***TASK*** the task is to summarize an input biomedical literature in six sentences 
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    Input: Summary We report here the results of 27 patients who underwent hyperthermic isolated limb perfusion with low-dose TNFα ( 1 mg ) and doxorubicin ( 8.5 mg/l of limb volume ) for locally advanced soft tissue sarcomas . A tumor response was observed in 85 % of cases . After a median follow-up of 30 months , limb salvage and local disease control were achieved in 82 and 85 % of patients , respectively . Locoregional toxicity was low or mild in 14 patients , while 2 patients had severe limb toxicity . Systemic side effects were negligible . The perfusate/plasma area under the curve ( AUC ) ratio for TNFα was 56 . HILP with low-dose TNFα and DXR proved to be an active neoadjuvant drug regimen against limb-threatening STS BACKGROUND Prospect i ve application of the French Sarcoma Group ( FSG ) method of surgery reporting in soft tissue sarcoma ( STS ) in a single centre . METHODS Patients with primary STS of the extremities or trunk wall consecutively operated at the same institution from January 1996 to December 2002 were evaluated for local recurrence ( LR ) . There were 205 patients , with AJCC/UICC stages III and IV in 51 % of cases . Resection types according to FSG were R0 in 147 , R1 in 53 and R2 in five cases . Radiotherapy was delivered in 163 patients and chemotherapy in 103 . Multivariate analysis was performed . Overall five-year survival was 75 % . Median follow-up for surviving patients was 53 months . RESULTS Actuarial five-year LR incidence was 13 % in 200 patients with gross resection ( R0+R1 ) , it was 7 % in R0 and 30 % in R1 patients ( p<0.0001 ) . At univariate analysis , significant prognosticators for LR were age , histotype , tumour invasion , grade and resection type R. At multivariate analysis , resection R1 ( relative risk ( RR ) 4.3 , p=0.001 ) and grade 3 ( RR 3.9 , p=0.013 ) independently predicted LR . Combining these two variables produced three prognostic groups for LR : group 0 ( no factor , n=70 ) , group 1 ( one factor , n=94 ) and group 2 ( two factors , n=36 ) with five-year LR of 4 % , 12 % and 39 % , respectively ( p=6.4x10(-7 ) ) . CONCLUSION This first prospect i ve evaluation of surgery reporting in STS evidence s a fourfold , highly discriminating difference in LR between resections R0 and R1 Background In a prior r and omized phase II trial comparing hyperthermic isolated limb perfusion ( HILP ) with four different doses of tumor necrosis factor alpha ( TNF-α ) , no dose effect was detected for response , but systemic toxicity was far lower with low-dose TNF-α . The objective of the present study was to confirm these data on a larger sample size of locally advanced or recurrent extremity soft tissue sarcomas with low-dose TNF-α . Methods We assessed a prospect i ve data base comprising 100 HILP ( 38–40 ° C ) with melphalan ( 10 mg/L ) and TNF-α ( 1 mg ) . The remnant tumor was resected 2 months later . Results Among 52 recurrences , 18 were in a previously irradiated field . Stages according to the American Joint Committee on Cancer classification were II ( 19 patients ) , III ( 78 patients ) , and IV ( 3 patients ) . The site/size were : 30 patients /57 mm and 70 patients /86 mm for the upper and lower limbs , respectively . Tumor grade s ( FNCLCC ) were 1 ( 23 patients ) , 2 ( 34 patients ) , and 3 ( 43 patients ) . Fifty-one patients had received systemic chemotherapy before HILP . Responses on magnetic resonance imaging were 30 % complete , 49 % partial , 9 % no change , and 12 % progression . No mortality or systemic toxicity occurred . Local toxicity ( Wieberdink ) attained grade 2 ( 16 patients ) , 3 ( 5 patients ) , and 4 ( 1 patient ) . Limbs were able to be saved in 87 % patients . Three-year overall survival and the local recurrence rate were 89 % and 18 % , respectively . Age , sex , tumor size , recurrence , uni- or multifocality , grade , preoperative chemotherapy , and a previously irradiated field were not predictive of response or local toxicity . Conclusions We confirm that 1 mg of TNF-α is as effective as the st and ard dose and results in no systemic toxicity BACKGROUND The optimal dose of TNF-alpha delivered by isolated limb perfusion ( ILP ) in patients with locally advanced soft tissue sarcoma is still unknown . PATIENTS