Khaled Aslan
email: aslanalm@loria.fr

Hala Skaf-Molli

Pascal Molli
email: molli@loria.fr

From Causal History to Social Network in Distributed Social Semantic Software

Keywords: Distributed Collaboration System, Semantic Wiki, Causal History, Social Network

Web 2.0 raises the importance of collaboration powered by social software. Social software clearly illustrated how it is possible to convert a community of strangers into a community of collaborators producing all together valuable content. However, collaboration is currently supported by collaboration providers such as Google, Yahoo, etc. following "Collaboration as a Service (CaaS)" approach. This approach arises privacy and censorship issues. Users have to trust CaaS providers for both security of hosted data and usage of collected data.

Alternative approaches including private peer-to-peer networks, friend-to-friend networks, distributed version control systems, distributed peer-to-peer groupware, support collaboration without requiring a collaboration provider. Collaboration is powered with the resources provided by the users.

If it is easy for a collaboration provider to extract the complete social network graph from the observed interactions. Obtaining social network informations in the distributed approach is more challenging. In fact, the distributed approach is designed to protect privacy of users and thus makes extracting the whole social network difficult.

In this paper, we show how it is possible to compute a local view of the social network on each site in a distributed collaborative system approach.

INTRODUCTION

Software as a service is the current trend in software deployment where an application is hosted as a service and provided to users across the Internet. This model inspired the collaboration as a service, where a service provider offers collaborative and social network services.

The social relations provided by the social services are important to push further the collaboration between people. Since it is important to evaluate the location of actors in the network in order to understand networks and their participants; measuring the network location is essential.

These measures give us insight into the various roles and

Copyright is held by the authors.

Web Science Conf. 2010, April 26-27, 2010, Raleigh, NC, USA.

. groupings in a network: where are the clusters and who is in them, who is in the core of the network, and who is on the periphery.

The social service provider has access to all the data which arises privacy and censorship issues [START_REF] Gross | Information revelation and privacy in online social networks[END_REF], since it can exploit the whole social network relations and interactions among the users.

In order to overcome these issues, new decentralized approaches were proposed. They provide collaborative services without a dedicated service provider. Users can create their own collaborative network and share the collaborative services offered by the system using their own resources. Skype [START_REF] Heinla | Skype[END_REF] and Distributed Version Control Systems (DVCS) [START_REF] Allen | ClearCase MultiSite: Supporting Geographically-Distributed Software Development[END_REF] (e.g. Git [START_REF] Hamano | Git -fast version control system[END_REF] and Mercurial [START_REF] Mackall | Mercurial-a fast, lightweight source control management system[END_REF]) demonstrated that it is possible to communicate and share data without the need for a collaboration provider. Although distributed systems provide the required collaborative services, they do not provide the social services offered by centralized systems. In distributed systems there is no central point with a global vision of the social network which is able to build and reflect the social relations among people.

Other approaches use private peer-to-peer networks [START_REF] Rogers | How to disappear completely: A survey of private peer-to-peer networks[END_REF] where the resources and the infrastructure are provided by the users participating in the network. Groove [START_REF]Microsoft office groove[END_REF] is a groupware for collaborative editing which consists of isolated local networks. This system provides group-based network service which allows direct connections between the users of the group. Multi-synchronous semantic wiki [START_REF] Rahhal | Multi-synchronous collaborative semantic wikis[END_REF] is another approach which allows direct connections between sites who know one another i.e. friend-to-friend network [START_REF] Biddle | The darknet and the future of content distribution[END_REF]. However, the collaboration model is very different from CaaS approach. With CaaS software, users mainly collaborate through read-write operations in one shared space provided by the collaboration provider. While in distributed social software, collaboration occurs by replicating shared data and synchronizing multiple workspaces continuously.

The previous model hides the social relations among sites participating in the network. Synchronizing workspace requires exchanging causal histories of operations. By analyzing the causal history on each site, we are able to reveal the social relations and reconstruct on each site a social network graph. So we can see our friends of friends.

This graph represents a local view of the social network and not the whole social network. Users can see their locations in their own local graphs. This approach can enrich the collaboration among the sites with new social services, while at the same time preserving the sites' privacy, since every site has a local vision of the network, and they do not rely on a service provider to maintain the social network.

In this paper we extend the collaboration services provided by multi-synchronous semantic wiki with new social network services. We infer the social relations using semantic reasoning by exploiting the semantic causal history. It allows users to discover their friend-of-friend relations. However it does not allow them to connect to their friends of friends. In Section2 we present the multi-synchronous semantic wiki system. Then in Section3 we explain our approach in details. In Section4 we validate the approach and discuss the obtained results. Finally we conclude the paper in Section5.

MULTI-SYNCHRONOUS SEMANTIC WIKI

Semantic wikis have emerged as a new generation of collaborative editing tools, we have many examples such as Semantic MediaWiki [START_REF] Krötzsch | Semantic mediawiki[END_REF], IkeWiki [START_REF] Schaffert | IkeWiki: A Semantic Wiki for Collaborative Knowledge Management[END_REF], SWooki [START_REF] Skaf-Molli | Peer-to-peer semantic wikis[END_REF] c'estand SweetWiki [START_REF] Buffa | Sweetwiki: A semantic wiki[END_REF]. They support mass collaboration for editing structured and unstructured data. In standard collaborative applications, when a modification is made by one user, it is immediately visible by others. However, in multisynchronous applications, modifications made by one user is not visible by others. It becomes visible only when a user validates his modifications (commits his changes). A visible change does not imply immediate integration by others. Concurrent modifications will be integrated only when users will decide it.

In a multi-synchronous semantic wiki approach [START_REF] Rahhal | Multi-synchronous collaborative semantic wikis[END_REF], users are allowed to build their own cooperation network by explicitly declaring with whom they would like to cooperate. Every user can run a multi-synchronous semantic wiki server on her machine, and she can create and edit semantic wiki pages locally, then she can share these pages with others. Moreover she can decide with whom to share these pages, and from whom to accept modifications. By this way users create a friend-to-friend network.

In fact sharing a modification in multi-synchronous semantic wiki is accomplished using a capability-based access control approach [START_REF] Levy | Capability-and Object-Based System Concepts[END_REF]. A user who modified a page can push a capability to users with whom she would like to share these modifications. This will permit the selected users to integrate the modifications into their local copies; if they decide to pull these modifications.

The modifications are stored in patches. We have a previous relation defined between two patches to guarantee the causality. So the set of patches constitutes the causal history which is necessary to satisfy the CCI criteria [START_REF] Weiss | Logoot-undo: Distributed collaborative editing system on p2p networks[END_REF]. CCI consistency means Causality, Convergence, and Intention preservation. Thus, causality criterion ensures that all operations ordered by a precedence relation, in the sense of the Lamports happened-before relation [START_REF] Lamport | Times, Clocks, and the Ordering of Events in a Distributed System[END_REF] will be executed in same order on every site. The system converges if all replicas are identical when the system is idle (eventual consistency). Intention preservation means that an operation effect observed on a copy, must be observed in all copies whatever any sequence of concurrent operations applied before. Actually there is also a changeset concept defined in multisynchronous semantic wiki; which contains the patches, but we omitted the discussion of this concept for simplicity.

The collaboration model in a multi-synchronous semantic wiki hides the social relations among the sites. We will reveal these relations by transforming the previous relation between the patches into social relations among the sites participating in this network. In figure 1 shows an illustration of our approach. We show how we are going to discover the friend-of-friend relations. In this example we see the interaction between the sites participating in the network. It should be noted that in reality this interaction is not known by any site. This interaction generated a causal history on site2 for instance. This site has pulled from two sites only (site1 and site4) so it has a direct friend relation with these two sites. But it does not know the existence of the other sites in the network. By investigating its own causal history site2 will find patches generated on site3 and these patches has been pulled by site4. So now site2 knows the existence of site3 and the existence of a relation between site4 and site3. The deduced knowledge is represented by the dotted arrows in figure 1, this knowledge does not apply that site2 can pull from site3 since it does not have the capability required to pull from it.

The next section presents how we can reconstruct this social network among the sites, visualize those relations and furthermore calculate the network centrality measures.

FROM CAUSAL HISTORY TO SOCIAL RELATIONS

Although there is no direct friendship relation defined in a multi-synchronous semantic wiki, users can manage their relations with others implicitly by controlling from whom to accept modifications and to whom send or publish their modifications. This interaction is recorded in the causal history which is stored at each user's site. Each site participating in a multi-synchronous semantic wiki network keeps According to DSMW ontology, a patch is a collection of operations generated at one site, and it is linked to other patches by the previous transitive relation. Each patch contains the following information:

-PatchID: which is a combination of the siteID and the site logical clock.

-onPage: the page where the patch was applied.

-hasOperation: pointer to the operations generated during the save of the page.

-previous: pointer to the precedent patch.

In order to be able to build the social relation among the sites, we extend DSMW ontology as follows:

1-We define hasSite object property from Patch to Wik-iSite as follows:

hasSite ≡ ∃(hasP ull -1 ).∃(inP ullF eed).∃(hasP atch -1 ).P atch 2-We add an object property which check if one site knows another site. We check if we have a previous relation between patch P 1 generated on site S1 and patch P 2 generated on site S2, if that is the case then this means that S1 pulled P 2 from S2 which eventually means that S1 knows S2. This is calculated using the following inference rule: knows(S1, S2) ∃P 1.(hasSite(P 1, S1) ∃P 2.(hasSite(P 2, S2) previous(P 2, P 1)

Where P 1, P 2 are both patches, and S1, S2 are both sites. By taking the previous modifications into account we can rebuild a "FOAF:knows" relation [START_REF] Miller | The friend of a friend (foaf) project[END_REF] between the sites based on the push/pull feeds with a simple inference from the history using a semantic reasoner. Figure 2(b) shows these modifications.

The example in figure 3 shows the interaction between five sites. site1 creates a wiki page, then site2 and site3 pull form site1; eventually site2 modifies the page; at the same time site3 makes some modifications too, then site4 pulls from site3; by its turn site4 modifies the page, then site5 pulls from site4 and modifies the page too. Finally site2 pulls from site5.

