V Galant

B Grégoire

M Lengelé

Hamoir

J P Van Damme

S Schmitz

J P Machiels

C Galant

V Grégoire

B Lengelé

MD Marc Hamoir
email: marc.hamoir@uclouvain.be

Dr Van Damme

Lengelé

Prognostic factors and assessment of staging systems for head and neck soft tissue sarcomas in

Keywords: Soft tissue sarcoma, head and neck cancer, prognostic factors, staging system

Prognostic factors and assessment of staging systems for head and neck soft tissue sarcomas in adults

Introduction

Sarcomas are rare tumours (3 to 4. 5 cases/100.000 persons per year) belonging to the family of non-epithelial malignant tumours. [START_REF] Penel | Prognostic factors for adult sarcomas of head and neck[END_REF][START_REF] Zahm | The epidemiology of soft tissue sarcoma[END_REF] They are divided into two types: sarcomas from soft tissues and sarcomas from bone or cartilaginous tissues. The management and outcomes of these two types of tumour are very different. [START_REF]Atlas of Clinical Oncology -Cancer of the head and neck, 2001-chapter 17:Soft tissue and bone tumour[END_REF] Only 5-10 % of sarcomas from soft tissue are located in the head and neck region where they represent less than 1% of all head and neck tumours. 4,[START_REF] Singh | Adult head and neck soft tissue sarcomas : treatment and outcome[END_REF] In Belgium (population of 10,4 million people ), the theoretical annual incidence of head and neck soft tissue sarcomas (HNSTS) is around 30 cases. There are seven tertiary referral centers and the lack of a centralised public health policy explains the difficulty in gathering a high number of patients in referral centres. To the best of our knowledge, this article is the first to analyse data on a series of Belgian patients diagnosed with HNSTS. The primary objective of this study was to analyse the outcome of HNSTS in our institution and to determine the most relevant prognostic factors.

In the literature, there are usually two staging systems described for use with sarcoma patients. The first, proposed by the American Joint Committee on Cancer (AJCC), and by the International Union Against Cancer (UICC) is the most frequently used. [START_REF]AJCC Cancer staging handbook Sixth Edition, 2002-chapter 22:Soft tissue sarcoma[END_REF] The second, proposed by the Memorial Sloan-Kettering Cancer Center (MSKCC), was described by their authors as easier to use (Table 1). [7][START_REF] Hajdu | The role of the pathologist in the management of soft tissue sarcomas[END_REF] Using our data, we compared the two staging systems, to better assess which was the most relevant for the prognostic value of patients with HNSTS.

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Materials and methods

The medical records of 42 patients over 18 years old, with HNSTS diagnosed at St-Luc University Hospital, a tertiary referral centre, between 07/1988 and 01/2008 were retrospectively reviewed.

Prognostic factors

The following variables of potential prognostic value were collected: gender, age at diagnosis, radiation history (sarcomas were labelled as radiation-induced based on the criteria of Arlen: histological confirmation of sarcoma, a different histology in relation to the previous cancer, tumour in or in the burden of the radiation field and a minimum interval of 3 years 9 ), symptoms, anatomical site, dates of the consecutive treatments, surgical margins ( In the head and neck, wide margins are not always easy to achieve because of anatomical limitations. In our study, margin status was considered as follows: Margins were defined as negative when at least 1cm free or less than 1 cm when wider margins were not possible to achieve because of anatomical factors, but when the surgeon believed he had performed a complete resection or with a well encapsulated tumour on the pathological report; margins were defined as close when less than 1 cm and the surgeon believed he had performed a borderline resection, peroperative extracapsular spread or with histological evidence of extracapsular spread; margins were defined as positive when they were macroscopically or microscopically invaded), radiation therapy (total dose), chemotherapy (type of cytotoxic agents and number of treatment courses), the presence of lymph nodes or distant metastasis at diagnosis, size of the tumour (<5cm vs. >5cm), extension (superficial or deep compared to the superficial fascia), histological type and subtype (with the exclusion of dermatofibrosarcoma protuberans and angiosarcoma which are excluded by the AJCC staging system [START_REF]AJCC Cancer staging handbook Sixth Edition, 2002-chapter 22:Soft tissue sarcoma[END_REF] ) , grade according to the National Cancer Institute (NCI) (all the tumours which could be graded I to III according to AJCC and MSKCC staging systems. [START_REF]AJCC Cancer staging handbook Sixth Edition, 2002-chapter 22:Soft tissue sarcoma[END_REF][START_REF] Hajdu | The role of the pathologist in the management of soft tissue sarcomas[END_REF] The files of 29 patients with insufficient medical records or follow up were excluded from the study.

End points:

The end points of this study were overall survival (OS), disease-free survival (DFS) and disease-specific survival (DSS). OS was defined as the time interval between the date of the first treatment and death or last follow-up, DFS was defined as the time interval between the date of first treatment and death or disease progression, DSS was defined as the time interval between the date of first treatment and death related to sarcoma. OS, DFS and DSS were analysed for all possible prognostic factors.

The average follow-up after treatment was 54 months (range: 1 -240 months).

Statistics:

Survival probability was calculated using the Kaplan Meier method. [START_REF] Kaplan | Non parametric estimation for incomplete observations[END_REF] Median OS, DFS and DSS were calculated for each prognostic variable.

Univariate analysis was carried out with the LOG-RANK test. Multivariate analysis of each prognostic factor significantly affecting the survival in univariate analysis was carried out using the COX model (proportional hazards model). The survival differences were considered as statistically significant when the p value was < 0.05.

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6

Results

Patient's characteristics

The male/female ratio was 1/1.1 (20 males and 22 females). Median age at diagnosis was 50 (range 18 -91 years). Localizations of HNSTS were at the paranasal sinus in 17 patients, in the neck, including parotid gland area in 10 patients, the scalp and face in 9 patients, and the upper aerodigestive tract (oral cavity, larynx, superior oesophagus) in 6 patients. The most frequent histological subtypes were undifferentiated sarcoma in 7 patients, leiomyosarcoma in 6 patients, malignant peripheral nerve sheath tumour (MPNST) in 5 patients and rhabdomyosarcoma in 5 patients. The most frequent clinical manifestation was progressive developing of a painless mass in half of the patients and less frequently nasal obstruction with or without epistaxis and dysphonia. Most tumours were < 5cm (30/42) and deep infiltration through the superficial fascia was mentioned on pathology or imaging reports in 35/42 patients. Three patients were staged as N1 and one patient was staged as M1 at time of diagnosis.

Histological grade I was diagnosed in 9 tumours and grade II-III in 33 tumours. Sixteen patients had a medical history of cancer (other than sarcoma) and 10 had been previously treated with radiotherapy. Eight of those 10 patients developed a radio-induced sarcoma, according to the Arlen criteria. The median time interval between previous radiotherapy and diagnosis of sarcoma was 252 months (range: 72-480 months). Five-year OS of radioinduced HNSTS patients was 58%, which compared with a 5-year OS rate of 56% in the group of non radio-induced HNSTS patients.

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Treatment characteristics

Thirty-nine patients were treated with primary curative-intent surgery. Margins were negative in 10, close in 17, positive in 10 and unspecified in 2. Three patients had a non-resectable paranasal sinus sarcoma and were primarily treated with chemotherapy and radiotherapy.

Radiotherapy was used in 18 patients : pre or postoperative in 16 patients with curative intent and alone or combined with chemotherapy in 2 patients with non-resectable tumours. The mean total dose was 58 Gy (range: 22 -72 Gy). Chemotherapy was used in 10 patients, as adjuvant in 8 patients and exclusive or combined with radiotherapy in 2 patients (table 2).

AJCC and MSKCC staging systems

Excluding 6 patients with a diagnosis of dermatofibrosarcoma protuberans or angiosarcoma, (not considered by the AJCC staging system), 25 patients were classified T1 (21 as T1b) and 11 were classified T2 (9 as T2b). According to the AJCC staging system, 8 patients were stage I, 19 stage II, 5 stage III and 4 stage IV. According to the MSKCC staging system, 2 patients were staged as stage 0, 7 as stage I, 19 as stage II, 7 stage III and 1 as stage IV (table 2).

The prognostic value of the AJCC staging system was more relevant than the MSKCC staging system. In relation to DSS, the prognostic value was statistically significant in the two systems but was found more significant in the AJCC system (p=0.018 vs. p=0.048). For OS, the prognostic value reached the level of significance in the AJCC system (p=0,054) but was not statistically significant in the MSKCC system (p=0,198). For statistical reasons, the 2 patients staged as stage 0 in the MSKCC staging system (not used in the AJCC staging system) were included in the group of patients MSKCC stage I. With a comparable MSKCC or AJCC stage, the median OS was similar. With DSS, the prognostic value of the two

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ACCEPTED MANUSCRIPT 8 systems for stage was good and statistically significant although the median survival was slightly higher in stage II when compared to stage I. This was probably explained by the limited size of our series.

Prognostic factorsunivariate analysis:

Because almost all patients were treated by curative-intent surgery (3 patients with nonresectable tumours were treated palliatively with chemo or radiotherapy), this factor was excluded from statistical analysis.

For OS, the univariate statistical analysis showed that distant metastasis or lymph node metastasis at diagnosis had a statistically significant prognostic value (p=0.032) whereas the AJCC staging system showed only a trend (p=0.054). Median OS of patient N1 or M1 was 9 months compared with 30 months for the rest of the population.

For DFS, achieving clear margins (p=0.007) was a statistically significant prognostic factor (table 2, figure 1) whereas radiotherapy showed only a trend for a better prognosis (p=0.053).

In the case of negative margins, the median DFS was 92 months compared to 13 months in the case of positive margins. In the case of close margins, the median DFS was 14 months, comparable to the median DFS of patients with positive margins (figure 1).

