IL-3 beta gene (IG.Ad.CMV.rIL-3 beta). In contrast, a single intratumoral injection or intravenous administration did not affect tumor growth. Dose-finding studies demonstrated a dose-dependent response with a loss of antitumor effect below 1 x 10(9) IU of IG.Ad.CMV.rIL-3 beta. Perfusions with adenoviral vectors bearing a weaker promoter (MLP promoter) driving the rIL-3 beta gene did not result in antitumor responses, suggesting that the rIL-3 beta-mediated antitumor effect depends on the amount of rIL-3 beta protein expressed by the infected cells. Furthermore, it was shown by direct comparison that ILP with IG.Ad.CMV.rIL-3 beta in the ROS-1 osteosarcoma model is at least as efficient as the established therapy with the combination of TNF-alpha and melphalan. Treatment with IG.Ad.CMV.rIL-3 beta induced a transient dose-dependent leukocytosis accompanied by an increase in peripheral blood levels of histamine. Leukocyte infiltrations were also histopathologically demonstrated in tumors after perfusion. These results demonstrate that ILP with recombinant adenoviral vectors carrying the IL-3 beta transgene inhibits tumor growth in rats and suggest that cytokine gene therapy using this administration technique might be beneficial for clinical cancer treatment.

Background: As the morbidity and mortality rates associated with emergency resection in patients with a ruptured hepatocellular adenoma are high, the authors have favoured initial non-operative management in haemodynamically stable patients., Methods: A retrospective study was performed to evaluate the treatment of ruptured hepatocellular adenoma., Results: Over a 21-year interval, 12 patients presented with a ruptured hepatocellular adenoma. Haemodynamic observation and support was the initial management in all 12 patients. Three underwent urgent laparotomy and gauze packing because of haemodynamic instability; no emergency liver resection was necessary. Eight patients had definitive surgery; three developed postoperative complications but none died. Regression of the tumour was observed in three of four patients treated conservatively., Conclusion: The initial management of a ruptured hepatocellular adenoma should be haemodynamic stabilization. Definitive resection is required for rebleeding or for tumours exceeding 5 cm in diameter. A conservative approach may well be justified in case of regression of an asymptomatic adenoma.

Objective: To evaluate the potential of isolated limb perfusion (ILP) for efficient and tumor-specific adenovirus-mediated gene transfer in sarcoma-bearing rats., Summary Background Data: A major concern in adenovirus-mediated gene therapy in cancer is the transfer of genes to organs other than the tumor, especially organs with a rapid cell turnover. Adjustment of the vector delivery route might be an option creating tumor specificity in therapeutic gene expression., Methods: Rat hind limb sarcomas (5-10 mm) were transfected with recombinant adenoviruses. Intratumoral luciferase expression after ILP was compared with systemic administration, regional infusion, or intratumoral injection using a similar dose of adenoviruses carrying the luciferase marker gene. Localization studies using lacZ as a marker gene were performed to evaluate the intratumoral distribution of transfected cells after both ILP and intratumoral injection., Results: Intratumoral luciferase activity after ILP or intratumoral administration was significantly higher compared with regional infusion or systemic administration. After ILP, luciferase gene expression was minimal in extratumoral organs, whether outside or inside the isolated circuit. Localization studies demonstrated that transfection was confined to tumor cells lying along the needle track after intratumoral injection, whereas after ILP, lacZ expression was found in viable tumor cells and in the tumor-associated vasculature., Conclusions: Using ILP, efficient and tumor-specific gene transfection can be achieved. The ILP technique might be useful for the delivery of recombinant adenoviruses carrying therapeutic gene constructs to enhance tumor control.

Nitric oxide (NO) is an important molecule in regulating tumour blood flow and stimulating tumour angiogenesis. Inhibition of NO synthase by L-NAME might induce an anti-tumour effect by limiting nutrients and oxygen to reach tumour tissue or affecting vascular growth. The anti-tumour effect of L-NAME after systemic administration was studied in a renal subcapsular CC531 adenocarcinoma model in rats. Moreover, regional administration of L-NAME, in combination with TNF and melphalan, was studied in an isolated limb perfusion (ILP) model using BN175 soft-tissue sarcomas. Systemic treatment with L-NAME inhibited growth of adenocarcinoma significantly but was accompanied by impaired renal function. In ILP, reduced tumour growth was observed when L-NAME was used alone. In combination with TNF or melphalan, L-NAME increased response rates significantly compared to perfusions without L-NAME (0-64% and 0-63% respectively). An additional anti-tumour effect was demonstrated when L-NAME was added to the synergistic combination of melphalan and TNF (responses increased from 70 to 100%). Inhibition of NO synthase reduces tumour growth both after systemic and regional (ILP) treatment. A synergistic anti-tumour effect of L-NAME is observed in combination with melphalan and/or TNF using ILP. These results indicate a possible role of L-NAME for the treatment of solid tumours in a systemic or regional setting., (Copyright 2000 Cancer Research Campaign.)