By investigating site2's history shown in figure 4(a). We Where the solid-line arrows represent the direct relations between sites (by exchanging capabilities) while the dotted-line arrows represent the deduced relations which do not imply the ability to pull from these sites, since site2 has not the capabilities of these sites. By applying this approach on all the sites, each site will have a local vision of his friend-of-friend network. We should take into consideration that the causal history keeps on growing and it will not delete previous entries. This means that the local vision at one site of the network keeps on growing as much as the site consumes from other sites. In the following section we present our validation and discuss the obtained results.

RESULTS

In order to compute the social network metrics with high confidence, we need a large dataset so we populated the DSMW ontology with the causal history of Mercurial repository for the Adium project [START_REF] Schoenberg | Adium : Instant messaging client[END_REF], which follows a multisynchronous interaction mode. The causal history that we analyzed is composed of 3128 patches (changesets in Mercurial terms) generated by 31 developers contributing to this project, over a period of 18 months. We were able to reveal 588 knows relations between the developers of this project. We calculated the key parameters of the social network graph, in order to compare it with a real social network graph parameters. In the following we will explain the obtained results.

A graph is considered small-world, if its average clustering coefficient is significantly higher than a random graph constructed on the same vertex set, and if the graph diameter is much smaller than the order of the graph [START_REF] Amaral | Classes of behavior of small-world networks[END_REF]. The calculated parameters show that the extracted social network graph follow the small-world hypothesis.

Social network parameter Calculated value

Network diameter 3 Clustering coefficient 0.634 Graph density 0.632

We also computed the centrality measures identified by [START_REF] Freeman | Centrality in social networks conceptual clarification[END_REF] and illustrated the results using Gephi [START_REF] Bastian | Gephi: An Open Source Software for Exploring and Manipulating Networks[END_REF] the figures below show the obtained results. First we calculate the degree centrality which considers nodes with higher degrees as more central, highlighting the local popularity of an actor in its neighborhood. The way that we used to generate the social network graph created a directed graph so we have to calculate the inDegree centrality as shown in figure 5(a) (the number of incoming connections) and outDegree centrality as shown in figure 5(b) (the number of outgoing connections).

Then we calculated the betweenness centrality which focuses on the capacity of a node to be an intermediary between any two other nodes. The results are illustrated in figure 6(a). This figure shows clearly that we have one special actor in the network (most probably the project coordinator).

Finally we calculated the closeness centrality of the graph nodes which represents the node capacity to be reached by any other node in the network. From the results shown above we clearly see that we have extracted the local social network and based on the data we used, we see that the social network characteristics follow the small-world model, and we can see that we have some important actors in our network.

CONCLUSION

In this paper, we extended the collaborative services offered by multi-synchronous semantic wiki with new social services by exploiting the causal history using semantic queries. Therefore, each site participating in this collaborative network can have a local view of its social network without the need for a third-party service provider, and using its own resources.

We validated the approach using data from a software engineering application. And we found that the extracted network follows the small-world model. We will extend the validation furthermore, first over causal histories with more actors, then by applying the approach directly on DSMW sites as soon as we get enough data from such sites. Then we will integrate this social services directly inside DSMW. Finally we will develop the approach further by including the timestamps and the frequency of publishing/consuming among the different sites in order to quantize a proximity metric between sites.

Figure 1 :

 1 Figure 1: General approach illustration

2 (

 2 a) DSMW ontology snapshot (b) DSMW ontology extension snapshot

Figure 2 :

 2 Figure 2: DSMW ontology

Figure 3 :

 3 Figure 3: Collaboration scenario

Figure 4 :

 4 Figure 4: Social network extraction

Figure 6 (

 6 b) shows the calculated closeness centrality. (a) inDegree centrality (b) outDegree centrality

Figure 5 :

 5 Figure 5: Degree centrality

Figure 6 :

 6 Figure 6: Betweenness and closeness centrality


Dr Alison R Evans
email: alisone@gum.ucl.ac.uk

Graham J Hart

Richard Mole

Catherine H Mercer

Violetta Parutis

Christopher J Gerry

John Imrie

Fiona M Burns

Central and East European migrant men who have sex with men: an exploration of sexual risk in the UK

Keywords: HIV, STD, Sexual behaviour, Gay men, Migration & Health

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INTRODUCTION

On 1 st May 2004, Czech Republic, Estonia, Hungary, Latvia, Lithuania, Poland, Slovakia and Slovenia (the Accession 8 or A8) joined the European Union (EU), followed by Romania and Bulgaria (A2) on 1 st January 2007. The accession of these ten Central and Eastern European (CEE) countries resulted in a large influx of predominantly young economic migrants to the UK.

[1]

The levels of syphilis reported across the CEE region are varied. In 2007, new syphilis diagnoses (per 100,000) were 22.7 in Romania, compared to 6.2 in the UK and 2.2 in Poland. However, new diagnoses of HIV (per 100,000) were higher in the UK (12.0) than all CEE countries with the exception of Estonia (40.7) and Latvia (15.8), [START_REF]Health for all database[END_REF] where the HIV epidemic is largely driven by injecting drug use. [START_REF] Delpech | The impact in the UK of the Central and Eastern European HIV epidemics[END_REF] Within the population of men who have sex with men (MSM), the number of new HIV diagnoses in all ten CEE countries has remained lower than in Europe as a whole (with rates of HIV diagnoses per million men aged 15-64 ranging from 1.1 in Romania to 35.1 in Slovenia). The UK has the highest rate of newly diagnosed cases of HIV infection among MSM in Europe (130.1 per million men). [START_REF] Likatavičius | An increase in newly diagnosed HIV cases reported among men who have sex with men in Europe, 2000-6: implications for a European public health strategy[END_REF] Although homosexuality is no longer a criminal offence in CEE countries, stigmatization and discrimination are widely reported in the region. [5,6] This may impact upon the sexual knowledge and behaviours of CEE MSM, as well as their willingness to access sexual health services. Furthermore, migrants are characterized as risk-takers, with the risks that they take in moving from one country to another filtering through to other areas of their lives. [START_REF] Duckett | Migrants' Right to Health[END_REF] The extent to which sexual risk behaviours are practised by CEE migrant MSM in the UK therefore requires investigation.

As part of the SALLEE project (sexual attitudes and lifestyles of London's Eastern Europeans), this study set out to examine the risk for HIV and STIs, and use of sexual health services among migrant CEE MSM in the UK.

METHODS

Participants and procedure

The SALLEE project was based on a cross-sectional survey and semi-structured in-depth interviews with CEE men and women living in London. The methods are described in detail elsewhere. [START_REF] Evans | The sexual attitudes and lifestyles of London's Eastern Europeans (SALLEE Project): design and methods[END_REF] The analysis presented here is based on the cross-sectional survey and used a specific strategy for recruiting CEE MSM from across the UK, as described below.

Data source

We conducted an anonymous, online questionnaire in twelve languages (the ten official languages of the CEE countries plus English and Russian) which took about ten minutes to complete. No financial incentive to take part was offered. After respondents ticked a box to indicate consent, they were asked questions on background information, including sociodemographic characteristics and use of general practitioner (GP) services; sexual health, including sexual practices, numbers of partnerships, use of condoms, paying for sex, STIs and HIV, and use of sexual health services; and questions on injecting and recreational drug use.

Where possible, questions from previously validated questionnaires were used in order to maximize their reliability and validity.

Eligible respondents were literate men aged 18 years and over who self-identified as migrants from one of the ten CEE countries. The men in the present study were recruited via two popular dating websites for gay men in the UK. The questionnaire was posted online and a link to it was placed on banners which appeared when men were browsing the personal profiles of London men in Gaydar (www.gaydar.co.uk) for 6 weeks (March to April 2009). A link was also placed on the homepage of GayRomeo (www.gayromeo.com) for 4 weeks (April to May 2009). While the SALLEE project was primarily interested in CEE migrants in London, the online invitation in Gaydar and GayRomeo was extended to respondents throughout the UK.

Statistical analysis

Standard statistical tests including chi-square, Student's t-test and Mann-Whitney U test were used to examine associations between place of residence and background characteristics, risk behaviour and health service use. Linear-by-linear associations were examined to assess the effect of length of time in the UK on risk behavior and health service use, by grouping respondents' length of stay into yearly intervals up to five years (eg up to one year, 1 to 2 years), then over five years. Logistic regression modelling was used to obtain odds ratios (OR) and adjusted odds ratios (aOR) to examine the association between unprotected anal intercourse (UAI) with a casual partner and background characteristics, commercial sex, recreational drug use and HIV status (which are associated with UAI in other MSM populations). Analysis was performed using SPSS12.0 (SPSS Inc, Chicago, Illinois, USA).

The study was granted approval from the Camden & Islington Community Research Ethics Committee (07/H0722/110).

RESULTS

Background characteristics

Over the course of the recruitment via Gaydar and GayRomeo, a total of 691 online responses were submitted by men who were eligible for the study. Eligibility was restricted to men reporting one or more male sexual partners in the past five years, so that only men who were homosexually active were included in the analysis. More men were recruited from GayRomeo (65%, n=449) than Gaydar (35%). Men living outside London were more likely to be recruited from GayRomeo than men living in London (80.1% vs 58.6%, p<0.001) (table 1). 29 years old (s.d.=6.9 years). The majority were working, educated to degree level, came from one of the A8 countries rather than Bulgaria or Romania, completed the questionnaire in their native language and had been in the UK for more than one year. Most men had arrived in the UK since May 2004 (73.0%). Sex with women in the past year was reported by 6.5% of men. There were no significant differences between London men and those who were living outside London on any of these variables (table 1).

Men who had been in the UK for longer were more likely to live in London: 65.0% of men who had been in the UK for up to one year compared to 80.3% of men who had been in the UK for more than five years (p=0.008).