For DSS, N1 or M1 at diagnosis (p=0.002), AJCC stage (p=0.018) (figure 2), MSKCC stage (p=0.048) and margins (p=0.042) were statistically significant prognostic factors whereas adjuvant radiotherapy showed only a trend for a better survival rate (p=0.051). Patients with an early AJCC or MSKCC stage had a median DSS of 56 months for stage 1 and 66 or 60 months respectively for stage II, whereas patients with an advanced stage had a median DSS

Prognostic factors -multivariate analysis:

After multivariate statistical analysis, the only factor remaining statistically significant was negative margins for DFS (p=0.039) when the initial AJCC stage showed only a trend regarding OS (p=0.054).

The survival probability curves are shown in figure 3.

Discussion

Comparison with previously reported series HNSTS are rare tumours. Most recent publications report on series with about 50 patients or fewer, often not being comparable with our study as they mix adult and paediatric populations or report different histological subtypes (e.g. all sarcomas, soft tissues only, or with the exclusion of some histological subtypes). [START_REF] Penel | Prognostic factors for adult sarcomas of head and neck[END_REF][START_REF] Singh | Adult head and neck soft tissue sarcomas : treatment and outcome[END_REF][START_REF] De Bree | Prognostic factors in adult soft tissue sarcomas of the head and neck : a single-centre experience[END_REF][START_REF] Colville | Multidisciplinary management of head and neck sarcomas[END_REF][START_REF] Penel | Head and neck soft tissue sarcomas of adult : prognostic value of surgery in multimodal therapeutic approach[END_REF] To date, the two most important published series included no more than one hundred patients. 4,[START_REF] Bentz | Head and neck soft tissue sarcomas : a multivariate analysis of outcomes[END_REF] This explains numerous disparities between published series. In our series, the 5-year OS, DFS and DSS are respectively 57%, 47% and 72%. These results are comparable with the data found in the literature reporting a 5-year OS between 32% and 87%, a 5-year DFS between 27% and 74% and a 5-year DSS between 81 and 83%. [START_REF] Penel | Prognostic factors for adult sarcomas of head and neck[END_REF][START_REF]Atlas of Clinical Oncology -Cancer of the head and neck, 2001-chapter 17:Soft tissue and bone tumour[END_REF]4,[START_REF] De Bree | Prognostic factors in adult soft tissue sarcomas of the head and neck : a single-centre experience[END_REF] Our series shows a very slight female predominance, confirmed by some authors [START_REF] De Bree | Prognostic factors in adult soft tissue sarcomas of the head and neck : a single-centre experience[END_REF][START_REF] Kiatisevi | The outcomes and prognostic factors of patients with soft-tissue sarcoma[END_REF] , but invalidated by others. [START_REF]Atlas of Clinical Oncology -Cancer of the head and neck, 2001-chapter 17:Soft tissue and bone tumour[END_REF][START_REF] O'sullivan | Soft tissue sarcoma[END_REF] The median age at diagnosis is 50 years old, comparable to the one found in the literature. [START_REF] Penel | Prognostic factors for adult sarcomas of head and neck[END_REF][START_REF]Atlas of Clinical Oncology -Cancer of the head and neck, 2001-chapter 17:Soft tissue and bone tumour[END_REF][START_REF] De Bree | Prognostic factors in adult soft tissue sarcomas of the head and neck : a single-centre experience[END_REF][START_REF] O'sullivan | Soft tissue sarcoma[END_REF][START_REF] Kraus | Prognostic factors for recurrence and survival in head and neck soft tissue sarcomas[END_REF] In our series, even if the median DSS is clearly better in the case of superficial infiltrations (96 months versus 38 months.), the difference is not statistically significant, -probably because the number of patients in our study was too small. Huber et al. have shown that the absence of deep extension is the best prognostic factor. 4 Few authors have identified this factor specifically, rather considering the size of the tumour as a poor prognostic factor. [START_REF] Bentz | Head and neck soft tissue sarcomas : a multivariate analysis of outcomes[END_REF][START_REF] Dudhat | Prognostic factors in head and neck soft tissue sarcomas[END_REF][START_REF] Mendenhall | Adult head and neck soft tissue sarcomas[END_REF][START_REF] Potter | Sarcomas of the head and neck[END_REF][START_REF] Le | Prognostic factors in adult soft-tissue sarcomas of the head and neck[END_REF] In our series, tumour size is not a statistically significant prognostic factor. The histological grade is often identified as a prognostic factor. [START_REF]AJCC Cancer staging handbook Sixth Edition, 2002-chapter 22:Soft tissue sarcoma[END_REF][START_REF] Bentz | Head and neck soft tissue sarcomas : a multivariate analysis of outcomes[END_REF][START_REF] Dudhat | Prognostic factors in head and neck soft tissue sarcomas[END_REF][START_REF] Tran | Sarcomas of the head and neck : prognostic factors and treatment strategies[END_REF][START_REF] Pandey | Soft tissue sarcoma of the head and neck region in adults[END_REF] In our study, even if OS, DSS and DFS are systematically better for patients with grade I sarcoma in comparison with grade II or III, the differences are not statistically significant, again probably due to the limited number of patients studied.

In our series, the presence at diagnosis of lymph node or distant metastasis is rare but has an impact on survival as has been reported by others [START_REF] Penel | Prognostic factors for adult sarcomas of head and neck[END_REF][START_REF] De Bree | Prognostic factors in adult soft tissue sarcomas of the head and neck : a single-centre experience[END_REF][START_REF] Kiatisevi | The outcomes and prognostic factors of patients with soft-tissue sarcoma[END_REF] The AJCC recommends staging all patients with no evidence of lymph node metastasis or distant metastasis N0 and M0.

In a review of 1225 patients, Zagars et al. have confirmed that the localization in the head and neck area was a negative prognostic factor for DSS and DFS. [START_REF] Zagars | Prognostic factors for patients with localized soft-tissue sarcoma treated with conservation surgery and radiation therapy : an analysis of 225 patients[END_REF] As our series shows, and in accordance with others, no specific anatomical localization in the head and neck makes an impact on the prognosis. 4,[START_REF] De Bree | Prognostic factors in adult soft tissue sarcomas of the head and neck : a single-centre experience[END_REF] Again, this is probably due to the small number of patients in our series, as in the other studies. In the head and neck region, wide margins after surgery are not always easy to achieve because of anatomical limitations. Negative margins have a major impact on DFS: the median DFS of patients with close margins, is similar to the median DFS of patients with positive margins. These results confirm the major impact of curative surgery with wide clear margins on prognosis. [START_REF] Penel | Prognostic factors for adult sarcomas of head and neck[END_REF]4,[START_REF] De Bree | Prognostic factors in adult soft tissue sarcomas of the head and neck : a single-centre experience[END_REF][START_REF] Penel | Head and neck soft tissue sarcomas of adult : prognostic value of surgery in multimodal therapeutic approach[END_REF][START_REF] Bentz | Head and neck soft tissue sarcomas : a multivariate analysis of outcomes[END_REF][START_REF] Kraus | Prognostic factors for recurrence and survival in head and neck soft tissue sarcomas[END_REF][START_REF] Dudhat | Prognostic factors in head and neck soft tissue sarcomas[END_REF][START_REF] Kraus | Sarcomas of the head and neck[END_REF] Because of the difficulties in obtaining negative margins in the head and neck, some authors have reported that the combination of radiotherapy with surgery increased the survival rate and decreased the risk of local recurrence. [START_REF]Atlas of Clinical Oncology -Cancer of the head and neck, 2001-chapter 17:Soft tissue and bone tumour[END_REF][START_REF] Tran | Sarcomas of the head and neck : prognostic factors and treatment strategies[END_REF] The trend for a better DFS in our patients treated with postoperative radiotherapy supports the concept of adjuvant radiotherapy in patients with borderline margins. In relation to DSS, radiotherapy seems to be a poor prognostic factor in univariate analysis (36 versus 72 months). These paradoxical results are biased since all patients treated with surgery alone did not have factors of poor prognosis. The role of chemotherapy is generally considered as limited [START_REF]Atlas of Clinical Oncology -Cancer of the head and neck, 2001-chapter 17:Soft tissue and bone tumour[END_REF][START_REF] Engel | Preoperative chemotherapy for localised resectable soft-tissue sarcomas of the extremities : the experience at the university of California[END_REF][START_REF]Adjuvant chemotherapy for localised resectable soft-tissue sarcoma of adults : meta-analysis of individual data[END_REF] but is proposed in advanced stages. [START_REF] Blay | Advanced soft-tissue sarcoma: a disease that is potentially curable for a subset of patients treated with chemotherapy[END_REF] In our series, use of chemotherapy is not associated with significant survival improvement, mainly because its use was restricted to unresectable or palliative disease.

As reported by others, some prognostic factors are advanced while others, even if recognised in the literature, are not identified. 4,[START_REF] De Bree | Prognostic factors in adult soft tissue sarcomas of the head and neck : a single-centre experience[END_REF][START_REF] Pandey | Soft tissue sarcoma of the head and neck region in adults[END_REF] Most published series, including ours, report on too limited number of patients or are too heterogeneous. Therefore we feel it essential to set up national and international databases, which could facilitate a prospective multicenter registration for those patients.

Comparison between AJCC and MSKCC staging systems

The value of the AJCC sarcoma staging system is sometimes debated. Nevertheless, it provides the possibility of combining all the studied factors through grade and TNM classification. This is why we staged our patients according to the TNM classification, excluding many patients due to incomplete data or histological types not accepted by the AJCC 6 th edition . [START_REF]AJCC Cancer staging handbook Sixth Edition, 2002-chapter 22:Soft tissue sarcoma[END_REF] In our series, the AJCC staging system's prognostic value is more relevant than the prognostic value of the MSKCC system. This information should be validated in larger multicenter series. The advantages of the MSKCC staging are its simplicity of use and the existence of a

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12 stage 0 for very good prognosis. However, the number of patients staged MSKCC 0 in our series is too small to pass comment on its clinical significance. The weakness of the MSKCC system is that, contrary to the AJCC system, it does not take the lymph node status into account. Interestingly, the prognostic value of the AJCC and MSKCC staging systems become comparable and statistically insignificant when patients staged N1 are excluded from the univariate analysis (data not reported in the article). This explains why, in our series, the prognostic value of staging is higher using the AJCC staging system than using the MSKCC system.