Tumor necrosis factor-alpha is a multifunctional cytokine and its potential as antitumor agent has been extensively investigated for the treatment of cancer: Initial enthusiasm was tempered when systemic treatment with TNF-alpha was found to cause severe toxic side effects in phase I/II studies. Other applications were sought and a revival of the drug was its application in combination with the cytotoxic drug melphalan in isolated limb perfusion (ILP). Here we discuss the pre-clinical and clinical studies which led to the success in treatment of patients with irresectable extremity soft tissue sarcoma and multiple melanoma in-transit metastases confined to the limb. This achievement may herald the development of new applications of TNF-alpha in isolated organ perfusion settings. An extension of its use may be found in the application of less toxic TNF-mutants or encapsulated in sterically stabilized liposomes. The review concludes with the possible application of low dose TNF-alpha, which can be given systemically, to enhance the anti-tumor potency of formulated drugs (such a liposomal doxorubicin) by increasing solid tumor targeting.

An isolated limb perfusion model (ILP) using soft tissue sarcoma bearing rats (BN175) was used to study antitumour activity of a tumour necrosis factor alpha mutant (TNF-SAM2) in combination with melphalan and doxorubicin. Progressive disease was demonstrated after ILP without agents (sham) or with 50 micrograms TNF-SAM2. ILP with 40 micrograms melphalan or 400 micrograms doxorubicin resulted in no change of tumour volume or progressive disease five days after perfusion. Partial and complete response rates were demonstrated in 76% of rats when the combination of TNF-SAM2 and melphalan was used. TNF-SAM2 in combination with doxorubicin was synergistic as well with a 70% response rate. Histopathologically these responses consisted of hemorrhagic necrosis of the coagulative type. 2 In conclusion, TNF-SAM2 has similar antitumour activity in combination with melphalan or doxorubicin as rHuTNF in sarcoma-bearing rats and is eligible to be tested in clinical ILP or organ perfusion settings because of its potential decreased toxicity.

Isolated hepatic perfusion (IHP) is an attractive approach to treating nonresectable liver tumors, because the effects of systemic chemotherapy are poor and its application is hampered by severe general toxicity. In clinical and experimental settings, the efficacy of isolated limb perfusion (ILP) with tumor necrosis factor-alpha (TNF alpha) in combination with melphalan to treat melanoma in transit and soft-tissue sarcoma has been well established. In an ILP model in rats, the authors previously observed synergistic anti-tumor effects of TNF and melphalan on BN 175 soft-tissue sarcoma extremity tumors. The aim of the current study was to determine whether similar synergy in anti-tumor effects could be achieved by treating experimental BN 175 soft-tissue sarcoma liver tumors by IHP using these agents. The authors found that IHP with TNF and melphalan resulted in a dramatic increase in regional concentrations of perfused agents with virtually no concomitant systemic leakage. Isolated hepatic perfusion with only carrier solution resulted in a significantly diminished growth rate of BN 175 liver tumors compared with the growth rate of tumors in nonperfused rats. Perfusion with melphalan alone resulted in minimal anti-tumor effects. Perfusion with only TNF had a slight growth-stimulatory effect on the BN 175 liver tumors, but no negative effects on tumor growth were observed. When TNF was added to melphalan, a dramatic anti-tumor effect was observed. Thus, as in the rat ILP setting, the anti-tumor effect is augmented when TNF is added to IHP with melphalan to treat BN 175 soft-tissue sarcoma tumor-bearing rats. Strikingly, the tumor response was potentiated at relatively low concentrations of TNF compared with concentrations that elicited synergy with melphalan in ILP.

Several possible mechanisms for the synergistic anti-tumour effects between tumour necrosis factor alpha (TNF-alpha) and melphalan after isolated limb perfusion (ILP) have been presented. We found a significant sixfold increase in melphalan tumour tissue concentration after ILP when TNF-alpha was added to the perfusate, which provides a straightforward explanation for the observed synergism between melphalan and TNF-alpha in ILP.