Risk behaviour

Compared to men living outside London, London men were significantly more likely to report that they had been paid for sex in the UK (15.4% vs 6.8%, p=0.005), ever been diagnosed with an STI (34.1% vs 22.5%, p=0.003) and taken recreational drugs in the past year (41.5% vs 25.2%, p<0.001) (table 2). They were more likely to have ever paid for sex with a man (15.0% vs 9.8%, p=0.068). They were also less likely to report assortative sexual mixing (whereby their last partner was from their home country) (18.6% vs 29.1%, p=0.003). Almost half the men reported that their most recent partner was from the UK (47.6%) and a further 15.4% of most recent partners were from another European country.

The majority of men living in London and elsewhere in the UK reported anal intercourse (AI) with a man in the past year (92.4% and 89.8% p=0.269). London men reported more AI partners in the past year than men living elsewhere (median=5 vs 3, p<0.001).

Health service use in the UK

Compared to men living elsewhere, London men were more likely to have attended a sexual health clinic in the UK (53.2% vs 36.6%, p<0.001), to have obtained condoms from health services in the UK in the past year (32.6% vs 21.1%, p=0.004) and to have tested for HIV (83.0% vs 68.3%, p<0.001) (table 2). A somewhat larger proportion of men living outside London were registered with a GP (79.3% vs 72.3%, p=0.053) but they were not more likely to have attended the GP for reasons related to sexual health in the past year (18.3% vs 17.2%, p=0.722).

Migration and integration

The longer men had been in the UK, the less likely they were to report assortative sexual mixing (33.6% to 14.9%, p<0.001) and the more likely they were to report recreational drug use in the past year (31.4% to 41.4%, p=0.005). (fig 1). Figure 1 also illustrates how men who had been in the UK for longer reported more partners and more new partners. Men who had been in the UK for over two years reported more than 10 male partners in the last five years more frequently than men who had been in the UK for less time (67.6% vs 48.6%, p<0.001). Men who had been in the UK for over two years also reported a median of 3 new AI partners in the past year compared to a median of 2 among men who had been in the UK for less time (p=0.002).

Most of the other risk behaviours listed in table 2 were not associated with time in the UK: there were no significant associations between length of time in the UK and being paid for sex, injecting drugs, anal intercourse in the past year, UAI with a casual partner, non-concordant UAI with a casual partner and non-concordant UAI with a main partner. However, the data suggested that ever being diagnosed with an STI increased the longer men had been in the UK, rising from 27.6% of men who had been in the UK for up to one year to 37.2% of men who had been in the UK for at least five years (p=0.035); and men who had been in the UK for longer were also somewhat more likely to report ever paying for sex (12.4% to 18.1%, p=0.026).

GP registration increased the longer men had been in the UK (44.3% to 87.9%, p<0.001). Men who had been in the UK for longer were also more likely to have attended a sexual health clinic in the UK (24.6% to 67.2%, p<0.001) and to report ever having an HIV test (68.1% to 86.7%, p=0.001). Men were less likely to return to their home country two or more times during their first year in the UK compared to men who had been in the UK for a year or more (39.3% vs 63.1% made at least two trips home in the previous year, p<0.001).

STI and HIV diagnosis

Almost one third of men (30.7%) reported that they had ever been diagnosed with an STI.

Gonorrhoea was most commonly reported (11.1% of all respondents), followed by Chlamydia (10.5%) and Syphilis (7.3%) (table 3). The majority of men reported that their STIs had been diagnosed in the UK (77.8% of those reporting Chlamydia, 68.0% of those reporting Syphilis and 56.6% of Gonorrhoea). Just under 5% of men reported being HIV positive (n=32) and London men were more likely to report that they were HIV positive (5.6% vs 3.1%, p<0.001). Most HIV positive men reported being diagnosed in the UK (78.1%). Men were asked the year of their HIV diagnosis. The majority had been diagnosed since 2004 (80.6%) and 12.9% were diagnosed in 2009 (the year of the study).

Unprotected anal intercourse

Unprotected anal intercourse (UAI) with a casual partner was reported by 28.3% of all men in the past year, 22.8% reported UAI with a casual partner of unknown or discordant HIV status and 17.1% reported UAI with a main partner of non-concordant HIV status (no significant differences by place of residence). UAI with a casual partner of discordant or unknown HIV status was more common in men known to be HIV positive (46.9%) than HIV negative or untested men (18.8% or 27.7% respectively, p<0.001). In a multivariate model (table 4), UAI with a casual partner was associated with being HIV positive (vs HIV negative: aOR=0.16, p<0.001; untested: aOR=0.23, p=0.001), taking recreational drugs in the past year (aOR=2.07, p<0.001) and being paid for sex in the UK (aOR=2.20, p=0.004).

DISCUSSION

CEE MSM in the UK are at significant risk for acquisition and transmission of STIs and HIV through UAI with non-concordant casual partners, sexual mixing and commercial sex. They were more likely to report STI diagnoses when they had been in the UK for longer and a high proportion of STIs and HIV were reported as diagnosed in the UK. These findings suggest that CEE MSM are at greater risk following migration to the UK.

The self-reported HIV prevalence among CEE MSM was relatively low, with under six percent of CEE London men reporting that they were HIV positive compared to eleven percent of men in a similarly recruited web sample of London gay men [START_REF] Elford | The Internet and HIV study: design and methods[END_REF] and twelve percent in a community survey of London gay men conducted at the same time (personal communication D Mercey 2010). However, a substantially larger proportion of new HIV diagnoses among CEE men in the UK result from sex between men compared to diagnoses among men across the CEE region. [START_REF] Delpech | The impact in the UK of the Central and Eastern European HIV epidemics[END_REF] We found that assortative sexual mixing decreased the longer men stayed in the UK and partner numbers increased after a period of two years in the UK. The low prevalence of new HIV diagnoses among CEE MSM in their countries of origin [START_REF] Likatavičius | An increase in newly diagnosed HIV cases reported among men who have sex with men in Europe, 2000-6: implications for a European public health strategy[END_REF] means that assortative sexual mixing between CEE MSM is likely to be protective against STI and HIV infections. Barriers to HIV testing in CEE countries [START_REF] Danziger | Compulsory testing for HIV in Hungary[END_REF]11] may mean that HIV is more likely to remain undiagnosed among MSM in CEE countries compared to the UK but the high prevalence of HIV among MSM in the UK is likely to increase exposure to infection when CEE men have partnerships with men who are not from their home country. By comparison, the majority of heterosexual CEE migrants report that their most recent partner was from their home country. [START_REF] Burns | Sexual and HIV risk behaviour in Central & Eastern European migrants in London[END_REF] It is possible that CEE MSM seek out partners from other countries in response to the homophobia in their home countries. Whatever the mechanisms, sexual mixing requires continued monitoring to clarify its role in the acquisition and transmission of HIV and STIs.

Our ). [START_REF] Hickson | Testing targets: findings from the United Kingdom gay men's sex survey 2007[END_REF] We found that the likelihood of practising non-concordant UAI with a casual partner did not change with time in the UK or place of residence. Limited data from CEE countries suggest that UAI is practiced among a substantial proportion of MSM [11,[START_REF] Csepe | HIV risk behaviour among gay and bisexual men in Budapest, Hungary[END_REF][START_REF] Kabakchieva | High levels of HIV/STD risk behaviour among Roma (Gypsy) men in Bulgaria: patterns and predictors of risk in a representative community sample[END_REF] and condom use may not alter following migration to the UK. Data are needed to explore the extent to which individuals practice UAI before and after migration.

UAI with a casual partner was more likely among men who were HIV positive, had taken recreational drugs in the past year and been paid for sex in the UK. Previous work shows that HIV positive London men were more likely to report non-concordant UAI with casual partners than men who were of negative or unknown HIV status; [START_REF] Bolding | Gay men who look for sex on the Internet: is there more HIV/STI risk with online partners?[END_REF] and recreational drug use is also associated with UAI. [START_REF] Koblin | High-risk behaviors among men who have sex with men in 6 US cities: baseline data from the EXPLORE study[END_REF] The association with sex work is of particular concern, given that 15% of CEE MSM in London reported that they had been paid for sex in the UK. It is possible that recruiting men through gay dating websites might have increased the number of sex workers in our sample. However, the proportion of East European men attending a clinic for male sex workers in London increased from less than 1% in the mid-nineteen nineties to 8% over the following six to seven years [START_REF] Sethi | HIV, sexually transmitted infections, and risk behaviours in male sex workers in London over a 10 year period[END_REF] and numbers likely to have increased further following EU accession. Further research is needed to understand when and how CEE MSM take up commercial sex work and the risks involved.

The primary limitation of the study is that it recruited MSM via gay websites and such samples are more likely to include men with higher levels of sexual risk behaviour than found in the general population of MSM. [START_REF] Evans | Men who have sex with men in Great Britain: comparison of a self-selected internet sample with a national probability sample[END_REF] This method of recruitment, however, has become increasingly common in behavioural surveillance among gay men and data collected in this way therefore benefit from comparability. CEE migrants come from ten different countries across an area of wide regional variation. The relatively small sample size of our study did not provide sufficient statistical power to analyse data at the country level. In addition, we cannot be sure that our sample represents the distribution of CEE nationalities among MSM in the UK. Not only are data on the nationality of CEE migrants to the UK incomplete but they may not reflect the distribution of MSM from CEE countries. Finally, although a reassuringly high number of men reported that they had been tested for HIV, the study is limited by its reliance on self-report and the absence of biological samples. This should be considered in future studies.

Our findings indicate that CEE MSM are at significant risk for acquisition and transmission of STIs and HIV in the UK. This may have important implications for cross-border transmission of infections, given the fluidity of the movement among CEE MSM between their home countries and the UK. CEE MSM regularly returned to their home countries which creates the opportunity for transmission of infections between countries. Access to sexual health services in the UK is therefore an important factor in managing sexual health among CEE MSM both in the UK and their countries of origin. These findings are furthermore relevant to sexual health services throughout the UK, given that men living in London and elsewhere in the UK were as likely to practise UAI with a non-concordant casual partner. Interventions aimed at MSM should be accessible to CEE MSM with information available in CEE languages if possible and alternative strategies for health promotion and HIV/STI prevention may be important among new arrivals.