Conclusion

Soft tissue sarcomas are rare tumours in the head and neck. Achieving negative margins after primary surgery is the most important prognostic factor, providing the best chance of local control and survival. In our series, adjuvant radiotherapy and chemotherapy are of limited value. As emphasized by many other authors, we believe that those tumours should exclusively be managed in centers with extensive expertise in head and neck oncology, including surgical teams able to achieve wide tumour resection and to reconstruct large composite surgical defects. 1,22,25,,27,29 To better identify prognostic factors, it seems essential to set up national and international databases allowing a prospective registration for those patients.

5 NCI

 5 were reviewed by the same pathologist C.G.), TNM classification and staging relating to

  of 13 months for stage III and 11 months for stage IV. Patients with MSKCC stage 0 had a median DSS of 98 months, better than that of patients staged AJCC stage I (56 months) or MSKCC stage I (49 months), but the difference was not statistically significant. Patients staged N0 -M0 had a median DSS of 58 months compared to 11 months in patients staged N1 M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 9 or M1 at diagnosis. In the case of negative margins, the median DSS was 97 months compared with 43 months in the case of close margins and 22 months when margins were invaded.

Figure 1 .

 1 Figure 1. : Disease-free survival (DFS) probability according to the margin status.

Figure

  Figure(s)

Figure 2 .Figure 3 .

 23 Figure 2. : Disease-specific survival (DSS) probability related to stage grouping according to the AJCC staging system.

Acknowledgments.

Mr Nicolas Buyse for the amount and quality of time spent on statistical analysis and for his expertise in this field.

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MD a , Giorgio Zavagno
email: giorgio.zavagno@unipd.it

Marta Dona

MD Enrico Orvieto

MD a , Simone Mocellin

MD a , Sandro Pasquali

MD Elena Goldin

Marcello Lo Mele

MD Valentina Belardinelli

MD Donato Nitti

MD a , Marta Donà

MD b Marcello Lo Mele

Separate Cavity Margins Excision As A Complement To Conservative Breast

Keywords: Breast cancer, Breast conservation surgery, Margins, Re-excision, Local recurrence

Background: Positive lumpectomy margins (LM) usually mandate re-excision. However, approximately half of these patients have no residual tumour in the re-excision specimen. The aim of this study was to investigate if separate cavity margin (CM) excision can safely reduce the need of re-operation.

Methods: Rate of re-operation for margin involvement and incidence of residual tumour in the reexcision specimen were retrospectively evaluated in 237 patients (group A) who underwent lumpectomy alone, and in 271 patients (group B) treated by lumpectomy and CM excision. Patients with positive LM (group A) or CM (group B) underwent re-excision.

Results:

In the group A, 50/237 patients (21.1%) had LM+ and underwent re-excision. In the group B, 74/271 patients (27.3%) had LM+, but tumour was found within the CM specimen in 46 patients (17.0%), 24 LM+ and 22 LM-, and reached the CM cut edge in only 15 (5.5%), who finally underwent re-excision. Residual tumour was found in the re-excision specimen in 28/50 patients (56.0%) of the group A and in 7/15 patients (46.7%) of the group B.

Conclusions:

Separate CM excision strongly decreases the rate of re-operation for involved margin. However, the finding of various combinations of LM and CM status and the evidence that CM excision does not improve the positive predictive value of margin involvement suggest prudent conclusions. Only long term follow up of patients treated according to the CM status can exclude that the reduced rate of re-operations allowed by this procedure would expose to an increased risk of local recurrence.

INTRODUCTION

Breast conservation surgery (BCS) has been recognized to be as effective as mastectomy in terms of survival in patients with early breast cancer [START_REF] Fisher | Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer[END_REF][START_REF] Veronesi | Twenty year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer[END_REF]. However, patients who undergo BCS are exposed to a life-long risk of local recurrence [START_REF] Schnitt | Risk factors for local recurrence in patients with invasive breast cancer and negative surgical margins of excision: where are we and where are we going?[END_REF].

The evidence of a positive resection margin at histology, defined as the presence of tumour cells at the cut edge, indicates an incomplete tumour excision and significantly increases the risk of local recurrence, therefore mandating re-excision or mastectomy [START_REF] Singletary | Surgical margins in patients with early-stage breast cancer treated with breast conservation therapy[END_REF].

The traditional method for margins assessment involves inking of the lumpectomy specimen, which is oriented with sutures at the moment of excision, and evaluating microscopically if tumour cells are present at the inked cut edges. Following this procedure, however, in about half of the patients re-operated because of positive lumpectomy margins (LM) no residual tumour is found at histology of the re-excision specimen [START_REF] Cellini | Factors associated with residual breast cancer after reexcision for close or positive margins[END_REF][START_REF] Scopa | Evaluation of margin status in lumpectomy specimens and residual breast carcinoma[END_REF][START_REF] Dillon | A pathologic assessment of adequate margin status in breast-conserving therapy[END_REF][8]. The causes of this paradoxical finding are still not clear, but it has been suggested that some of the LM defined as positive are in fact "false positive", as a result of technical drawbacks such as shrinkage of the specimen, seeping of the ink into the specimen or dislocation of tumour cells towards the margins [9][10][11]. The separate excision of the cavity margins (CM) at the time of lumpectomy might overcome these drawbacks, and indeed it has been reported that this procedure reduces the finding of positive margins and, consequently, the need for reexcisions [11][12][13][14][START_REF] Jacobson | Do additional shaved margins at the time of lumpectomy eliminate the need for re-excision?[END_REF][START_REF] Tengher-Barna | Prevalence and predictive factors for the detection of carcinoma in cavity margin performed at the time of breast lumpectomy[END_REF][START_REF] Rizzo | The effects of additional tumor cavity sampling at the time of breast-conserving surgery on final margin status, volume of resection and pathologist workload[END_REF].

The aim of the present study was to evaluate the utility of separate CM excision, by comparing retrospectively the volume of surgical specimens, the frequency of re-operation for positive margins and the rate of residual tumour in the re-excision specimens in two series of patients with infiltrating breast cancer who underwent lumpectomy with or without separate CM excision. In addition, we investigated retraction of the surgical specimen, a potential cause of false positive LM, by assessing the volumetric changes of the specimen before and after surgical excision.

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PATIENTS AND METHODS

Patient selection and study design CM excision was introduced in our practice as a routine part of BCS in 2004. From January 2001 to December 2008, a total of 808 breast cancer patients underwent BCS in our institution: 400 had BCS without CM excision (period 2001-2004) and 408 underwent BCS with CM excision (period 2004-2008). Among these 808 patients, 300 were excluded from the study because of one of the following conditions: incomplete chart data, histological diagnosis of pure ductal carcinoma in situ, presence of non-palpable tumour or history of neoadjuvant treatment. Patients with non-palpable tumours were excluded because we usually do not perform separate CM excision in these cases.

The charts of remaining 508 patients with palpable invasive cancer were reviewed and the following data were collected: age at diagnosis, histotype, presence of extensive intraductal component (EIC), tumour size, histologic grade, nodal status, hormone receptor status, margin status, and volume of excised breast tissue. These 508 patients were subdivided in two groups: 237 patients without CM excision (group A) and 271 with CM excision (group B).

The volume of excised breast tissue was extracted from the gross description of the pathology report by multiplying the three main diameters of the specimen (lenght, width and height). In group B, the volume of separately excised CM was added to that of the lumpectomy specimen.

The status of the LM was assessed in all patients. Additionally, the status of the CM specimens was evaluated in patients of the B group. All margins were defined as positive when tumour cells were found at the cut edge of the specimen and negative when the cut edge was tumour-free, independently from the distance of tumour cells from the surface. The presence of tumour in the CM specimen was reported even if it did not reach the cut edge.

Re-operation (re-excision or mastectomy) was undertaken in the presence of one or more positive LM in group A and one or more positive CM in the group B.

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The mean volume of excised breast tissue, the status of margins, the rate of re-operation and the presence of residual tumour in re-excision specimens in the patients of the two groups were compared.

In order to investigate the degree of specimen retraction, the volume of the lumpectomy specimens was measured before excision and immediately after excision in a small group of 12 patients.

Surgery

Lumpectomy was performed aiming to obtain a rim of healthy tissue around the tumour of at least 1cm. In patients of the group B, the surface of the residual cavity was subdivided, depending on its shape, in two to four distinct sectors (usually medial, lateral, superior and inferior) and each sector was excised maintaining a uniform thickening of approximately 5mm. If excision did not reach the skin or fascia, additional superficial or deep CM were usually taken. In each CM sample, the outer surface was marked by a suture.

In patients selected for re-operation because of positive margins, re-excision comprised all the scar tissue. If conservative re-excision was not possible, a formal simple mastectomy was performed.

Assessment of variation of specimen volume

The degree of tissue retraction due to surgical excision was evaluated in 12 patients.

Since direct measurement of the volume of the specimen before excision was obviously impossible, we proceeded by measuring the three main diameters of the specimen (lenght, width and height) before and after excision. The estimated volume was calculated by multiplying the three diameters.

The pre-excision diameters were measured intraoperatively after skin and subcutaneous incision but before starting parenchymal dissection, by assessing the lenght and width of the specimen at the border of the planned parenchymal excision, while the height was recorded as the distance between the skin plane and the pectoral muscle at the site of operation.

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The same three diameters were measured immediately after lumpectomy on the specimen laying on its deep surface.

Pathology

At definitive histology of the lumpectomy specimen, performed after inking the margins, the tumour-margin distance was specified for the closest margin. Margins were defined as positive when invasive or intraductal cancer was found directly at the cut edge of the specimen. In group B, the pathologist examined each oriented CM specimen and reported if residual disease was found within the tissue specimen and if tumour cells were found at the outer cut edge of the specimens.