We have shown previously that isolated limb perfusion (ILP) in sarcoma-bearing rats results in high response rates when melphalan is used in combination with tumour necrosis factor alpha (TNF-alpha). This is in line with observations in patients. Here we show that ILP with doxorubicin in combination with TNF-alpha has comparable effects in two different rat sarcoma tumour models. The addition of TNF-alpha exhibits a synergistic anti-tumour effect, resulting in regression of the tumour in 54% and 100% of the cases for the BN175-fibrosarcoma and the ROS-1 osteosarcoma respectively. The combination is shown to be mandatory for optimal tumour response. The effect of high dose TNF-alpha on the activity of cytotoxic agents in ILP is still unclear. We investigated possible modes by which TNF-alpha could modulate the activity of doxorubicin. In both tumour models increased accumulation of doxorubicin in tumour tissue was found: 3.1-fold in the BN175 and 1.8-fold in the ROS-1 sarcoma after ILP with doxorubicin combined with TNF-alpha in comparison with an ILP with doxorubicin alone. This increase in local drug concentration may explain the synergistic anti-tumour responses after ILP with the combination. In vitro TNF-alpha fails to augment drug uptake in tumour cells or to increase cytotoxicity of the drug. These findings make it unlikely that TNF-alpha directly modulates the activity of doxorubicin in vivo. As TNF-alpha by itself has no or only minimal effect on tumour growth, an increase in local concentrations of chemotherapeutic drugs might well be the main mechanism for the synergistic anti-tumour effects.

An isolated limb perfusion (ILP) model using soft tissue sarcoma-bearing rats was used to study prerequisites for an effective ILP, such as oxygenation of the perfusate, temperature of the limb, duration of the perfusion and concentration of tumour necrosis factor (TNF). Combination of 50 microg TNF and 40 microg melphalan demonstrated synergistic activity leading to a partial and complete response rate of 71%. In comparison to oxygenated ILP, hypoxia was shown to enhance anti-tumour activity of melphalan alone and TNF alone but not of their combined use. Shorter perfusion times decreased anti-tumour responses. At a temperature of 24-26 degrees C, anti-tumour effects were lost, whereas temperatures of 38-39 degrees C or 42-43 degrees C resulted in higher response rates. However, at 42-43 degrees C, local toxicity impaired limb function dramatically. Synergy between TNF and melphalan was lost at a dose of TNF below 10 microg in 5 ml perfusate. We conclude that the combination of TNF and melphalan has strong synergistic anti-tumour effects in our model, just as in the clinical setting. Hypoxia enhanced activity of melphalan and TNF alone but not the efficacy of their combined use. For an optimal ILP, minimal perfusion time of 30 min and minimal temperature of 38 degrees C was mandatory. Moreover, the dose of TNF could be lowered to 10 microg per 5 ml perfusate, which might allow the use of TNF in less leakage-free or less inert perfusion settings.

Isolated limb perfusion (ILP) with TNFalpha, melphalan (M), and IFNgamma results in high tumor response rates in patients with soft tissue sarcomas, melanomas and other tumors. IFNgamma can act synergistically in combination with TNFalpha but in clinical studies this has not been fully investigated. In the BN175 rat sarcoma limb perfusion model we investigated the role of IFNgamma. There were 8 different treatment groups: (I) sham ILP (n=9); (II) IFNgamma alone (n=10); (III) TNFalpha 50 microg (n=9); (IV) TNFalpha + IFNgamma (n=6); (V) melphalan (M) 40 microg (n=11); (VI) M + IFNgamma (n=6); (VII) TNFalpha + M (n=27); (VIII) TNFalpha + M + IFNgamma (n=9). Tumor response and hindlimb function were analyzed. In group I-VI no tumor regressions were observed at 5 days after ILP. ILP with TNFalpha + M had highly effective response rate (RR) of 73%; complete response (CR) rate 55%), very similar to RR in patients. Addition of IFNgamma increased the RR by 16% to 89% and the CR rate by 23% to 78%. This difference was not statistically significant. When IFNgamma was added to TNFalpha or TNFalpha + M it increased limb toxicity significantly (p<0.05 and p<0.005). Since such regional toxicity has not been observed in patients while similar increases in tumor response rates have been reported with IFNgamma it is of importance to define the role of IFNgamma in the clinical setting.