In addition, culturally sensitive prevention programmes may benefit men who do not identify as gay or bisexual. The UK has a duty of care to ensure that MSM from CEE countries are aware of sexual health services in the UK and able to access them.

Word count: 3,048

Key messages

• HIV prevalence among MSM in Central and East European (CEE) countries is much lower than among MSM in the UK.

• Following migration to the UK, CEE MSM report more sexually transmitted infections and HIV diagnosed in the UK than diagnosed elsewhere.

• CEE MSM in the UK report high levels of risk behaviour including commercial sex and recreational drug use.

• CEE MSM return regularly to their home countries and these findings have important implications for cross-border transmission of infections.

Median

Percentage of men whose most recent male partner was from home country Percentage of men using recreational drugs in past year Percentage of men who had more than 10 male partners in past five years Median number of new AI partners in past year

Figure 1 :

 1 Figure 1: Change in assortative sexual mixing, use of recreational drugs and number of male partners over time in the UK

Table 1 : Background characteristics, by place of residence All men London men Non-London men p value 1 n = 691 n = 485 n = 206

 1

		n	%	n	%	n	%
	Age (mean; sd)	29.0 (6.9)	29.21 (7.16)	28.45 (6.36)	0.186
	Working	552	80.0	387	80.0	165	80.1	0.937
	Completed higher education	378	54.8	275	56.8	103	50.0	0.100
	Born in A8 country	586	88.0	408	87.7	178	88.6	0.766
	Completed questionnaire in native language	557	80.6	390	80.4	167	81.1	0.842
	More than one year in UK	556	81.9	397	83.2	159	78.7	0.163
	Had heterosexual sex (past year)	45	6.5	36	7.4	9	4.4	0.137
	Recruited via GayRomeo	449	65.0	284	58.6	165	80.1	<0.001

1 London men compared to non-London men

The majority of men (70.2%) lived in London and the rest (n=206) were distributed throughout the UK: 42.2% in the South of England, 18.0% in the Midlands, 18.0% in the North of England, 15.5% in Scotland, 3.9% in Northern Ireland and 2.4% in Wales. The mean age of all men was

Table 2 : Risk behaviour and health service use, by place of residence

 2

		All men	London men	Non-London men	p value 1
		n = 691		n = 485	n = 206
		n	%	n		%	n	%
	Commercial sex
	Ever been paid for sex	147	21.5	111	23.2	36	17.5	0.096
	Been paid for sex in UK	88	12.8	74	15.4	14	6.8	0.005
	Ever paid for sex with man	92	13.5	72	15.0	20	9.8	0.068
	Paid for sex with man in UK	43	6.3	36	7.5	7	3.4	0.112
	Use of recreational drugs
	Taken recreational drugs (past year)	250	36.7	199	41.5	51	25.2	<0.001
	Ever injected drugs	32	4.7	23	4.8	9	4.4	0.832
	Sexually transmitted infection
	Ever diagnosed with STI	210	30.7	164	34.1	46	22.5	0.003
	Sexual partnerships and practices
	More than 10 male partners (past 5 years)	428	61.9	323	66.6	105	51.0	<0.001

1 London men compared to non-London men; 2 AI = anal intercourse; 3 among men who had been tested for HIV

Table 3 : Sexually transmitted infections reported by CEE MSM and diagnosis in the UK

 3

		Ever diagnosed	Diagnosed in the UK
		n	%	n 1	%
	Chlamydia	72	10.5	56	77.8
	Gonorrhoea	76	11.1	43	56.6
	Genital herpes	30	4.4	12	40.0
	Genital warts	50	7.3	27	54.0
	Non-specific urethritis	47	6.9	34	72.3
	Syphilis	50	7.3	34	68.0

Table 4 : Factors associated with unprotected anal intercourse with a casual partner

 4

				Adjusted odds
		Odds ratio (95% CI)	p	ratio 1 (95% CI)	p
				n = 616
	Age	1.01 (0.98, 1.03)	0.598	1.04 (0.98, 1.04)	0.582
	Working	0.84 (0.56, 1.26)	0.405	0.71 (0.45, 1.15)	0.163
	Completed higher education	0.95 (0.68, 1.33)	0.773	1.02 (0.69, 1.51)	0.921
	From Bulgaria or Romania	1.27 (0.77, 2.09)	0.354	1.82 (1.02, 3.23)	0.041

1 adjusted for all other factors included in this table

  findings suggest that CEE MSM report comparable levels of risk to those in the general MSM population in London and the UK. Nearly one third of CEE MSM in London reported UAI with a casual partner in the past year compared to one quarter of gay men in a community sample in London (personal communication D Mercey 2010). CEE MSM throughout the UK reported similar amounts of UAI with a casual partner of unknown or discordant HIV status to non-concordant UAI reported in another UK sample of MSM (23% vs 26%

Acknowledgements:

We are grateful for the expert guidance provided by our expert and community advisory boards. We would also like to thank GayRomeo and Gaydar for fielding the questionnaire and everyone who took part in the study. This study was supported by the MRC Sexual Health and HIV Research Strategy Committee and the North Central London Research Consortium (NoCLoR) Grant Enhancement Fund. The views expressed are those of the authors and not necessarily those of the MRC, NoCLoR or the Health Departments. Contributors: FB, CM, CG, RM, JI, GH participated in the design of this study. AE, VP and FB were responsible for study coordination and data collection. AE conducted the statistical analysis and was the lead writer of this paper. All authors have contributed to the drafting of the manuscript and have seen and approved the final version.

Funding: This study was supported by the MRC Sexual Health and HIV Research Strategy Committee and the North Central London Research Consortium (NoCLoR) Grant Enhancement

Fund. The sponsors of the study had no role in study design, the collection, analysis or interpretation of the data, the writing of the report or the decision to submit the paper for publication.

Conflicts of Interest


E J M Siemerink
email: e.j.m.siemerink@int.umcg.nl

M Schaapveld
email: m.schaapveld@nki.nl

J T M Plukker
email: j.t.m.plukker@chir.umcg.nl

N H Mulder
email: n.h.mulder@int.umcg.nl

MD G A P Hospers
email: g.a.p.hospers@int.umcg.nl

Effect of hospital characteristics on outcome of patients with gastric cancer: A population based study in North-East Netherlands

Background: Surgical resection is an important factor in the curative treatment of gastric cancer. However a variety of aspects of surgical treatment that potentially influence outcome are still not well defined. This study aims to assess the influence of hospital type, referral pattern and proximal or distal location of the tumour on the ultimate survival.

Methods: From January 1994 to January 2007, a total of 5245 patients were diagnosed with gastric adenocarcinoma in the region of the Comprehensive Cancer Centre North-East Netherlands. Hospitals in this region were categorized into three types: teaching university (TU), teaching non-university (TNU), and non-teaching hospitals (NT). The influence of hospital type, referral for surgery and location of the tumour on the relative survival of

operated patients was studied.

Results: Of the 5245 patients, 2334 patients underwent surgery. For operated patients, the 5year relative survival was 42.5% for the TU versus 34.0% and 35.5% for respectively TNU and NT hospitals (p=0.064), with no difference (p=0.38) in relative survival (25.6-31.9%) in the proximal tumours. A significant difference was found between the hospitals in the 5-year relative survival in the distal tumours; 59.7% in the TU versus 36.4% in the TNU and 36% in the NT (p=0.03 univariate), however this was not confirmed in the multivariate analysis (p=0.184). High referral centres did not perform better as far as survival is concerned than low referral hospitals.

In conclusion the hospital type in our region did not significantly influence outcome of surgery for gastric cancer.

Introduction

Although decreasing in incidence, gastric cancer still is diagnosed in more than 2000 patients per year in the Netherlands. In the past decades half of them died of their disease within 5 years after diagnosis. Currently, gastric cancer ranks as the fourth cause of cancer death in the western world [START_REF] Ferlay | Estimates of the Cancer Incidence and Mortality in Europe in 2006[END_REF].

It is widely recognised that prognosis depends on factors related to tumour and patient. The stage of the tumour is of paramount importance, and the patient age and especially comorbidity are highly relevant factors in predicting outcome [START_REF] Catalano | Gastric Cancer[END_REF].

More recently however, other variables, related to surgeon and even hospital characteristics have been recognised to be potentially important for the ultimate fate of the patient. These hospital related factors might be important, as the overall survival in Japan, were patients undergo more extensive curatively intended resection methods, is higher [START_REF] Catalano | Gastric Cancer[END_REF].

Data demonstrating the importance of various structural characteristics including the hospital volume, surgeon volume and hospital type where the surgical intervention is performed as well as the experience and expertise of the surgical team itself, remain equivocal [START_REF] Chowdhury | A Systematic Review of the Impact of Volume of Surgery and Specialization on Patient Outcome[END_REF][START_REF] Fujita | Influence of Surgeon's Volume on Early Outcome After Total Gastrectomy[END_REF][START_REF] Thompson | Hospital Volume Does Not Influence Long-Term Survival of Patients Undergoing Surgery for Oesophageal or Gastric Cancer[END_REF][START_REF] Meguid | The effect of volume on esophageal cancer resectons: What constitutes acceptable resection volumes for centers of excellence?[END_REF].

In the population based study described here, we analysed some of these aspects in relation to the patient survival. Data were provided in a group of gastric cancer patients treated in all hospitals in the North-East region of the Netherlands regarding the hospital type and the location of the tumour, whether proximal or distal in the stomach. The outcome of this study is important in the discussion on centralization of surgical cancer care.

Patients and Methods

Patients

All patients diagnosed with primary invasive gastric cancer from January 1994, until January 2007 were selected for entry in the study by the regional cancer registry of the Comprehensive Cancer Centre North-East Netherlands.