Statistical methods

Tumour characteristics of the two groups of patients were compared using the chi-square test for categorical variables and the t-test (or Mann-Whitney test) for continuous variables, as appropriate.

The association between the frequency of re-excision for positive margins (dependent variable) and a set of covariates (CM excision, age, histotype, presence of EIC, tumour size, histological grade, nodal status, hormone receptor status) was assessed by means of multivariate binary logistic regression (stepwise model selection). Age and tumour size were evaluated as continuous variables, while the other parameters were categorical variables. All tests were two-tailed. The alpha level of significance was set to 5%. All statistical analyses were performed using the SPSS 13.0 statistical package (SPSS Inc., Chicago, IL, USA).

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RESULTS

The mean age at diagnosis was 58.6 years (range 30-91) in group A and 58.3 years (range 18-88) in group B.

The clinicopathological characteristics of patients are reported in Table 1.

The mean volume of lumpectomy specimens was 110.7 cm 3 in group A and 101.2 cm 3 in group B.

In the latter, the mean volume of CM specimens was 16.2 cm 3 , so that the total mean volume of excised breast tissue was 117.4 cm 3 .

Findings at histology in the resection margins and re-excision specimens in the two groups of patients are summarized in Figure 1 and 2. Among the 237 patients of the A group, 187 (78.9%) had negative and 50 (21.1%) had positive LM (Figure 1). Among the 271 patients of the B group, 197 (72.7%) had negative and 74 (27.3%) had positive LM. In this group, residual cancer was found within the CM specimens in 46/271 (17.0%) patients, 24 out of the 74 patients with positive LM (32.4%) and 22 out of the 197 patients with negative LM (11.2%). Residual cancer in the CM was invasive in 31 (67.4%) cases and intraductal in 15 (32.6%) cases. Among these 46 patients, however, only 15 had tumour involvement of the outer cut surface of the CM specimens and therefore only 15/271 (5.5%) patients of the B group were finally considered to have positive CM (Figure 2).

Since the presence of positive margins indicated re-operation, a total of 65/508 (12.8%) patients underwent further surgery, which consisted of conservative re-excision in 40 patients and mastectomy in 25 patients. Re-operation was performed in 50/237 (21.1%) patients in the A group and in 15/271 (5.5%) patients in the B group. Therefore, CM excision was associated to a decreased frequency of second operations for positive margins (chi-square test p value: <0.0001). This finding was confirmed by multivariate analysis, since the risk of re-operation for positive margins significantly increases when CM excision is not performed (odds ratio [OR] = 5.97; 95% confidence interval [CI]= 3.49-10.20; p-value <0.0001). Among the tested covariates, the only other significant factor was age, since the risk of re-operation decreases with ageing (OR= 0.97; CI= 0.95-0.99; p-value= 0.006).

Residual cancer in the re-excision or mastectomy specimen was found in 35/65 patients (53.8%), and its frequency was similar in the two groups: 56.0% (28/50) in group A and 46.7% (7/15) in group B. In group A, residual cancer in the re-excision specimen was invasive in 19/28 (67.8%) and intraductal in 9/28 (32.2%). In group B, residual cancer found at re-operation was invasive in 5/7 (71.4%) and intraductal in 2/7 (28.6%).

Evaluation of the volume of the lumpectomy specimen before and after excision in 12 patients showed a reduction of all the diameters after excision (mean lenght: 76 vs 71 mm, mean width 54 vs 46 mm, mean height 37 vs 30 mm), leading to a 45% reduction of the mean estimated volume (151.8 vs 98.0 cm 3 ).

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DISCUSSION

We found that separate CM excision reduced the re-operation rate for involved margins from 21.1% (Group A) to 5.5% (Group B). The value of these findings has the limits of any retrospective study.

However, similar results are found if only patients with CM excision (group B) are considered, since 27.3% of them would have been re-excised on the basis of positive LM, whereas addition of CM excision reduced the actual re-operation rate to 5.5% (Figure 2). These results are consistent with those reported by other authors who compared the rate of involvement of LM and CM.

Although there were differences in the criteria used to define a margin as positive, they all found that CM excision led to a relevant decrease of re-excisions for positive margins [11 -17].

While reducing the incidence of margin positivity, however, CM excision does not improve the predictive value of involved margin on the status of the surrounding breast tissue. In fact, the incidence of residual cancer the re-excision specimen was similar in the two groups (Figures 1 and2).

Explanations of why the separate excision of a thin rim of tissue from the residual cavity after lumpectomy decreases so impressively the finding of margin involvement can only be speculative.

The simplest hypothesis is that addition of CM excision to lumpectomy increases the volume of removed tissue, finally leading to a wider excision. However, the average thickness of CM in our series was only 5 mm and the average volume of excised tissue in patients with or without CM excision was not significantly different (117.4 and 110.7 cm 3 , respectively). Moreover, if we examine the consequences of additional CM excision in the 74 patients of the B group with positive LM (Figure 2), we find that it allowed radicalization of an incomplete tumour removal only in 9/74 (12.2%) patients, those with a positive LM who had residual tumour within the CM specimens that did not reach the outer cut edge. In the other 65 patients with positive LM, CM excision did not contribute to eradicate residual tumour since in 15/74 (20.3%) the cut edge of CM specimen was also involved and re-excision was required, while in 50/74 (67.6%) patients no residual tumour was found in the CM specimens.

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10 An alternative hypothesis is that separate excision of the CM decreases the rate of margin positivity because it overcomes the problem of false positive LM. In fact, it has been suggested that in some cases the involvement of LM found at histology is a false positivity due to technical drawbacks. In some cases, handling of the specimen could displace tumour cells toward the margins, especially if the tumour is friable and the specimen undergoes radiography with compression [10]. Conversely, ink may seep into the specimen through defects on the surface, especially in fatty specimens [11].

Finally, tissue retraction which normally follows the detachment of the specimen from the surrounding tissues brings the cut edges closer to the tumour, so that the tumour-margins distance measured by the pathologist is smaller than the true in vivo distance [9]. We investigated this last mechanism in a little group of patients by assessing the volume of the excision specimens before and after surgery, and found that the excised specimens lost approximately 45% of their original volume. Separate CM excision might overcome the problem of false positive LM, since CM are removed and processed separately from the lumpectomy specimen. Of course, CM specimens are themselves exposed to the same technical drawbacks, so that the outer CM cut edge could be erroneously classified as positive. This hypothesis could contribute to explain why, in our series, no tumour has been found in the CM specimens of 50/74 patients (67.6%) with positive LM, and why 8/15 patients (53.3%) with positive CM (tumour at the ink) who underwent re-operation had no residual tumour in the re-excision specimen (Figure 2). Finally, a third hypothesis is that CM examination might fail to recognize residual tumour foci scattered at various distance from the index lesion in patients with multifocal tumours, leading to a false negative diagnosis. In fact, the probability to recognize additional foci which are not in continuity with the main tumour is proportional to their number and density in the peritumoural area and to the extent of tissue that is excised and examined by the pathologist. This hypothesis could explain why in our series the incidence of residual tumour within the narrow (5 mm) CM specimens in patients with positive LM in the B group (24/74= 32.4%)was significantly lower than that found in much wider re-excision specimens in patients with positive LM in the A group (28/50= 56.0.8%)

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ACCEPTED MANUSCRIPT 11 (p=0.014). Clearly, this hypothesis implies that in patients with multifocal tumours, separate CM examination tends to underestimate the presence of additional cancer foci, increasing the rate of false-negative diagnosis and the potential risk of local recurrence.

In our opinion, all these mechanisms could play a role to explain the dramatic reduction of marginal positivity and re-operation rate observed with CM excision.

In order to discuss the role of LM and CM examination in patients submitted to BCS, it must be remembered that many breast cancer are multifocal. Holland et al. clearly demonstrated on 282 mastectomy specimens that cancerous foci were present around the main tumour in 63% of cases and that in 43% of cases these foci were beyond 2 cm from the reference mass [START_REF] Holland | Histologic multifocality of Tis, T1-T2 breast carcinomas. Implications for clinical trials of breast-conserving surgery[END_REF]. These results were confirmed by further similar studies [START_REF] Vaida | Multicentricity of breast cancer: whole organ analysis and clinical implications[END_REF].

Our findings support the relevant frequency of multifocal tumours. In fact, 22/46 (47.8%) patients with residual tumour in the CM specimens had negative LM (Figure 2), suggesting that the residual foci were not in continuity with the index lesion. In no one of these patients the tumour involved the outer cut edge of the CM specimen, so they did not undergo re-excision and we have no data on the presence of further cancer foci in the residual breast.

For practical purposes, we can schematically consider the following scenarios. a-Lumpectomy leads to complete excision of a unifocal tumour. In this case, both LM and CM should be disease-free (Fig. 3a). However, artefacts due to specimen retraction or others technical drawbacks could lead to false-positive LM in some patients: in these cases, the absence of residual tumour in the CM specimens could correctly avoid a useless re-excision (Figure 3b). b-Lumpectomy does not completely remove a unifocal tumour, but addition of CM radicalizes the tumour excision. In this case LM are positive and residual tumour is found in the CM specimens, but it does not involve the CM cut edge (unless CM false positivity for technical drawbacks) and a useless re-operation is therefore avoided (Figure 3c). c. Nor lumpectomy neither CM excision completely remove an unifocal tumour. In this case, the finding of positive LM and involvement of CM cut edge correctly indicate re-excision (Figure 3d).

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The possible scenarios in patients with multifocal tumours are more complex.

In these cases the status of LM, as well as that of CM, cannot reliably discriminate between the presence and the absence of residual tumour in the surrounding gland.