Objective: Analysis of the diagnostic approach and management of 20 patients with hepatocellular adenoma, 1979-1996., Setting: University Hospital Rotterdam-Dijkzigt, Rotterdam, the Netherlands., Design: Retrospective and follow-up analysis., Method: Medical records of patients with histologically proven hepatocellular adenoma were analysed with respect to complaints, diagnostic approach and therapeutical management. Follow-up took place at the outpatient department where history-taking, physical examination, ultrasonography and hepatitis B and C serology tests were performed., Results: In the period 1979-1996, 20 patients with hepatocellular adenoma were treated. Eight patients (mean tumour size 3.2 cm (1.5-5)) were treated conservatively, 12 (mean tumour size 8.1 cm (6-10)) underwent hepatic resection; four because of rupture of the tumour. Serum liver enzyme values did not contribute to the diagnosis. Of the lesions 78% were diagnosed correctly by ultrasonography and 71% by computer tomography. Median follow-up of the patients treated operatively was 73 months (1-204). One patient died three years after an incomplete resection of a hepatocellular adenoma, because of a hepatocellular carcinoma. Ultrasonography did not demonstrate any recurrent tumours in the other patients. In the group of patients conservatively treated (median follow-up 39 months (24-72)) two patients died because of a hepatocellular carcinoma. Ultrasonography demonstrated stable tumour diameters in three patients and regression in three others., Conclusion: Based on the literature and the presented experience surgical treatment is the treatment of choice in patients with large (> or = 5 cm diameter) hepatocellular adenomas because of the risk of malignant transformation and rupture of the tumour. With smaller tumours (< 5 cm) a conservative treatment may suffice in hepatitis virus negative patients, including withdrawal of oral contraceptives followed by thorough ultrasound follow-up of tumour size. In case of tumour growth or complaints a resection of the tumour is indicated.

Introduction: Isolated limb perfusion (ILP) with TNFalpha in combination with melphalan and IFNgamma has resulted in an immediate and dramatic tumor response in patients. Such an effect was also noted following ILP in a rat sarcoma model. This model enables us to investigate several factors responsible for the TNFalpha-induced tumor responses. We applied total body irradiation (TBI) to reduce white blood cell count, to investigate the contribution of leukocytes to the anti-tumor effect of TNFalpha., Methods: Small fragments of the nonimmunogenic BN 175 sarcoma were implanted sc in the lower hind leg. A 5 Gy TBI was performed before ILP at a tumor diameter of approximately 15 mm. The hind limbs of 63 rats were perfused and were divided into 6 groups: group 1, sham perfusion, n = 9; group 2, TBI + sham perfusion, n = 6; group 3, TNFalpha 50 microgram, n = 9; group 4, melphalan 40 microgram, n = 9; group 5, TNFalpha 50 microgram + melphalan 40 microgram, n = 22; group 6, TBI + TNFalpha + melphalan ILP, n = 8. In addition, 10 rats were perfused for histological analysis at 24 h post-ILP., Results: We observed in Group 1: 9/9 progressive disease (PD); Group 2: 6/6 PD; Group 3: 9/9 PD; Group 4: 9/9 no change (NC) of tumor diameter for at least 4 days; Group 5: 6/22 NC, 16/22 complete remission (CR), 12/16 of which showed skin necrosis at the tumor site; and Group 6: 7/8 NC and 1/8 CR (without skin necrosis). After TBI, WBC reduction of 80-95% was observed, while the number of platelets was not significantly reduced and platelet aggregation was maintained at 72 %. Histological analysis revealed decreased hemorrhagic necrosis associated with the absence of PMN infiltration at the tumor margins in the TBI rats., Conclusion: TBI and the associated reduction in WBC count decreased the tumor response by TNFalpha and melphalan significantly and abrogated the immediate response of skin necrosis at the tumor site, as found in rats treated with TNFalpha and melphalan without TBI. These data strongly suggest that leukocytes play an important role in the hemorrhagic effects of TNFalpha., (Copyright 1998 Academic Press.)

The clinical success of the application of tumor necrosis factor-alpha (TNFalpha) in isolated limb perfusions in patients with advanced sarcomas, melanomas and other tumors has renewed the interest in this agent as an anticancer drug. At the Rotterdam Cancer Center, we have developed an interactive preclinical-clinical TNFalpha program that explores new methods to use TNFalpha in various settings. Regional organ perfusion models were developed and the effectivity of targeting of TNFalpha to the tumor by means of systemic administration of liposomes are tested. Furthermore various drugs and mechanisms that may enhance the activity of TNFalpha are under investigation. A summary of this comprehensive program is presented here.