Comprehensive Cancer Centre North-East Netherlands

This regional cancer registry is a population based registry which covers the north-eastern part of the Netherlands, a mainly rural area with a population of about 3.3 million. The area is served by 22 community hospitals, among which 8 teaching hospitals, and one university hospital, five radiotherapy departments and nine pathology laboratories. Reports of all new, cytological or histological proven cancer cases are submitted to the regional cancer registry regularly through these pathology laboratories. The national hospital discharge databank, to which hospitals in the region provide the discharge diagnosis of all admitted patients on a yearly basis, further completes case ascertainment.

Data collection.

After notification, trained registry clerks abstract all relevant data directly from patient records, including pathology and surgery reports, within the hospitals. Data collection occurs at a minimum of 6 months after cytological or histological diagnosis in order to document all aspects of the primary therapy. All patients are staged according to the TNM system [7;8].

In the Netherlands the municipal population registries contain information on the vital status of their inhabitants. Since October 1994 population data from all Dutch municipalities are collected in a national database. Vital status was established through linkage of cancer registry data with the national automated population registry.

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5

Variable definitions and Statistics

The referral rate was calculated as the proportion of all operated patients, within the population of patients diagnosed in a given hospital, which were operated in another hospital.

Survival time was calculated from the date of diagnosis and ended at the date of death or the date of most recent linkage with the national automated populated registry, whichever came first. The 5-year overall survival rates were estimated using the actuarial method and survival was compared with the log rank test. Besides overall survival, relative survival rates were estimated. The relative survival is an estimate for the disease-specific survival and is calculated by dividing the absolute overall survival in our cohort by the expected survival based on age, sex and period matched mortality rates from the general population. The main advantage of using the relative survival is that it does not rely on cause of death information and captures both direct and indirect mortality due to gastric cancer and its treatment.

Multivariate analysis of relative survival was performed according to the method described by Dickman et al [START_REF] Dickman | Interpreting trends in cancer patients survival[END_REF].

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Results

Patients

In the period January 1994 until January 2007, 5245 patients were diagnosed with gastric adenocarcinoma of which 3440 were male. The median age was 72.3 (range: 18.5-98.3) years.

Patient characteristics are described in Table 1. A large proportion of the patients was diagnosed at an advanced stage, 2714 patients were in stage IIIA or higher. A further 954 patients were insufficiently staged. One hundred ninety-four patients were diagnosed in the university hospital, 2869 in the non-university teaching hospitals and the remaining 2182 patients were diagnosed in community hospitals.

As table 1 shows, 2334 patients underwent surgery. Older age (p<0.001), advanced or unknown stage (p<0.001) and proximal tumour location (p<0.001) resulted in a lower probability of tumour resection. A tumour with intermediate or poor differentiation was also associated with less surgery, but this was highly correlated with stage. In all, 40.2% of the patients diagnosed in non-teaching hospitals were operated on, compared to 45.6% and 43.5% for non-university teaching and university hospitals, respectively (p=0.162). Only a minority of the operated patients received (neo)adjuvant chemotherapy, respectively 57 out of 2334 patients.

Hospitals characteristics

A total of twenty-three hospitals participated with fourteen non-teaching hospitals, eight teaching hospitals and one university hospital. For proximal gastric cancers a difference in stage distribution was observed (p=0.039) due to a higher frequency of patients with stage III and a lower frequency of stage IV cancers among patients operated in the university hospital.

For the non-proximal tumours there were no meaningful differences in stage and sub-site distribution between the three hospital types. There was some imbalance in the distribution

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7 over the age-groups (p<0.001), with slightly younger patients operated in the university hospital although overall the age distribution did not appear to differ that much when analysed categorical (Table 2).

Referral characteristics

Of all operated patients 6 % were referred for surgery. Referral differed markedly by tumour sub-site, however. Of the operated patients with a tumour located in the proximal part of the stomach 18.0% were referred for surgery, while only 2.6% of the operated patients with a non-proximal tumour (body or distal part of the stomach) were referred for surgery. The nonteaching hospitals referred 10.9% of the operated patients diagnosed in their hospitals, 35.2% of the patients with proximal and 4.6% of the patients with non-proximal tumours. Of the fourteen non-teaching hospitals, seven had a high propensity to refer (referral rates 50-83%) patients with proximal gastric cancers for surgery and three hospitals rarely (0.0%-10.0%) referred patients. The eight non-university teaching hospitals referred 2.8% of the patients diagnosed in their hospitals, 8.2% of the patients with proximal and 1.2% of the patients with non-proximal tumours (Table 3).

Survival in relation to patient, tumour and hospital characteristics

The 5-year relative survival rate in the period of 1994-2006 for men with gastric cancer was 34.0% versus 37.4% for women. Age over 70 had a detrimental effect on survival compared to age <60 years with an excess mortality risk of 1.17 (1.01-1.34; p=0.022). The 5-year relative survival markedly decreased with more advanced stage, respectively 85.0% in stage IA, 62.0% in stage IB, 32.5% in stage II, 13.5% in stage III, 6.3% in stage IV (p<0.001).

Assessing all operated gastric cancers combined; 5-year relative survival did not significantly differ by hospital type, referral pattern or volume of the centres. Although relative survival

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appeared to be somewhat better in the TU, as the 5-year relative survival was 42.5% for the TU versus 34.0% and 35.5% for respectively TNU and NT hospitals (p=0.064 univariate).

Survival was also analysed separately for patients with proximal and non-proximal tumour.

For proximal tumours outcome was strongly associated with stage, but neither hospital volume, nor teaching characteristics were significant factors. However in univariate analysis 5-year relative survival of the non-proximal tumours was significantly better in the TU compared to TNU and non-teaching hospitals (p=0.033 univariate) (Table 4). After adjusting for sex, age, period, stage, volume, referral and time since diagnosis this differences no longer reached statistical significance. Survival with respect to age, stage, volume (< 5, 5-9 and ≥ 10 patients/year) and referral rate (<5%, 5-15% and>15%) was not different between the hospital types (Table 4).

Survival before and after the year 2000, for all types of gastric cancer combined did differ.

For proximal cancer the results were similar between the two periods. However survival for non-proximal cancer was better in the later period. This improvement was not related to any of the hospital factors (volume teaching academic).

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Discussion

In this population based study patient characteristics such as gender and age distribution are comparable to other European countries [START_REF] He | Recent Trends of Cancer in Europe: a Combined Approach of Incidence, Survival and Mortality for 17 Cancer Sites Since the 1990s[END_REF]. Age, subsite and histology type are known factors in explaining survival variability [START_REF] Verdecchia | Explaining Gastric Cancer Survival Differences Among European Countries[END_REF]. In our study older age, advanced or unknown stage, poorly differentiated tumours and proximal location resulted in lower probability of resection. Moreover in gastric cancer both tumour (T) and nodal (N) status are important elements in determining treatment plans and independent prognostic factors of long-term survival [START_REF] Schwarz | Recurrence Patterns After Radical Gastrectomy for Gastric Cancer: Prognostic Factors and Implications for Postoperative Adjuvant Therapy[END_REF][START_REF] Roukos | Pathological Serosa and Node-Based Classification Accurately Predicts Gastric Cancer Recurrence Risk and Outcome, and Determines Potential and Limitation of a Japanese-Style Extensive Surgery for Western Patients: a Prospective With Quality Control 10-Year Follow-Up Study[END_REF][START_REF] Siewert | Prognostic Relevance of Systematic Lymph Node Dissection in Gastric Carcinoma. German Gastric Carcinoma Study Group[END_REF].

However factors that are neither patient nor tumour related have been reported to influence the outcome of curative intended surgery in cancer patients. Some of them are related to the experience and expertise of the surgical team and the case volume. Others stem from nononcological surgical experience, such as expertise in extensive transplantations. Several studies demonstrated hospital and surgeon volume to have an important impact on short and long term survival in patients with potentially curative resection in different cancer types.

Better outcome was also found in specialised centres [START_REF] Halm | Is Volume Related to Outcome in Health Care? A Systematic Review and Methodologic Critique of the Literature[END_REF][START_REF] Birkmeyer | Hospital Volume and Late Survival After Cancer Surgery[END_REF][START_REF] Birkmeyer | Surgeon Volume and Operative Mortality in the United States[END_REF][START_REF] Billingsley | Surgeon and hospital characteristics as predictors of major adverse outcomes following colon cancer surgery: understanding the volume-outcome relationship[END_REF]. Verhoef et al. described significantly better outcome in oesophageal cancer surgery in the university hospital compared with other, non-university teaching and non teaching, hospitals in our region [START_REF] Verhoef | Better Survival in Patients With Esophageal Cancer After Surgical Treatment in University Hospitals: a Plea for Performance by Surgical Oncologists[END_REF].

As shown in oesophageal cancer, some studies also support the impact of hospital and surgeon related factors on short and long-term results in gastric cancer [START_REF] Meyer | The Influence of Case Load and the Extent of Resection on the Quality of Treatment Outcome in Gastric Cancer[END_REF][START_REF] Hansson | Survival in Stomach Cancer Is Improving: Results of a Nationwide Population-Based Swedish Study[END_REF][START_REF] Bachmann | Cohort Study in South and West England of the Influence of Specialization on the Management and Outcome of Patients With Oesophageal and Gastric Cancers[END_REF].