Negative LM and CM could indicate that lumpectomy completely removed a multifocal tumour (Figure 4a). However, negative margins cannot exclude that residual foci persist beyond the excised area (Figure 4b). Residual foci can be found in the lumpectomy specimen, at the LM, in the CM specimens or at CM cut edge and their position within the excised tissues is casual and gives no reliable information on the status of the residual breast (Figure 4 b-d). These view is consistent with the results of several studies which report that initially negative margins do not exclude nor the possibility that residual tumour is found at re-excision [START_REF] Scopa | Evaluation of margin status in lumpectomy specimens and residual breast carcinoma[END_REF][START_REF] Hewes | Importance of routine cavity sampling in breast conservation surgery[END_REF] neither the risk of local recurrence [START_REF] Singletary | Surgical margins in patients with early-stage breast cancer treated with breast conservation therapy[END_REF][START_REF] Peterson | Outcomes in breast cancer patients relative to margin status after treatment with breast-conserving surgery and radiation therapy: the University of Pennsylvania experience[END_REF]22].

However, CM status could give some information even in the presence of multifocal disease, since the probability of finding additional foci in the CM specimen is proportional to the number of foci: therefore, absence of residual tumour in the CM specimen suggest that if additional foci persist beyond the excised area, their burden should be minimal and therefore they have a high probability to be sterilized by radiotherapy.

In conclusion, it is clear that only mastectomy can guarantee the complete excision of breast tumours, because many of them have additional foci at various and unpredictable distance from the main tumour mass. BCS is a practicable choice because postoperative radiotherapy can sterilize in most cases minimal residual foci, leading to the acceptably low rate of local recurrence evidenced by log-term results of large clinical trials. The aim of BCS should be to completely excise unifocal tumours and to remove as much tumour as possible in patients with multifocal lesions. Margin evaluation can definitely help to achieve the first goal, while in the case of multifocal tumours their usefulness is limited. Separate CM excision leads to a relevant decrease of re-operation after BCS and probably overcomes the problem of false-positive LM. However, long term results are required in order to exclude that this procedure exposes to an increased risk of local recurrence.

Figure 1 -Figure 2 -Figure 3 -Figure 4 -

 1234 Figure 1 -Flow diagram summarising margin status and surgical treatment in 237 patients who

  Figure 1

Table 1 -

 1 Features of patients who underwent lumpectomy alone (group A) or lumpectomy followed by separate cavity margins excision (group B) compared by means of chi-square (categorical variables) or Mann-Whitney (continuous variables) test

	Variables

* = chi-square ^ = Mann-Whitney


M Moschetta

A A Stabile Ianora

A Marzullo

A Scardapane

G Angelelli

Stabile Ianora Aa

Moschetta Marco
email: marco.moschetta@gmail.com

Vessel probe CT protocol in the study of esophageal carcinoma: can it improve preoperative

Keywords:

Vessel probe CT protocol in the study of esophageal carcinoma: can it improve preoperative T staging?

Introduction

Esophageal carcinoma is relatively rare and represents the ninth most common cancer in industrialized countries, with an incidence of 3-4/100 000 persons. In Europe and United States it represents approximatively 1% of all malignancies and the sixth leading cause of death related to cancer [START_REF] Brown | Incidence of adenocarcinoma of the esophagus among white Americans by sex, stage, and age[END_REF][START_REF] Parker | Cancer Statistics[END_REF]. About 90% of esophageal tumors consist of carcinomas, with a 40-60% incidence for squamous cell forms (SCC) and 30-50% for adenocarcinomas of the esophago-gastric junction (AEG), with the latest representing 80% of tumors arising from Barrett's esophagus [START_REF] Bollschweiler | Demographic variations in the rising incidence of esophageal adenocarcinoma in white males[END_REF][START_REF] Yousef | The incidence of esophageal cancer and highgrade dysplasia in Barrett's esophagus: a systematic review and meta-analysis[END_REF]. The prognosis of patients with esophageal cancer depends on the stage of disease at the time of diagnosis. An accurate evaluation of both depth of esophageal wall invasion and lymph node and distant organ involvement is crucial for choosing an optimal therapeutic strategy, also considering the possibility of preoperative chemo-radiotherapy and individualized treatments. Surgery remains the main therapeutic option and accurate preoperative staging is important to increase the survival of these patients [START_REF] Fiore | Multimodal imaging of esophagus and cardia cancer before and after treatment[END_REF]. For the staging of esophageal cancer, endoscopy is used to detect visceral wall abnormalities. At the moment, endoscopic ultrasonography (EUS) is the most common way of evaluating the T parameter; however, this technique is invasive [START_REF] Panebianco | 3D CT protocol in the assessment of the esophageal neoplastic lesions: can it improve TNM staging?[END_REF]. Computed tomography (CT) yields useful information on tumor location, size, extension and surgical resectability. The depth evaluation of mural invasion is also improved with clinical application of multidetector CT (MDCT) and multiplanar reconstructions (MPR) [START_REF] Panebianco | 3D CT protocol in the assessment of the esophageal neoplastic lesions: can it improve TNM staging?[END_REF]. As far as we know, no study has evaluated vessel probe (VP) reconstructions in the T staging of esophageal carcinoma, although it has been recently performed in the gastric cancer staging as a rapid and automatic software which generates accurate imaging of the gastric wall layers in the lesion site with high spatial and contrast resolution and simultaneously in multiple planes [START_REF] Moschetta | Preoperative T staging of gastric carcinoma obtained by MDCT vessel probe reconstructions and correlations with histological findings[END_REF]. The aim of this study is to evaluate the diagnostic accuracy of 16-row MDCT in the preoperative T staging of esophageal cancer and to compare T staging findings obtained by transverse images and VP in MPR mode reconstructions with histology. diagnosis was based on histological examination on needle biopsies during endoscopy, CT and EUS findings and broncoscopy. In all cases histology confirmed the malignant nature of the lesions: 18 cases proved to be SCCs and the remaining 13 were AEGs. Histological T staging was based on the international TNM classification as defined by the American Joint Committee on Cancer, shown in Table 1 [START_REF] Green | AJCC cancer staging manual[END_REF].

CT protocol

All studies were performed using 16-slice CT (TSX-101A-Aquilion, Toshiba Medical System, Tochigi, Japan). Unenhanced MDCT was not performed. Shortly before CT scanning (approximatively 20 s) patients ingested 7 g of effervescent granules (Duogas, Bracco, Milan, Italy) that generate CO2 with a small amount of water. We did not administer any antiperistaltic drug and an optimal esophageal distension was reached and well tolerated in all cases. Contrast-enhanced MDCT images were obtained after intravenous injection of iodinated contrast material (Iomeron 400; Bracco, Milan, Italy) into a cubital vein using a 16-18 G needle and an automatic injector

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(MK-IV, Medrad, Pittsburgh, PA) at a dose of 1.5 ml/kg body weight and injection rate of 3.5 ml/s. A biphasic technique was used, with CT acquisition performed in the arterial and portal venous phases (mean start delay of 35 s for the arterial and 70 s for the portal phase) with the following parameters: slice thickness 1 mm; increment 0.8 mm; pitch 1.75; rotation time 0.5 s; 120/250 KVp/mAs. CT images were obtained with patients in the supine position during a single breath hold in full inspiration. CT data were acquired from neck to lower pole of the kidneys in the arterial phase and from neck to the pubic symphysis in the portal phase, for complete tumor staging. The entire procedure was performed within 15 minutes. All MDCT data were transferred to a workstation (HP XW 6400) equipped with dedicated software (Vitrea 4.1, Vital Images, Minneapolis, MN) for image reconstructions. The post-processing programme used was VP in MPR mode. Arterial phase was used to evaluate the T staging in order to take advantage of the maximum enhancement of the esophageal wall, which is crucial to use VP software. VP is a programme that allows vessels to be simultaneously examined in 3D, curved reformat and crosssectional reformat views. It can study and measure arteries from between 0.5 and 18 mm in diameter and calculate the degree of stenosis. It can display images in a variety of formats, including automatic and simultaneous orthogonal cross-sections, orthogonal MPR, oblique and curved MPR, 3D and curved reformat views [START_REF] Moschetta | Preoperative T staging of gastric carcinoma obtained by MDCT vessel probe reconstructions and correlations with histological findings[END_REF]. This fast and simple to use software can also be useful for examining the esophageal wall on contrast-enhanced MDCT, clicking on the lesion site.

Starting from simple transverse images, VP in MPR mode automatically generates a reference line along the major axis of structures with the maximum enhancement values and displays the best views in multiple curved planes. It also explores the whole thickness of the visceral wall and adjacent structures, which can be useful for preoperative T staging.

Image Analysis

Each examination was evaluated independently by two abdominal radiologists (GA, AASI) with more than 10 years experience in abdominal CT and image reconstruction. They were aware that all patients had proven esophageal cancer, but they were blinded to the endoscopic results, tumor

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6 location, size and morphological features. A final diagnosis was reached by consensus. The two radiologists evaluated transverse CT images and VP in MPR mode reconstructions in two different sessions, at an interval of 10 days, in a random order. The entire image analysis was performed within 15 minutes per patient. Images were assessed for the presence and site of lesion, thickness, appearance and density of the esophageal wall at the lesion site, depth of visceral wall invasion, morphology of periesophageal fat and infiltration of mediastinal organs. In accordance with literature on CT criteria for T staging, focal thickening greater than 3 mm was considered to indicate a neoplastic lesion [START_REF] Ba-Ssalamah | Dedicated multi-detector CT of the esophagus: spectrum of diseases[END_REF]. Good, intermediate and poor tumor enhancement indicated respectively higher attenuation, isoattenuation and lower attenuation compared with the adjacent normal esophageal wall. T staging obtained by MDCT was based on the international TNM classification, as shown in Table 1 [START_REF] Ba-Ssalamah | Dedicated multi-detector CT of the esophagus: spectrum of diseases[END_REF]. MDCT staging was then compared with histological evaluation.

Statistical Analysis

Sensitivity and diagnostic accuracy values were calculated for axial images alone or in combination with VP in MPR mode reconstructions. The chi-square test was used to compare categorical variables and proportions. A two-tailed probability (P) value of less than 0.05 was considered to indicate a statistically significant difference. In order to evaluate the interobserver agreement between the two readers and the diagnostic reliability of the technique, Cohen's kappa (k) test was used. A k value of more than 0.81 was considered to represent almost perfect agreement and values of 0.61-0.80 and 0.41-0.60 to represent substantial and moderate agreement, respectively. All calculations were performed using NCSS2007® statistical software.