Objective: To determine the short and long term results of trigger fingers treated with a local injection of corticosteroid., Design: Prospective analysis., Setting: 'Zuiderziekenhuis', Department of General Surgery, Rotterdam, the Netherlands., Method: In 55 patients with 62 trigger fingers the affected flexor sheath was injected with a long-acting corticosteroid. All patients were followed up for at least one year., Results: With one or two steroid injections 60 of the 62 trigger fingers were treated successfully. During the follow-up period the cumulative recurrence rate was 33% after one year., Conclusion: The treatment of trigger fingers with a local injection of steroids is a simple and safe procedure but the risk of recurrence in the first year is considerable.

Explosions of the colon as a result of the use of diathermy in the presence of gas mixtures of oxygen, hydrogen and/or methane have been previously described in the literature. This danger is present during colonoscopic polypectomy as well as during colonic surgery. The following case is presented to alert to the potential hazards of bowel gas during electrosurgery.

Objective: Analysis of the diagnostic approach, therapy and management of focal nodular hyperplasia (FNH) of the liver., Setting: University Hospital Rotterdam-Dijkzigt, Rotterdam., Design: Retrospective follow-up analysis., Method: Medical records of patients with histologically proven FNH were analysed with respect to complaints, diagnostic approach and therapeutic management. Follow-up took place at the outpatient clinic where history-taking, physical examination, ultrasonography and hepatitis B and C serology tests were performed., Results: Thirty-one patients with histologically proven focal nodular hyperplasia were treated: 19 were treated conservatively, 12 underwent hepatic resection; one of these patients died postoperatively. Follow-up investigation was carried out in 16 and 9 patients, respectively. Laboratory results did not contribute to the diagnosis. Computed tomography was the most reliable imaging method; 71% of the lesions were correctly diagnosed. After a median follow-up of 52 months none of the patients treated conservatively showed tumour growth on ultrasonography., Conclusions: The most efficient approach to confirm the diagnosis of focal nodular hyperplasia consists of an ultrasound-guided needle biopsy and histological examination of the specimen. Conservative management is the treatment of choice in focal nodular hyperplasia. Hepatic resection should only be performed in symptomatic patients, in case of tumour growth or of uncertain histological diagnosis, to exclude a malignant process.

In the present study, generally accepted risk factors for developing a primary incisional hernia are reviewed for their influence on the development of recurrent incisional hernia. The records of 417 patients undergoing an incisional hernia repair between 1980 and 1989 at the University Hospital Rotterdam were reviewed retrospectively, and in the event no hernia recurrence was documented, patients were asked to visit the outpatient department for physical examination. Patients having a primary incisional hernia (n = 302) were selected and patient related factors of gender, age, obesity, chronic cough, prostatism, constipation, diabetes mellitus and the use of corticosteroids were analyzed. In addition, operation related factors, including the technique of operation (mainly, one layer interrupted and one layer continuous closures), use of drains, use of antibiotics, wound contamination (fecal or purulent spill), duration of operation, technique of anesthesia, wound complications, mortality and period of hospitalization, were analyzed. Hernia related factors--the hernia-free interval, original operation, type of incision and the size of the hernias--were also analyzed. Statistical analysis of the data was performed using the chi-square test to compare percentages between groups. Cumulative percentages of patients having a recurrence along time were calculated using life-table methods. Of the group of primary incisional hernias, four patients lacked follow-up evaluation and were excluded, leaving 298 patients for study. With a mean follow-up period of 34.9 months, the recurrence rate was 36 percent; 45 percent had recurrence in the first year, 64 percent in the second year and 78 percent of all recurrences occurred within three years. Therefore, a follow-up evaluation of at least three years is recommended. The cumulative (life-table) recurrence rate after five years was 41 percent. After second, third and fourth incisional hernial repair, recurrence rates were higher (56, 48 and 47 percent, respectively). Except for the size of the hernia, none of the studied parameters led to a significantly higher recurrence rate. Obesity, diabetes mellitus, lower midline incision and wound infection did have higher recurrence rates, but these were not significant. Incisional hernias, smaller than 4 centimeters, had a significantly (p = 0.01) lower recurrence rate (25 percent) than larger hernias (41 percent). Considering these facts, a better technique is badly needed. In large defects, the use of inlay of prosthetic material consistently has the lowest recurrence rates. The question remains whether or not prosthetic material is also needed for repair of smaller hernias.

Between 1980 and 1987 a total of 163 patients were operated for unilateral recurrent inguinal hernia in the University Hospital Dijkzigt. Various factors were analysed statistically with the log rank test for their prognostic value to predict repeat recurrence. Lower repeat recurrence rates were found with increase of age (p = 0.05) and time passed since the previous hernia operation (p = 0.001). Using the actuarial method of analysis the total cumulative repeat recurrence rate after five years was 23%.