AND METHODS R and omised phase II trial comparing hyperthermic ILP ( 38 - 40 degrees ) with melphalan and one of the four assigned doses of TNF-alpha : 0.5 mg , 1 mg , 2 mg , and 3/4 mg upper/lower limb . The main end point was objective tumour response on MRI . Secondary end points were histological response , rate of amputation and toxicity . Resection of the remnant tumour was performed 2 - 3 months after ILP . The sample size was calculated assuming a linear increase of 10 % in the objective response rates between each dose level group . RESULTS One hundred patients ( 25 per arm ) were included . Thirteen per cent of patients had a systemic leakage with a cardiac toxicity in six patients correlated with high doses of TNF-alpha . Objective tumour responses were : 68 % , 56 % , 72 % and 64 % in the 0.5 mg , 1 mg , 2 mg and 3 or 4 mg arms , respectively ( NS ) . Sixteen per cent of patients were not operated , 71 % had a conservative surgery and 13 % were amputated with no difference between the groups . With a median follow-up of 24 months , the 2 year overall and disease-free survival rates ( 95 % CI ) were 82 % ( 73 % to 89 % ) and 49 % ( 39 % to 59 % ) , respectively . CONCLUSION At the range of TNF-alpha doses tested , there was no dose effect detected for the objective tumour response , but systemic toxicity was significantly correlated with higher TNF-alpha doses . Efficacy and safety of low-dose TNF-alpha could greatly facilitate ILP procedures in the near future Background . Locoregional control of soft tissue sarcomas of the limbs is achieved generally using a multidisciplinary approach consisting of conservative surgery combined with radiation therapy , intraarterial chemotherapy , or hyperthermic antiblastic perfusion ( HAP ) . Before surgery , HAP seems to be the more suitable tool in decreasing tumor mass and allowing limb‐sparing surgery . The authors ' aim was to ascertain the activity of HAP with doxorubicin against intermediate or high grade limb tumors Eighty patients with locally advanced , high grade soft tissue sarcoma of the extremities were studied prospect ively in order to determine the efficacy of hyperthermic antiblastic perfusion ( H.A.P. ) as the first step of a combined multimodality therapy . All of the patients have been evaluated in terms of functional results , loco-regional control and survival according to the different treatment schedules adopted . The first clinical trial employed H.A.P. , followed by surgery alone . Because the results obtained were unsatisfactory , the protocol was modified to include a continuous intra-arterial ( i.a . ) infusion of doxorubicin ( dx ) or radiotherapy before surgery . The best results have been obtained with the radiotherapy-including protocol showing a conservative surgery rate of 100 % and a 94 % rate of loco-regional control . The disease-free , distant disease-free and overall survival rates were 68 % , 75 % and 70 % , respectively . The importance of the treatment protocol has been confirmed in a multivariate analysis which demonstrated that the treatment protocol adopted is one of the prognostic factors with an independent value ( p = 0.06 ) Controversy has surrounded the role of isolated limb perfusion ( ILP ) for unresectable extremity sarcomas . However , there remains a group of sarcoma patients for whom amputation is the only potential treatment . Because systemic therapies are limited , the authors evaluated ILP in an effort to provide a limb‐salvage option OBJECTIVE The objective of the study was to achieve limb salvage in patients with locally advanced soft tissue sarcomas that can only be treated by amputation or functionally mutilating surgery by performing an isolated limb perfusion ( ILP ) with tumor necrosis factor ( TNF ) + melphalan ( M ) as induction biochemotherapy to obtain local control and make limb-sparing surgery possible . SUMMARY BACKGROUND DATA To increase the number of limb-sparing resections in the treatment of locally advanced extremity soft tissue sarcoma , preoperative radiation therapy or chemotherapy or a combination of the two often are applied . The ILP with cytostatic agents alone is another option but rarely is used because of rather poor results . The efficacy of the application of TNF in ILP markedly has changed this situation . METHODS In 8 cancer centers , 186 patients were treated over a period of almost 