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Results

Detection of primary tumor

All esophageal lesions were detected both in transverse images and VP in MPR mode reconstructions. Neoplasia were identified as pathological wall thickening, measuring between 5.5 and 30 mm (mean 12 mm), with a 10-80 mm longitudinal extension. In 29 out of 31 cases high enhancement was demonstrated at the arterial phase of contrast-enhanced CT examination, while in two patients poor enhancement was found at the lesion site. Eight presented polypoid morphology, 15 infiltrating and 8 presented ulcerative pattern. No case of "early cancer" was detected.

Depth of tumor penetration

The comparison between T radiological and histopathological staging is summarised in Table 2.

In 19 patients who underwent surgical treatment, at histopathological examination 7 were staged as pT2 (fig. 1) and 12 as pT3 (fig. 2). Twelve patients who underwent palliative treatment were staged as T4 because of the invasion of the tracheobronchial tree in 4 cases, aortic invasion in two (fig. 3) and tumor extension to the proximal portion of the stomach in the last six cases. Sensibility, negative predictive value (NPV) and overall diagnostic accuracy values of T staging with axial images were 67%, 64% and 79%, respectively, which improved to 83%, 78% and 89% with VP in MPR mode reconstructions (P < 0.05). Specificity and positive predictive value (PPV) of 100% was found for both axial images and VP in MPR mode reconstructions. With transverse images understaging occurred in four patients, whereas with VP images in two cases. Particularly, on transverse images 4 T3 forms were understaged: in 2 cases, irregular outer border of the esophageal wall was not detected; in the remaining 2 patients, small linear strands of soft tissue extending into the periesophageal fat were not recognized. The use of VP in MPR mode reconstructions allowed only 2 T3 carcinomas to be understaged, because of an inhomogeneous and poor enhancement at the lesion sites which did not allow lightly irregular outer border of the esophageal wall to be demonstrated. They were two patients affected by pT3 AEG arising from Barrett's metaplasia with a high mucin content.

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8 Almost perfect agreement between the two readers was found (k=0.83).

Discussion

Diagnostic imaging of esophageal carcinoma

Esophageal carcinoma has a survival rate of 5% at 5 years and poor prognosis is due to high infiltrative tendency towards mediastinal organs and high incidence rate of haematic and lymph node metastases [START_REF] Wayman | Evaluation of local invasion by esophageal carcinoma: prospective study of prone computed tomography scanning[END_REF][START_REF] Holscher | Staging of squamous esophageal cancer: accuracy and value[END_REF]. Accurate preoperative staging of esophageal cancer is essential for the planning of optimal therapy and could influence the survival rate. Therefore, EUS, CT, magnetic resonance imaging (MRI), positron emission tomography (PET) and PET-CT can be performed.

EUS allows to depict the internal structure of the esophageal wall, the tumor penetration can be demonstrated with excellent detail and it can guide fine needle aspiration cytology confirmation [START_REF] Wu | Preoperative TN staging of esophageal cancer: comparison of miniprobe ultrasonography, spiral CT and MRI[END_REF]. In the evaluation of T parameter, EUS has a diagnostic accuracy rate of 52%-92%, but this technique is operator-dependent, with a restricted field of view and it cannot evaluate haematic and lymph node metastases. In addition, often the instrument cannot go beyond lumen strictures caused by tumor growth [START_REF] Ligresti | Diagnosis of esophagogastric tumours[END_REF][START_REF] Sandha | Is positron emission tomography useful in locoregional staging of esophageal cancer? Results of a multidisciplinary initiative comparing CT, positron emission tomography and EUS[END_REF][START_REF] Munro | Oesophageal cancer: a view over overviews[END_REF]. MRI presents the same diagnostic capability as CT, although some experiences have reported sensibility and specificity values of 100% and 84% respectively for MRI and 100% and 80% respectively for CT in the evaluation of the mediastinal invasion [START_REF] Wu | Preoperative TN staging of esophageal cancer: comparison of miniprobe ultrasonography, spiral CT and MRI[END_REF][START_REF] Takashima | Carcinoma of the esophagus: CT vs MR imaging in determining respectability[END_REF]. PET and PET-CT has demonstrated diagnostic accuracy values of 48-90% in the staging of esophageal cancer. However, these techniques are mostly used in case of advanced forms, especially for evaluating the response to combined chemo-and radiotherapic treatments [START_REF] Sandha | Is positron emission tomography useful in locoregional staging of esophageal cancer? Results of a multidisciplinary initiative comparing CT, positron emission tomography and EUS[END_REF][START_REF] Vinjamuri | Added value of PET and PET-CT in oesaophageal cancer: a review of current practice[END_REF][START_REF] Bruzzi | PET-CT of esophageal cancer: its role in clinical management[END_REF].

CT staging of esophageal carcinoma

Despite the advantages of the different techniques, MDCT currently remains the most commonly used examination in preoperative esophageal cancer staging because it allows to rapidly and non invasively evaluate the local extension of the tumor and to detect lymph adenopathies and distant metastases, with overall diagnostic accuracy values of 59-82% [START_REF] Panebianco | 3D CT protocol in the assessment of the esophageal neoplastic lesions: can it improve TNM staging?[END_REF][START_REF] Wu | Preoperative TN staging of esophageal cancer: comparison of miniprobe ultrasonography, spiral CT and MRI[END_REF][START_REF] Sandha | Is positron emission tomography useful in locoregional staging of esophageal cancer? Results of a multidisciplinary initiative comparing CT, positron emission tomography and EUS[END_REF][START_REF] Weaver | Comparison of special interest computed tomography, endosonography and histopathological stage of oesophageal cancer[END_REF][START_REF] Umeoka | Esophageal Cancer: Evaluation with Triple-Phase Dynamic CT-Initial Experience[END_REF][START_REF] Bonavina | Clinical outcome and survival after esophagectomy for carcinoma in elderly patients[END_REF]. In the preoperative staging of T parameter, CT reliability depends on the depth of tumor invasion. In fact,

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9

CT reliability is lower in detecting stages from T1 to T3 because CT examination does not allow to define intramural invasion, while sensibility values of 83-100% and 92-100% have been reported respectively for the definition of tracheo-bronchial tree and aortic-pericardial infiltration [START_REF] Wayman | Evaluation of local invasion by esophageal carcinoma: prospective study of prone computed tomography scanning[END_REF][START_REF] Kumbasar | Carcinoma of esophagus: radiologic diagnosis and staging[END_REF].

Vessel probe CT protocol

In our experience, the role of MDCT in the staging of esophageal carcinoma is globally confirmed, but new data emerge from the use of VP in MPR mode reconstructions in the T staging. This programme allows good detail of the esophageal wall architecture to be obtained after intravenous injection of contrast material and it can improve the diagnostic accuracy in the evaluation of tumor invasion depth by analysing wall enhancement at the lesion site [START_REF] Moschetta | Preoperative T staging of gastric carcinoma obtained by MDCT vessel probe reconstructions and correlations with histological findings[END_REF]. VP has significantly increased diagnostic accuracy (89%), sensibility (83%) and NPV (78%) in the definition of T parameter compared with CT transverse images (79%, 67% and 64%, respectively) and interobserver variation was low between the two observers, indicating that the reader experience was not a significant parameter and that this technique had good diagnostic reproducibility. In fact, the number of understaging errors has been reduced using VP in MPR mode reconstructions and this software could increase the reliability of MDCT in differentiating T2 from T3 forms [START_REF] Wu | Preoperative TN staging of esophageal cancer: comparison of miniprobe ultrasonography, spiral CT and MRI[END_REF][START_REF] Weaver | Comparison of special interest computed tomography, endosonography and histopathological stage of oesophageal cancer[END_REF].

However, the difficulty in distinguishing tumoral invasion of perilesional fat from desmoplastic reaction persists [START_REF] Korst | Imaging for esophageal tumours[END_REF]. Besides, obliteration of mediastinal fat layers is reported to be an important CT finding of neoplastic spread beyond the esophageal wall, consequently distinguishing between T3 and T4 forms [START_REF] Fiore | Multimodal imaging of esophagus and cardia cancer before and after treatment[END_REF]. In our series, T4 carcinomas have been correctly staged by using both transverse images and VP in MPR mode reconstructions, although it can be supposed that VP could facilitate the detection of advanced forms, thanks to the possibility of immediately and simultaneously examining the contact area between the tumor and mediastinal organs in different axial and longitudinal planes, one perpendicular to each other. Particularly, longitudinal extension of the contact surface between the tumor and aorta could represent a further useful criterion for predicting aortic invasion, in addition to the classic standard reference of measuring contact area in degrees on axial images, especially in case of 45 to 90º contact surfaces [START_REF] Umeoka | Esophageal Cancer: Evaluation with Triple-Phase Dynamic CT-Initial Experience[END_REF][START_REF] Kumbasar | Carcinoma of esophagus: radiologic diagnosis and staging[END_REF][START_REF] Iyer | Imaging of esophageal cancer[END_REF]. In fact, the greater the craniocaudal extension of the tumor, the more likely it is to be a case of T4, as already reported for EUS, which predicts advanced carcinomas thanks to longitudinal extensions of more than 5 cm [START_REF] Bhutani | Length of esophageal cancer and degree of luminal stenosis during upper endoscopy predict T stage by endoscopic ultrasound[END_REF]. Therefore, it can be supposed that VP in MPR mode reconstructions could facilitate the detection of tracheo-bronchial tree invasion, but further research is needed in this field. The use of VP in MPR mode reconstructions only needs the esophageal walls to be adequately distended by air and, as suggested by Umeoka et al [START_REF] Umeoka | Esophageal Cancer: Evaluation with Triple-Phase Dynamic CT-Initial Experience[END_REF], an arterial phase at 35 s to be performed because of the tumor's hypervascularity and neovascularity. In our study protocol, esophagus has been distended by effervescent powder 20 s before CT scanning in arterial phase and a marked difference in attenuation has been obtained between the lumen and the walls which is essential for the correct application of VP software. In fact, in 94% of patients high enhancement values have been detected at the lesion sites and it could be supposed that the two understaging errors by VP in MPR mode reconstructions can be due to the low enhancement at the lesion sites which negatively influences image post-processing and probably can vary basing on the different histological patterns. These two cases were demonstrated to be pT3 AEGs arising from distal Barrett's esophagus, which have been already decribed as the most difficult forms to be detected because of a high mucin content and a consequent different enhancing pattern on enhanced MDCT examination compared with SCCs [START_REF] Moschetta | Preoperative T staging of gastric carcinoma obtained by MDCT vessel probe reconstructions and correlations with histological findings[END_REF][START_REF] Umeoka | Esophageal Cancer: Evaluation with Triple-Phase Dynamic CT-Initial Experience[END_REF]. In conclusion, 16 row MDCT represents an accurate tool in the preoperative T staging of esophageal carcinoma. In case of T2 and T3 esophageal carcinoma, the use of fast, easy and automatic VP in MPR mode reconstructions increase the diagnostic accuracy compared with transverse images for the evaluation of local extension of the disease which is crucial for the choice of surgical or alternative treatments.