The 5-year overall survival rate in our study reflects reported stage-specific 5-year survival rates of 10-64% [START_REF] Hayes | Total Gastrectomy With Extended Lymphadenectomy for "Curable" Stomach Cancer: Experience in a Non-Japanese Asian Center[END_REF]. Patients treated in high referral hospitals did not have a better long term survival than those treated in low referral hospitals. Survival also seemed independent of hospital type for the whole group of surgical patients. Although relative survival appeared to be somewhat better in the TU compared to TNU and NT hospitals (42.5% versus 34.0% and 35.5% of TNU and NT (p=0.064)). This could partly be explained by an imbalance in

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10 tumour and patient characteristics between the hospital types. On average less patients, with lower stages of proximal gastric cancer and slightly younger of age were operated in the TU hospital (Table 2). With regard to survival and tumour location, there were no hospital related differences in outcome in proximal gastric cancer. However overall outcome in that location was worse compared to that in the distal stomach, an observation also found in the work of others [START_REF] Harrison | Proximal Gastric Cancers Resected Via a Transabdominal-Only Approach. Results and Comparisons to Distal Adenocarcinoma of the Stomach[END_REF][START_REF] Piso | Proximal Versus Distal Gastric Carcinoma--What Are the Differences?[END_REF][START_REF] Pacelli | Proximal Compared With Distal Gastric Cancer: Multivariate Analysis of Prognostic Factors[END_REF][START_REF] Pinto-De-Sousa | Clinicopathologic Profiles and Prognosis of Gastric Carcinomas From the Cardia, Fundus/Body and Antrum[END_REF]. For distal gastric cancer the univariate analysis showed a significant difference in the 5 year relative survival regarding hospital type, in favour of the university hospital (57.7 % versus 36.4% TNU and 36% NT). This difference could not be confirmed in multivariate analysis and to some extend might be explained by patient selection; the TU hospital operated on average, younger patients. Therefore, hypothetically maybe the high volume more experienced non-university hospitals (TNU and TU) have balanced the more academic approach of the TU resulting in no significant difference in survival. With regard to long-term survival we also did not observe hospital volume to play an important role. Of note, all surgeons in our region are low volume surgeons and the subdivision of centres based on volume of <5, 5-9 , ≥ 10 patients operated/ year served as a suitable separator between its 23 centres. Within this small window no striking differences were found in relation to survival.

Controversy on the role of surgical volume still remains, as is also discussed by other authors [3;5;6;28]. This observation suggests that other factors than sheer number of procedures are important for outcome. As in our case, the university hospital is a low volume hospital for gastric cancer, it becomes evident that other factors than the caseload prevail. The better outcome for oesophageal cancer surgery that Verhoef et al. described in our region might therefore not be attributed to the university hospital on basis of the highest volume but other hospital related qualities [START_REF] Verhoef | Better Survival in Patients With Esophageal Cancer After Surgical Treatment in University Hospitals: a Plea for Performance by Surgical Oncologists[END_REF]. This might also be the case for the benefit described by Bachmann et al., based on the difficulty to distinguish this volume aspect from other hospital related qualities [START_REF] Bachmann | Cohort Study in South and West England of the Influence of Specialization on the Management and Outcome of Patients With Oesophageal and Gastric Cancers[END_REF]. Quality of initial surgical care, for example extended It is interesting that comparison of the two observation periods showed an improvement in survival during the later period limited to distal cancer. The most likely cause of such differences is stage migration due to better diagnostics. However this would not readily explain the lack of improvement in proximal cancers.

In conclusion the hospital type in our region did not significantly influence outcome of surgery for gastric cancer. For future consideration however, gastric cancer surgery will require the guaranteed availability of multidisciplinary oncological teams experienced in multimodality treatments.

Conflicts of interest statement

There are no conflicts of interest.

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  fully reflected by operative mortality rates might play a role next to patient care in the follow up period after surgery. Enzinger et al. suggested delay in time of recurrence because of their observation that survival based on volume differences appear during the first 3 years after surgery [28].

Table 1 . Characteristics of patients diagnosed with gastric adenocarcinoma between 1994-2006, all patients combined, operated and non-operated patients

 1

			Total	operated	Not-operated
			N	N	N	*p-value
	Gender	Men	3440	1555	1885	0.157
		Women	1805	779	1026
	Age at diagnosis	<50	364	189	175	<0.001
		50-59	672	332	340
		60-69	1207	627	580
		70-79	1751	835	916
		80+	1251	351	900
	Histology	Adenocarcinoma, nos	4,051	1773	2278	<0.001
		Mucinous	282	158	124
		Signet ring cell	767	403	364
		No microscopic confirmation	145	0	145
	Tumour location	Cardia&fundus	1509	517	992	<0.001
		Body&curvature, nos	886	464	422
		Antrum&pylorus	1430	888	542
		Overlapping & unspecified	1420	465	955
	Differentiation	Good	144	99	45	<0.001
		Intermediate	1031	633	398
		Poor	2238	1231	1007
		Unknown	1832	371	1461
	Stage	Stage 1A	317	264	53	<0.001
		Stage 1B	562	464	98
		Stage 2	698	603	95
		Stage 3	807	598	209
		Stage 4	1907	386	1521
		Unknown/not applicable	954	19	935
	Therapy	Surgery	2277	2277	0	<0.001
		Surgery&CT	37	37	0
		Neoadjuvant CT&surgery	20	20	0
		CT	259	0	259
		CT&RT	15	0	15
		Other/none	2637	0	2637
	Total		5245	2334	2911
	* p-

value based on Chi-square or Fisher's exact test where applicable

	M A N U S C R I P T
	A C C E P T E D

Table 2 Stage and age distribution for operated patients according to hospital type were surgery was performed 1994-2006, stratified by tumour subsite

 2

			Total	Teaching,	Teaching, non-	Non-teaching	p-value
				university	university
		Stomach: cardia&fundus	N	N	N	N
	Stage	Stage 1A	41	9	23	9	0.039*
		Stage 1B	89	13	46	30
		Stage 2	171	22	100	49
		Stage 3	152	35	92	25
		Stage 4	61	7	38	16
		Unknown	3	2	0	1
	Age	<60	163	34	99	30	0.101
		60-69	174	23	100	51
		70+	180	31	100	49
		Median	65.4	64.4	64.8	66.8	0.169
		(IQR#)	(57.9-72.5)	(55.8-72.1)	(57.5-72.5)	(61.5-73.0)
	Total		517	88	299	130	100.0
		Stomach: other
	Stage	Stage 1A	223	14	121	88	0.409*
		Stage 1B	375	22	192	161
		Stage 2	432	17	248	167
		Stage 3	446	14	254	178
		Stage 4	325	13	181	131
		Unknown	16	2	6	8
	Age	<60	358	23	198	137	0.391
		60-69	453	18	251	184
		70+	1,006	41	553	412
		Median	71.7	70.1	71.8	71.8	<.001
		(IQR#)	(63.0-78.0)	(58.1-77.6)	(62.7-77.8)	(63.8-78.3)
	Tumour	Body&curvature, nos	464	20	252	192	0.359
	location	Antrum&pylorus	888	38	478	372
		Overlapping & unspecified	465	24	272	169
	Total		1817	82	1,002	733
	* Excluding stage unknown; # IQR=Inter Quartile Range

Table 3 . Hospital type, volume and referral pattern for gastric cancer-surgery for hospitals in the North-East Netherlands between 1994 and 2006

 3

	Hospital type

Table 4 Overall and relative 5-year survival and estimated excess risk of death with 95% confidence intervals (95% CI) for operated patients with gastric cancer, diagnosed between 1994-2006

 4

		All gastric cancers	Proximal gastric cancer		Distal gastric cancer
		Univariate	Multivariate	Univariate	Multivariate	Univariate	Multivariate
		5-year	5-year	EMR 95% CI*p-value 5-year	5-year	EMR	95% CI	*p-	5-year	5-year	EMR	95% CI	*p-
		OS		RS		OS	RS			value	OS	RS	value
	Sex				0.075					0.519			0.224
	male	27.1 34.0 1.00	24.7	28.6 1.00			28.0 36.0 1.00
	female	30.9 37.4 0.90 0.79-1.02	21.4	24.3 0.91 0.68-1.22		32.1 39.1 0.92 0.80-1.06
	Age				0.055					0.206			0.050
	< 60 (ref)	32.0 32.8 1.00	23.8	24.4 1.00			35.7 36.5 1.00
	60-69	31.5 35.0 1.03 0.89-1.21	28.8	31.9 0.85 0.64-1.12		32.6 36.1 1.13 0.94-1.37
	70+	25.1 36.8 1.17 1.01-1.34	20.3	27.6 1.09 0.83-1.44		25.9 38.4 1.23 1.04-1.45
	Period				0.001					0.092			0.014
	1994-1999	26.7 33.8 1.00	21.3	25.2 1.00			28.1 36.1 1.00
	2000-2006	30.0 36.3 0.83 0.74-0.94	27.5	30.9 0.83 0.65-1.04		30.9 38.1 0.84 0.73-0.96
	Stage				<0.001					<0.001			<0.001
	stage 1 (ref)	55.6 70.5 1.00	46.1	54.2 1.00			57.6 73.8 1.00
	stage 2	26.5 32.5 2.96 2.44-3.60	24.5	28.3 2.12 1.49-2.99		27.2 34.1 3.25 2.57-4.13
	stage 3	11.2 13.5 5.20 4.31-6.27	14.0	15.9 3.49 2.43-4.99		10.3 12.7 5.99 4.78-7.51
	stage 4	5.3		6.3 8.05 6.61-9.80	2.0	2.3 4.93 3.29-7.38		5.9	7.1 9.37 7.43-11.83
	Hospital type$				0.112					0.433			0.184

RS=relative survival, EMR=Excess Mortality Risk, 95% CI=95% Confidence Interval, n.a.=not applicable * p-values apply to the multivariate model, adjusted for time since diagnosis $ teaching status based on surgical subspecialisation # subdivision based on <5 versus 5-9 or ≥ 10 patients operated/ year based on all gastric cancers combined ^ subdivision based on <5%, 5-15% and >15% referral of patients for surgery based on all gastric cancers combined


Dr Robin L Jones
email: robin.jones@icr.ac.uk

J Mccall

A Adam

D O'donnell

S Ashley

O Al-Muderis

K Thway

C Fisher

I R Judson

Radiofrequency ablation is a feasible therapeutic option in the multi modality management of bone and soft tissue sarcoma

Keywords: Radio frequency ablation, sarcoma, response, progression, toxicity

The role of radiofrequency ablation (RFA) in metastatic sarcoma is not well defined. The aim of this study was to evaluate the efficacy and safety of RFA in a series of sarcoma patients. A retrospective search of a prospectively maintained database identified 13 gastrointestinal stromal tumour (GIST) patients and 12 with other histological subtypes treated with RFA. All the GIST patients received RFA for metastatic disease in the liver:

12 of these responded to the first RFA procedure and one achieved stable disease. Two GIST patients received RFA on two occasions to separate lesions within the liver and both responded to the second RFA procedure. Of the other subtypes: 7 underwent RFA to liver lesions, 5 of these responded to RFA, one progressed and 1 was not assessable for response at the time of analysis. All 5 patients with lung metastases achieved a response following their first RFA procedure. RFA was effective and well tolerated in this series of sarcoma patients. RFA may have a role in patients with GIST who have progression in a single metastasis but stable disease elsewhere. Further larger studies are required to better define the role of this technique in this patient population.