4.5 years . There were 107 ( 57 % ) primary and 79 ( 43 % ) recurrent sarcomas , mostly high grade ( 110 grade III ; 51 grade II ; and 25 very large , recurrent , or multiple grade I sarcomas ) . The composition of this series of patients is unusual : 42 patients ( 23 % ) had multifocal primary or multiple recurrent tumors ; median tumor size was very large ( 16 cm ) ; 25 patients ( 13 % ) had known systemic metastases at the time of the ILP . Patients underwent a 90-minute ILP at 39 to 40 C with TNF + melphalan . The first 55 patients also received interferon-tau . A delayed marginal resection of the tumor remnant was done 2 to 4 months after ILP . RESULTS A major tumor response was seen in 82 % of the patients rendering these large sarcomas resectable in most cases . Clinical response rates were : 33 complete response ( CR ) ( 18 % ) , 106 partial response ( PR ) ( 57 % ) , 42 no change ( NC ) ( 22 % ) , and 5 progressive disease ( PD ) ( 3 % ) . Final outcome was defined by clinical and pathologic response : 54 CR ( 29 % ) , 99 PR ( 53 % ) , 29 NC ( 16 % ) , and 4 PD ( 2 % ) . At a median follow-up of almost 2 years ( 22 months ; range , 6 - 58 months ) , limb salvage was achieved in 82 % . Regional toxicity was limited and systemic toxicity minimal to moderate , easily managed , with no toxic deaths . CONCLUSIONS In the setting of isolated limb perfusion , TNF is an active anticancer drug in patients . The ILP with TNF + melphalan can be performed safely in many centers and is an effective induction treatment with a high response rate that can achieve limb salvage in patients with locally advanced extremity soft tissue sarcoma The Scottish Intercollegiate Guidelines Network ( SIGN ) develops evidence based clinical guidelines for the NHS in Scotl and . The key elements of the methodology are ( a ) that guidelines are developed by multidisciplinary groups ; ( b ) they are based on a systematic review of the scientific evidence ; and ( c ) recommendations are explicitly linked to the supporting evidence and grade d according to the strength of that evidence . Until recently , the system for grading guideline recommendations was based on the work of the US Agency for Healthcare Research and Quality ( formerly the Agency for Health Care Policy and Research ) . 1 2 However , experience over more than five years of guideline development led to a growing awareness of this system 's weaknesses . Firstly , the grading system was design ed largely for application to questions of effectiveness , where r and omised controlled trials are accepted as the most robust study design with the least risk of bias in the results . However , in many areas of medical practice r and omised trials may not be practical or ethical to undertake ; and for many questions other types of study design may provide the best evidence . Secondly , guideline development groups often fail to take adequate account of the method ological quality of individual studies and the overall picture presented by a body of evidence rather than individual studies or they fail to apply sufficient judgment to the overall strength of the evidence base and its applicability to the target population of the guideline . Thirdly , guideline users are often not clear about the implication s of the grading system . They misinterpret the grade of recommendation as relating to its importance , rather than to the strength of the supporting evidence , and may therefore fail to give due weight to low grade recommendations . # # # # Summary points A revised system of determining levels of evidence and grade s PURPOSE To determine the toxicity and the therapeutic efficacy of the combination of the recombinant tumor necrosis factor alpha ( rTNF alpha ) , recombinant interferon gamma ( rIFN-gamma ) , and melphalan , we design ed a protocol using isolation limb perfusion ( ILP ) with hyperthermia for in-transit metastases of melanoma and recurrent sarcoma . The triple combination was chosen because of the reported synergistic antitumor effect of rTNF alpha with IFN-gamma and of rTNF alpha with alkylating agents . PATIENTS 
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CONCLUSION ILP induces a high tumour response rate , leads to a high limb salvage rate but is associated with a high recurrence rate .
It provides a limb salvage alternative to amputation when local control is necessary