Limitations

However, our study has some limitations represented by the short number of studied patients; absence of T1 forms and impossibility of having a comparison between CT and EUS in T2 and T3 staging. Therefore, further studies with larger number of patients and CT systems with more than

Pathologic TNM staging system developed by the American Joint Committee on Cancer (2002) and MDCT Criteria for T staging of gastric cancer (2009).

Table 2.

MDCT findings compared with histopathological results for each T stage. Esophageal carcinoma located at the middle third in a 65 year-old-man (T4). Transverse CT scan demonstrates irregular concentric thickening of the esophageal walls (arrowhead). Tumor invades the aorta with a circumferential adhesion area of more than 90º. VPs in MPR mode reconstructions confirm this finding in multiple oblique and longitudinal planes with a better evaluation of the contact area's extension between tumor and the aorta (arrows).

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  and August 2009, 31 patients (23 men and 8 women, aged 42-75 years, mean age 63.2 years) with endoscopic diagnosis and histologically proven esophageal cancer underwent 16-row MDCT examination 7 days after conventional endoscopy for preoperative staging. This study was approved by the institutional review board and written informed consent was obtained from all patients according to the Declaration of Helsinki principles. Tumor was located on the upper third (n= 3), middle third (n=15) or lower third (n=13). No cases of distant metastases occurred. Within two weeks of MDCT examination, 19 patients underwent surgical resection (esophagectomy). The resected organ was histologically evaluated to determine tumor penetration and depth and pathological findings served as the reference standard. Twelve patients affected by advanced cancer were treated with chemo-radiotherapy and subsequently with palliative esophageal stenting because of local extension of the disease. In these last patients, definitive

  and to evaluate the response to chemo-radiotherapy in patients with advanced forms.

Figure 1 .

 1 Figure 1.

Figure 2 .

 2 Figure 2.

Figure 3 .

 3 Figure 3.

Conflict of interest statement. The authors declare that they have no conflict of interest to the publication of this article. MDCT findings compared with histopathological results for each T stage.

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S W Nienhuijs

Hjt Rutten

Ejt Luiten

O J Repelaer Van Driel

Phm Reemst

Vepp Lemmens

MD Ihjt De Hingh

REDUCTION OF IN-HOSPITAL MORTALITY FOLLOWING REGIONALIZATION OF PANCREATIC SURGERY IN THE SOUTH-EAST OF THE NETHERLANDS

Keywords:

Background: In the late nineties of the former century, surgery for pancreatic and periampullary cancer in the southern part of The Netherlands was performed mainly in lowvolume hospitals (<5 resections/year). Results reported by the Comprehensive Cancer Center South (CCCS) in 2005 revealed the clearly disappointing results of this practice. The former stimulated the regionalization of pancreatic surgery by 3 collaborating surgical units into one non-academic teaching hospital in the eastern part of the CCCS-region starting from July 2005.

Methods: All of the 76 patients in this regional cohort group in whom a resection of a (peri-)pancreatic tumour was performed with curative intent have been followed up prospectively. The results of surgical morbidity and in-hospital mortality were compared with the results of the CCCS cohort group which were reported previously.

Results:

Ever since the regionalization the annual number of patients undergoing resection of a pancreatic tumour increased from 10 to 33, resulting in a total number of 76 patients.

Postoperative complications, reoperation rate and in-hospital mortality decreased significantly to 34,2%,18,4% and 2.6% respectively, as compared to 71,9%, 37,8 and 24,4% in the time period before regionalisation (p<0.01).

Conclusion:

These unique comparative prospective data derived from daily practice in a collaborative surgical region in The Netherlands (CCCS) support the need for centralisation of pancreatic surgery in order to improve standard of care in pancreatic surgery. This can be achieved by collaboration in a large regional hospital.

Introduction

Surgical resection is currently the only potential curative treatment available for patients diagnosed with localized pancreatic cancer. However, surgery for pancreatic cancer is challenging and usually regarded as a "high-risk procedure". During the last decade, several authors have reported that surgery-related mortality and morbidity can be reduced significantly when performed in high-volume centers [START_REF] Gordon | The Effects of Regionalization on Cost and Outcome for One General High-Risk Surgical Procedure[END_REF][START_REF] Lieberman | Relation of Perioperative Deaths to Hospital Volume Among Patients Undergoing Pancreatic Resection for Malignancy[END_REF][START_REF] Glasgow | Hospital Volume Influences Outcome in Patients Undergoing Pancreatic Resection for Cancer[END_REF][START_REF] Sosa | Importance of Hospital Volume in the Overall Management of Pancreatic Cancer[END_REF][START_REF] Simunovic | Relation Between Hospital Surgical Volume and Outcome for Pancreatic Resection for Neoplasm in a Publicly Funded Health Care System[END_REF]. In spite of the aforementioned, referral patterns of patients with operable pancreatic cancer have not changed impressively since. Up to today many patients are still treated in low-volume centres with varying results [START_REF] Van Heek | Hospital Volume and Mortality After Pancreatic Resection: a Systematic Review and an Evaluation of Intervention in the Netherlands[END_REF][START_REF] Riall | Trends and Disparities in Regionalization of Pancreatic Resection[END_REF][START_REF] Topal | Effect of Centralization of Pancreaticoduodenectomy on Nationwide Hospital Mortality and Length of Stay[END_REF][START_REF] Balzano | Effect of Hospital Volume on Outcome of Pancreaticoduodenectomy in Italy[END_REF].

In the southern part of The Netherlands, 10 hospitals spread over 17 locations each serving a population between 150.000-250.000 people are joined in the Comprehensive Cancer Center South (CCCS). Until recently, no official referral center for pancreatic surgery was appointed. Pancreatic surgery used to be performed in 8 hospitals, none of them performing more than 4 resections a year. In an effort to determine the need for regionalization of pancreatic surgery, the CCCS reviewed the quality of surgery for pancreatic cancer delivered from 1995-2000 [START_REF] Van Oost | Outcome of Surgical Treatment of Pancreatic, Peri-Ampullary and Ampullary Cancer Diagnosed in the South of The Netherlands: a Cancer Registry Based Study[END_REF]. The results were reported in 2005 and demonstrated a disappointing 24% overall postoperative mortality after pancreatic surgery.

In an effort to improve the quality of surgical care for pancreatic cancer, collaboration by regionalization was initiated in the eastern part of the CCCS-region shortly thereafter. The latter was accomplished by establishing a team of 5 dedicated surgeons from 3 collaborating surgical departments. These faculty level surgeons are all certified oncological surgeons with special interest in abdominal oncology and were all responsible for pancreatic surgery in their own hospital prior to regionalisation. All procedures involving the pancreas were performed by at least 2 surgeons from this team. Initial pre-operative work-up was performed by the referring hospital. However, all surgical procedures and postoperative care was concentrated in one single hospital (Catharina Hospital Eindhoven), while it was abandoned in the hospitals joining regionalization. The results of this procedure are reported in this prospective study.

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Methods:

In order to analyse the impact of regionalisation of pancreatic surgery on surgical outcome, results with regard to postoperative morbidity and mortality before regionalisation (period A: January 1995 until April 2000) were compared with similar data prospectively collected from the start of regionalisation (period B). Results with regard to period A have been reported previously in 2006 which were derived from the population based database of the CCCS [START_REF] Van Oost | Outcome of Surgical Treatment of Pancreatic, Peri-Ampullary and Ampullary Cancer Diagnosed in the South of The Netherlands: a Cancer Registry Based Study[END_REF].

Similarly as for period A, data of all patients from July 2005 to July 2009 (period B), diagnosed and operated on for a (pre-)malignant tumour of the pancreas, Vater's ampulla or the extra-hepatic ducts were collected prospectively. Cholangiocarcinomas of the upper main bile duct, necessitating a Klatskin-type resection as well as duodenal tumours were excluded. All of these patients were operated on in the Catharina Hospital Eindhoven by a regional surgical team of 5 dedicated oncologic surgeons. Primary endpoint was in-hospital mortality defined as mortality before discharge to the patient's home, a nursing home or rehabilitation centre. The recently published ISGPS-definitions were used for scoring of postoperative complications [START_REF] Wente | Delayed Gastric Emptying (DGE) After Pancreatic Surgery: a Suggested Definition by the International Study Group of Pancreatic Surgery (ISGPS)[END_REF][START_REF] Wente | Postpancreatectomy Hemorrhage (PPH): an International Study Group of Pancreatic Surgery (ISGPS) Definition[END_REF][START_REF] Bassi | Postoperative Pancreatic Fistula: an International Study Group (ISGPF) Definition[END_REF].