Introduction

Soft tissue sarcomas are rare cancers arising from mesodermal tissues. [START_REF] Clark | Soft-tissue sarcomas in adults[END_REF] Surgical resection is the mainstay of management for localized disease, but despite adequate excision approximately half of patients will develop metastaic disease. [START_REF] Clark | Soft-tissue sarcomas in adults[END_REF] Sarcomas comprise over 50 different histological subtypes, each with different biological characteristics, prognosis and response to therapy. The number of effective treatment strategies available to treat metastatic disease is limited. [START_REF] Clark | Soft-tissue sarcomas in adults[END_REF] Radiofrequency ablation (RFA) has emerged as an effective local therapy in the treatment of hepatocellular carcinoma and liver metastases secondary to colorectal cancer as well as other malignancies. [START_REF] Liapi | Transcatheter and ablative therapeutic approaches for solid malignancies[END_REF] This technique produces coagulative necrosis via an alternating high-frequency electric current in the radiofrequency range. This results in the movement of ions within the targeted lesion, and consequently frictional heat is created by the ions following the alternating current. [START_REF] Liapi | Transcatheter and ablative therapeutic approaches for solid malignancies[END_REF] Local intra lesional temperatures approach or exceed 100 0 C. RFA can achieve improved objective responses in a small number of treatment sessions, and the technique is usually regarded as most effective against small lesions (<3.5cm). Minor side effects include pain and discomfort. Other potential disadvantages include severe adverse events (including pain, cutaneous burns and fever) and death (reported as approximately 0.5%). [START_REF] Liapi | Transcatheter and ablative therapeutic approaches for solid malignancies[END_REF] To our knowledge there is little published data on the use of RFA specifically in the management of patients with sarcoma. [START_REF] Pawlik | Results of a single-center experience with resection and ablation for sarcoma metastatic to the liver[END_REF][START_REF] Amersi | Long-term survival after radiofrequency ablation of complex unresectable liver tumors[END_REF][START_REF] Hildebrand | Radiofrequency-ablation of unresectable primary and secondary liver tumors: results in 88 patients[END_REF][START_REF] Yasui | Thoracic tumors treated with CT-guided radiofrequency ablation: initial experience[END_REF][START_REF] Suh | Unresectable pulmonary malignancies: CT-guided percutaneous radiofrequency ablationpreliminary results[END_REF][START_REF] Strauss | Radiofrequency Ablation (RFA) of pulmonary metastases is safe and feasible in patients with relapsed bone and soft tissue sarcoma[END_REF] The aim of this study was to evaluate the efficacy of RFA to both lung and liver metastases in a series of sarcoma patients. A further aim was to document the complication rate associated with this technique in these patients.

M A N U S C R I P T A C C E P T E D

Materials and methods

Prior to commencing the study approval was obtained from the Royal Marsden Hospital Audit Committee. A retrospective search of a prospectively maintained database was made to identify sarcoma patients treated with RFA between October 2003 and April 2009. Patients who received their systemic therapy and were treated with RFA whilst receiving systemic therapy at the Royal Marsden were included in the analysis. Patients who had received RFA at other institutions and were referred to the Royal Marsden for further therapy or for a second opinion were excluded from the analysis. Patient demographics, histological subtype, treatment and survival data were obtained from the database. The time from diagnosis to ablation was also obtained from the database as well as systemic and other local therapies administered. Toxicity was retrospectively ascertained from the Royal Marsden electronic patient record. The number and size of lesions ablated was reviewed and the time to progression at ablated sites.

As per Royal Marsden Sarcoma Unit protocol, the histological diagnosis was confirmed by a sarcoma pathologist on referral (KT, CF).

RFA

RFA was performed by two experienced interventional radiologists (JM, AA). A baseline CT was performed prior to the procedure. Response was assessed by CT scan approximately 3 months post procedure unless otherwise indicated. The date of progression at the ablated site and systemic progression were recorded. Complications

M A N U S C R I P T A C C E P T E D

were documented following the procedure on the Royal Marsden electronic patient record system. Selection of GIST (gastro intestinal stromal tumour) patients for hepatic RFA was based on the appearance of progression at one site on the background of otherwise stable metastatic disease.

Selection of other sarcoma patients for RFA was based on the uncertainty of obtaining systemic disease control and the need for treating specific hepatic or pulmonary lesions, in order to obtain local control without subjecting a patient to surgery.

Statistical analysis

Follow-up data was available up to 20 th April 2009.

The GIST patients represented a homogenous group and therefore they were analysed separately from the patients with other sarcomas. Survival was determined by the Kaplan-Meier method and measured from the date of RFA until death from any cause and censored at last follow-up. Time to progression at the RFA site was measured from the start of RFA until a documented progression at the treated site. RFA episodes without progression were omitted from the analysis of progression. Differences between GIST and other histological subgroups were assessed by the logrank test.

Results

A total of 38 patients were identified of whom 13 had undergone RFA prior to referral to the Royal Marsden Hospital. Therefore, twenty-five patients treated with RFA were

GIST patients

Thirteen GIST patients with liver metastases were treated with RFA. The median age of these patients was 59 years (range 37-75): there were 12 males and 1 female. Eleven patients had surgical resection of the primary tumour at diagnosis and two presented with metastatic disease. Of these 13, one underwent a liver resection prior to hepatic RFA. The GIST patients received a median of 2 lines of systemic therapy (range 1-6). At the time of analysis 2 of these patients had died and 11 were still alive with a median follow-up of 26 months.

Response and toxicity in GIST patients

Of the 13 GIST patients treated with RFA, 12 achieved a response at the RFA site and one stable disease following the first RFA procedure. One patient had two liver lesions ablated during the same procedure, all the others underwent RFA to one lesion. The site and number of liver lesions ablated at first RFA, along with the response and complications are illustrated in Table 1.

Two patients received RFA on two occasions to separate lesions within the liver and both responded to the second RFA procedure.

All of these patients were treated with systemic therapy, 12 GIST patients underwent RFA whilst receiving first-line systemic therapy in the form of imatinib. The other patient underwent RFA whilst receiving re-challenge with imatinib 400 mg per day.

M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT

7 Two patients developed infections post procedure (one at the RFA site) and one developed atrial fibrillation with a rapid ventricular response. All three patients were treated with appropriate medical therapy and made a prompt recovery. One of the patients treated with two separate RFA procedures developed sepsis post second RFA.

Time to progression and overall survival in GIST patients

The median time to progression from date of ablation to progression at RFA site was 28 months, see Figure 1.

The median time to progression at other sites from date of RFA was 26 months (95%CI, 1-51). At the time of analysis, 7 patients were on first-line imatinib and a further 6 patients continued on first-line therapy for a median of 11 months (range 3-28) following RFA.

The 2-year overall survival from start of RFA was 77% (95%CI 35-94%), see Figure 2.

Median survival for this group of patients has not been reached.

Other sarcomas

Twelve patients with other sarcomas (i.e. not GIST) were treated with RFA, 7 to the liver and 5 to the lung. The median age of these patients was 50 years (range 33-71), there were 5 males and 7 females. The most common histological subtype was leiomyosarcoma (n=5) followed by chondrosarcoma (n=2) and fibrosarcoma (n=2).

Eleven of these patients underwent surgical resection of the primary tumour and one received radical radiotherapy to a primary malignant fibrous histiocytoma in the left popliteal fossa. Two patients underwent one further surgical resection for recurrent or

M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT
8 metastatic disease, one patient underwent two such procedures and 5 patients had a total of 3 separate operations for recurrent or metastatic disease. Two of these patients had not received systemic therapy at the time of analysis. Of the 12 sarcoma patients, five received one line of systemic therapy, two received 2 lines and three received 3 lines of therapy. At the time of analysis, 6 patients had died and 6 were alive.

Response and toxicity in other sarcoma patients

Of the 7 patients with liver metastases, 5 of these patients responded to RFA and one patient displayed progression at the RFA site on the post procedure scan. One patient was not assessable for response at the time of analysis (Table 2). Two of these patients displayed progression elsewhere on the 3 month post procedure CT scan.

One patient received 3 separate RFA treatments and responded on all 3 occasions. One patient received 4 separate RFA procedures and another 12 separate procedures. No toxicity was recorded following these multiple procedures.

All patients with lung metastases achieved a response following their first RFA procedure, and 2 displayed progression at other sites between 3-5 months post procedure.

Two of the patients with lung metastases were treated twice with RFA to separate lesions within the lung, one of whom displayed progression at the ablated site post procedure.

One patient underwent 1 thoracotomy and 3 underwent 2 separate thoracotomies prior to RFA. In addition, 3 patients underwent one thoracotomy, each, following RFA.

One patient developed a small pneumothorax post first RFA procedure, which did not require any medical intervention. Another patient had a pneumothorax following the

Time to progression and overall survival in other sarcoma patients

The median follow-up was 11 (range 2-54) months.

The median time to progression at RFA site (following first ablation) for patients with the other soft tissue tumours was 9 months (95%CI, 8-10 months), see Figure 1.

The median time to progression at other sites from date of RFA was 8 months (95%CI, 4-11).

The 2 year overall survival from RFA in this cohort 40% (95%CI, 10-70%), and the median overall survival from RFA was 19 months (95%CI, 12-26 months), see Figure 2.

GIST patients had significantly longer time to progression at RFA site (median time to progression 28 months, 95% CI undefined) compared to the combined group of patients with other sarcomas (9 months, 95% CI, 8-10 months). No significant difference in time to progression at other sites following RFA was observed between the GIST and the non-GIST group (p=0.2). However, GIST patients had significantly longer overall survival from RFA compared to the other group (p=0.01).

Discussion

Our study of a small series of sarcoma patients treated with RFA to the liver and lung indicates that this treatment modality may have a role in these conditions. Patients with GIST who have stable systemic disease on a tyrosine kinase inhibitor but have In other sarcomas the role of RFA is less clear, but it could be of value in a subgroup of patients deemed potentially resectable but not operable due to concurrent medical conditions. Of the 11 non-GIST patients assessable for response one progressed at the RFA on the post procedure scan. A further 4 achieved disease control at ablated sites but displayed progression elsewhere 3-5 months post procedure. This technique could potentially be offered to sarcoma patients who are symptomatic due to a solitary localized area of disease.

Our small exploratory study was retrospective and therefore any results must be interpreted with caution. We observed that GIST patients had significantly longer time to progression at ablation site compared to patients with other sarcomas. Furthermore, GIST patients had significantly longer overall survival from RFA compared to the group of other sarcoma subtypes. This is possibly explained by the heterogeneous nature of the non-GIST group who had received mutli modality therapy consisting of surgery, chemotherapy and radiotherapy for metastatic disease. Additionally, this group consisted of patients who had received RFA for lung and liver metastases.

RFA studies including sarcoma patients

A number of other retrospective studies have included sarcoma patients treated with RFA to the liver [START_REF] Pawlik | Results of a single-center experience with resection and ablation for sarcoma metastatic to the liver[END_REF][START_REF] Amersi | Long-term survival after radiofrequency ablation of complex unresectable liver tumors[END_REF][START_REF] Hildebrand | Radiofrequency-ablation of unresectable primary and secondary liver tumors: results in 88 patients[END_REF] and lung, [START_REF] Yasui | Thoracic tumors treated with CT-guided radiofrequency ablation: initial experience[END_REF][START_REF] Suh | Unresectable pulmonary malignancies: CT-guided percutaneous radiofrequency ablationpreliminary results[END_REF][START_REF] Strauss | Radiofrequency Ablation (RFA) of pulmonary metastases is safe and feasible in patients with relapsed bone and soft tissue sarcoma[END_REF][START_REF] Nakamura | Lung radiofrequency ablation in patients with pulmonary metastases from musculoskeletal sarcomas: an initial experience (R#2)[END_REF] but few have specifically analysed the value of this technique in sarcoma.

A study by Pawlik et al examined the role of hepatic resection and/ or RFA in a cohort of 66 sarcoma patients with metastatic disease in the liver. [START_REF] Pawlik | Results of a single-center experience with resection and ablation for sarcoma metastatic to the liver[END_REF] RFA alone was performed in 13 patients (19.7%) who had metastases in unresectable locations and in combination with surgery in 18 patients (27.3%). In their retrospective study, these authors found that patients treated with RFA alone or in combination had significantly worse disease-free survival (7.4 months) compared to those treated with surgical resection alone (18.6 months). However, they found no significant difference in overall survival between the cohort treated with RFA and surgical resection alone.

A retrospective study by Berber and colleagues assessed the value of laparoscopic RFA in 53 patients with non colorectal or hepatocellular cancers. [START_REF] Berber | Laparoscopic radiofrequency thermal ablation for unusual hepatic tumors: operative indications and outcomes[END_REF] Eighteen sarcoma patients were included in this study with liver only metastatic disease. The median survival of sarcoma patients following hepatic RFA in the study by Berber et al was 25 months.

Most of these patients had GIST all though the exact breakdown by histological subtype was not published.

M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT

Other ablative techniques

A number of other image-guided catheter-based therapies are available for the treatment of hepatic metastases, which include transcatheter arterial chemoembolisation (TACE), transcatheter arterial embolisation (TAE) and TAE with drug eluting beads. [START_REF] Liapi | Transcatheter and ablative therapeutic approaches for solid malignancies[END_REF] Hepatic artery embolisation/ chemoembolisation were originally developed as therapy for unresectable hepatocellular carcinoma. [START_REF] Yamada | Hepatic artery embolization in 120 patients with unresectable hepatoma[END_REF] The liver receives dual blood supply from the portal vein and hepatic artery, whereas hepatocellular carcinomas are supplied only by the hepatic artery. Consequently, embolisation of the hepatic artery produces selective ischaemic necrosis of the tumour while sparing the surrounding normal liver parenchyma.

Furthermore, the effect of a relatively small dose of a conventional chemotherapeutic agent, administered to the region, followed by embolisation may increase the efficacy of chemotherapy. Mavligit and colleagues reported, in 1995, on the use of hepatic chemoembolisation in a series of 14 patients with hepatic metastases secondary to gastrointestinal leiomyosarcoma (which would now be classified as gastrointestinal stromal tumours). [START_REF] Mavligit | Gastrointestinalleiomyosarcoma metastatic to the liver. Durable tumor regression by hepatic chemoembolization infusion with cisplatin and vinblastine[END_REF] Ten (70%) of these patients experienced a major regression (>50%), which were maintained for a median of 12 months, following an average of two hepatic chemoembolisation procedures. Shima et al treated 4 GIST patients with liver metastases with hepatic artery chemoembolisation. [START_REF] Shima | Aggressive surgery for liver metastases from gastrointestinal stromal tumors[END_REF] Three of these patients died of disease 17, 23 and 28 months following chemoembolisation and one was still alive 7 months after the procedure. There have also been reports of arterial chemoembolisation in localized osteosarcoma [START_REF] Chu | Clinicopathologic features and results of transcatheter arterial chemoembolization for osteosarcoma[END_REF] and hepatic angiosarcoma. [START_REF] Stambo | Hepatic angiosarcoma presenting as an acute intraabdominal hemorrhage treated with transarterial chemoembolization[END_REF][START_REF] Park | Primary hepatic angiosarcoma: imaging findings and palliative treatment with transcatheter arterial chemoembolization or embolization[END_REF] Percutaneous ethanol injection involves introducing single or multiple fine needles into the metastatic lesion and injecting ethanol (90-100%), thus causing cell death mainly by [START_REF] Evans | Ablative and catheter-delivered therapies for colorectal liver metastases (CRLM)[END_REF] A randomized trial of 232 patients with small hepatocellular carcinomas demonstrated those treated with radiofrequency ablation to have significantly longer survival compared to those treated with percutaneous ethanol injection. [START_REF] Shiina | A randomized controlled trial of radiofrequency ablation with ethanol injection for small hepatocellular carcinoma[END_REF] In addition, there are a number of alternative percutaneous thermal ablation techniques to treat patients with primary liver tumours and/ or metastases. Laser-induced thermotherapy uses optical fibres to deliver high energy laser radiation to the target region. [START_REF] Vogl | Malignant liver tumors treated with MR imaging-guided laser-induced thermotherapy: experience with complications in 899 patients (2,520 lesions)[END_REF] Microwave coagulation therapy involves the introduction of a thin microwave antenna directly into the tumour. [START_REF] Seki | Ultrasonically guided percutaneous microwave coagulation therapy for small hepatocellular carcinoma[END_REF] With the use of a microwave generator an electromagnetic wave is emitted through the exposed, non-insulated part of the antenna. This agitates water molecules in the surrounding tissue, which produces friction and heat and subsequently cell death by coagulative necrosis. In another technique, cryotherapy, the lesion is frozen by the introduction of liquid nitrogen or argon. 17

Conclusion

Our study has shown that RFA is feasible, tolerable and effective in the multimodality management of patients with metastatic sarcoma if the goal of therapy is local disease control. This technique has shown particular promise in GIST, and further prospective evaluation is required to confirm our preliminary findings. RFA is also a feasible therapeutic option in patients with other sarcoma subtypes with localised disease, in whom local disease control can be achieved without surgery. However, the exact role of RFA in such conditions remains to be defined, as systemic disease control often proves difficult, and further assessment in a larger cohort of patients is warranted.

  males and 8 females). The median age of these patients was 54 years (range 33-75) and the median follow-up was 21 months (range 2-60).

  a lung metastasis and this again did not require the insertion of a chest drain.

  metastatic site (presumably due to a resistant clone) seem particularly suitable for RFA. Consequently, RFA can delay a change in systemic therapy by achieving local control at the site of solitary disease progression in such patients.

  RFA was well tolerated in our series of patients treated by experienced interventional radiologists. All toxicities were easily manageable. Of the 20 patients who underwent RFA to the liver, two developed infections and one atrial fibrillation. Both patients who developed infections were treated appropriately with no long-term complications. Of the M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 11 pneumothorax was observed in two patients and neither required insertion of a chest drain.

Figure 1 .Figure 2 .

 12 Abbreviations: PD -progressive disease. LMS -leiomyosarcoma. SFT -solitary fibrous tumour. CS-chondrosarcoma.

Table 1 . Response, complications, size and number of liver metastases treated with RFA in GIST patients.

 1

	Patient	Site	Number of	Size (mm) Response	Complication
	number		lesions
			ablated
	1	Posterior	One	<10	Response	Sepsis
		right lobe
	2	Segment 2	One	25	Response	None
	3	Segment 7	Two	25 + 6	Response	None
		+ 5
	4	Segment 6	One	40	Response	None
	5	Segment 5/	One	35	Response	None
		8
	6	Segment 6	One	42	Response	Atrial
						fibrillation
	7	Left lobe	One	32	Response	None
	8	Segment 8	One	39	Response	None
	9	Segment 4a One	11	Response	None
	10	Segment 4a One	21	Response	None
	11	Segment 7/	One	30	Response	Infection
		8				RFA cavity
	12	Segment 5	One	20	Response	None
	13	Segment 8	One	15	Response	None

Table 2 . Location, number, size, response and complications in other sarcoma patients treated with radio frequency ablation.

 2