Statistics

Categorical variables were expressed in numbers and/or proportions. Continuous variables were provided with median value and range. The Fisher's exact test was used to analyze categorical data. A p-value less than 0.05 was considered statistically significant. For the present series actual survival rates were calculated. Numbers of survivors and at risk per follow-up were provided. Follow-up was completed until July 2009.

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Results

Patients and referral pattern

Before regionalisation (period A), 82 patients underwent a resection for a pancreatic tumour in the CCCS-region. These resections were performed in 8 hospitals. None of the hospitals performed more than 4 resections per year at that time. Regionalisation in the south-eastern part of the CCCS-region started in July 2005 (period B) when surgeons from 2 surgical departments joined efforts for patients with pancreatic cancer. During the first year in total 10 pancreatic resections for malignancy were performed. Shortly thereafter, neighbouring hospitals started to refer patients with pancreatic cancer to our hospital. In total 10 hospitals, all within the CCCS-region have referred at least 1 patient since the regionalisation. In January 2008 two surgeons from a third hospital joined the pancreatic team. Subsequently the number of pancreatic resection increased to 33 in the most recent year, leading to 76 resections for pancreatic cancer in this period (B).

Characteristics

Patient and tumour characteristics are comparable for before and after regionalisation (Table 1).

Morbidity and mortality

The results with regard to both operative and postoperative morbidity and mortality are demonstrated in table 2. The results concerning period A were published previously [START_REF] Van Oost | Outcome of Surgical Treatment of Pancreatic, Peri-Ampullary and Ampullary Cancer Diagnosed in the South of The Netherlands: a Cancer Registry Based Study[END_REF].

Peroperative complications, mainly comprising haemorrhage (9.8 vs. 3.9%) occurred less in patients operated by a regional surgical team although not statistically different (p=0.21).

The number of re-operations decreased significantly: 31 re-operations (38%) before and 14 Postoperative in-hospital mortality was significantly reduced following regionalisation from 24.4% to 2.6% (p<0.0001). Two patients died after regionalisation. The first patient, a 72year-old female, developed a fatal haemorrhagic cerebrovascular accident on the 6 th postoperative day following a Whipple's procedure for a T3N1 adenocarcinoma of the pancreatic head. A second 79-year-old male patient died of severe ARDS on the 6 th postoperative day following a pylorus preserving pancreaticoduodenectomy for a T2N0 distal cholangiocarcinoma complicated by a grade C leakage of the pancreaticojenostomy.

Results with regard to both short term and long-term survival are shown in Table 3. Both 3month (75% vs. 97%; p < 0.001) as well as 1 year survival (55% vs. 76%; p = 0.02) are significantly increased following regionalisation. There is a trend towards an improved survival after two years but this did not reach statistical significance (37% vs. 52%, p= 0.23).

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Discussion

This prospective cohort study on the effect of regionalisation of surgery for pancreatic cancer in the eastern part of the CCCS region in The Netherlands demonstrates that concentration in a high volume center and surgical treatment by a dedicated surgical team results in reduction of postoperative morbidity and mortality.

During the last decade several large population based studies have also demonstrated that hospital and surgeon-volume results in less post-operative complications and mortality (1-9;14;15). In some states in the USA this awareness has resulted in formal centralisation of pancreatic surgery and a subsequent decrease in postoperative mortality (7;16). However, nationwide effects of centralisation in the USA are not seen yet [START_REF] Turaga | In Hospital Outcomes After Pancreatectomies: an Analysis of a National Database From 1996 to 2004[END_REF]. Also in Europe most patients are still operated in low-volume centers as has been reported in recently published population-based studies from Italy, Belgium and the Netherlands (6;8;9). Without exception, these studies again confirm the inverse correlation between the number of resections per hospital and postoperative mortality. All authors of these studies invariably advocate further centralisation of pancreatic surgery in their countries. In the Netherlands the plea for centralisation has been initiated since 1995. Nevertheless, nationwide referral patterns over the last decade have not changed significantly since (6;15). The improvement of quality of care for surgical patients with pancreatic cancer is challenged by some authors claiming excellent results from low-volume hospitals [START_REF] Cunningham | Surgical Outcomes Following Pancreatic Resection at a Low-Volume Community Hospital: Do All Patients Need to Be Sent to a Regional Cancer Center?[END_REF] as well as by the observation that also highvolume centres may not always fulfil high standards of qualitative care [START_REF] Riall | Outcomes Following Pancreatic Resection: Variability Among High-Volume Providers[END_REF]. Finally, opponents of centralisation claim that at least a part of the beneficial results obtained by specialized centres may be due to case selection. Indeed, in a previous report we have also shown that patients seeking surgery in specialized centres outside our region more often were male, younger, in a better health and higher socioeconomic status as compared to patients who do not [START_REF] Van Oost | Outcome of Surgical Treatment of Pancreatic, Peri-Ampullary and Ampullary Cancer Diagnosed in the South of The Netherlands: a Cancer Registry Based Study[END_REF]. The latter is also confirmed by a study from the USA, reporting that patients referred to high-volume centres were more often white and had a better insurance as compared to patients treated in low volume centres [START_REF] Gordon | The Effects of Regionalization on Cost and Outcome for One General High-Risk Surgical Procedure[END_REF].

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Besides these objective data, more subjective arguments probably play an essential role in the reluctance of surgeons to refer patients to other hospitals. The complexity of pancreatic surgery is generally regarded as an interesting and alluring aspect of abdominal oncologic surgery by most surgeons. These surgeons feel that their profession may become less attractive once pancreatic surgery is no longer part of their surgical practice leaving them to carry on practising pancreatic surgery even with low patient volume.

The aforementioned has been daily practice for a long time in the CCCS-region where surgeons from 10 hospitals performed less than 5-resections per year. It was only after the publication of the disappointing results that an initiative was undertaken to improve the regional quality of care for this kind of surgery. One of the solutions might have been to

prohibit pancreatic surgery at all within the CCCS-region and to refer all patients to established centres for pancreatic surgery in the Netherlands. Due to logistics ( e.g. travelling time and the waiting lists in the referral centres) this option was regarded as unattractive. Instead, regional collaboration was sought which resulted in the successful establishment of a referral centre within the south-eastern part of the CCCS-region. In our opinion, the main reason for the current successful regionalization is that certified oncological surgeons with experience in pancreatic surgery from neighbouring hospitals were invited to participate in one collaborating surgical team. By doing so, they could refer the patients to a neighbouring centre but at the same time could continue to perform pancreatic surgery, even at a higher level,

The current study shows that this initiative of regional collaboration has improved both the short term and long term outcome of these patients. Several factors have probably contributed to this improvement. First of all, due to the higher exposure of the participating surgeons the surgical technique has improved. This is illustrated by a decrease in complications both during the operation and in the early postoperative period. Despite the decrease in postoperative complications, still a significant proportion of the patients suffer from a variety of complications. This is a well-known phenomenon in pancreatic surgery and is reported by many expert centres [START_REF] Buchler | Morbidity After Pancreatic Resection[END_REF]. The higher index of suspicion and early recognition

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of complications by medical and nursing staff due to higher exposure resulting in early treatment of these complications is of utmost importance in order to prevent postoperative mortality. The former may probably be the most important explanation for the success of regionalisation. Apart from earlier detection of complications, expanding experience with regard to minimal invasive treatment of complications, i.e. intervention radiology, results in a significant decrease in the need for reoperations. In the absence of experience with the nonoperative minimal invasive treatment of complications at the start of the regionalisation most complications were treated by reoperation resulting in a decreased but still high reoperation rate of 18% in the current series. However, with growing experience intervention radiologists currently treat most intra-abdominal fluid collections by CT-guided percutaneous drainage and the endoscopic treatment of anastomotic bleeding by gastroenterologists has become standard of care. Therefore, we expect that the number of reoperations will continue to fall with increasing experience. Also medical oncologists have become more familiar with this patient category and adjuvant chemotherapy is currently offered more frequently. The former may in part also contribute to the slight improvement in the two year survival observed in the recent period. Finally, there is evidence from several studies that also pathological examination of the resection specimen improves with growing experience resulting in better staging (21;22). Taken all together, treatment of patients who are operated on for pancreatic cancer has become an even more multi-disciplinary effort which benefits this group of patients. Recently, the multi-disciplinary approach was regarded as the most important contributory to the improved long-term survival of patients undergoing pancreatic resection in the MD Anderson Cancer Center [START_REF] Katz | Long-Term Survival After Multidisciplinary Management of Resected Pancreatic Adenocarcinoma[END_REF].

The beneficial effects of concentration of surgical care is not only limited to pancreatic surgery but involves many other procedures once regarded as "general surgery" such as for instance complex colorectal(24) and vascular surgery(25). It is likely that patient organisations and health care authorities will pursue concentration of such complex procedures in the near future. The present study shows that centralisation of complex surgical treatment not automatically implies that these patients should be referred to

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nationwide expert centres but that through collaboration high quality of care can be achieved in a high volume regional hospital. The call for centralisation should therefore no longer be regarded as a threat by general hospitals but as a chance to improve results through regional collaboration for this complex and challenging surgical pathology.

(

  18%) after regionalisation (p < 0.008). Reasons for reoperation were: early postoperative haemorrhage (3 grade B, 1 grade C), drainage of intra-abdominal abscesses (4 patients), drainage of grade C pancreatic leakages (4 patients) and delayed gastric emptying grade C due to adhesions (2 patients). Besides these operatively corrected complications another 5 M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT patients suffered from a grade A (4 patients) or grade B (1 patient) delayed gastric emptying, grade B pancreatic leakage (5 patients) and pneumonia (3 patients). Taken together, postoperative complications were significantly reduced after regionalisation (34,2% vs. 71,9%, p<0.0001).

  survivors and number of patients at risk with 3-months follow-up n=65 and 67, 1year n=34 and 45 and 2-years n=12 and 23

Table 1

 1

	A	B	p value

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