MD Léon Maggiori

MD Dominique Elias
email: dominique.elias@igr.fr

CURATIVE TREATMENT OF COLORECTAL PERITONEAL CARCINOMATOSIS : CURRENT STATUS AND FUTURE TRENDS

INTRODUCTION

Peritoneal dissemination or "carcinomatosis" from colorectal carcinoma is a form of disease progression which can affect 30 to 40% of patients [START_REF] Chu | Peritoneal carcinomatosis in nongynecologic malignancy. A prospective study of prognostic factors[END_REF][START_REF] Sadeghi | Peritoneal carcinomatosis from non-gynecologic malignancies: results of the EVOCAPE 1 multicentric prospective study[END_REF]. Natural history studies show that peritoneal carcinomatosis (PC) is uniformly fatal, with median survival not exceeding 6 months [START_REF] Jayne | Peritoneal carcinomatosis from colorectal cancer[END_REF]. For more than a decade, as an alternative approach to overcome this disease, a handful of centers have pursued aggressive cytoreductive surgery to resect macroscopic disease as much as possible, combining it with intraperitoneal chemotherapy (initially without and then with hyperthermia), to treat any residual occult disease.

The aim of this review is to report the current status of this novel combined treatment, focusing on issues that have been solved and those which continue to pose problem and attempting to foresee future developments.

1) A new therapeutic concept becoming increasingly popular

Concept

In 1980, Spratt was the first to describe the combination of maximal cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC) to treat a recurring peritoneal pseudomyxoma [START_REF] Spratt | Clinical delivery system for intraperitoneal hyperthermic chemotherapy[END_REF], but the main apostle of this method was PH Sugarbaker [START_REF] Sugarbaker | Rationale for perioperative intraperitoneal chemotherapy as a surgical adjuvant for gastrointestinal malignancy[END_REF]. The main principles are : treating the macroscopic (visible) malignant peritoneal disease with complete cytoreductive surgery (CCRS), and immediately after, treating the remaining microscopic (non visible) malignant peritoneal disease with HIPEC.

It is essential that surgery resects all tumor seeding greater than 1 mm because the chemotherapy bath cannot penetrate tumor seeding beyond 1-2 mm

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in depth [START_REF] Los | Direct diffusion of cis-diamminedichloroplatinum(II) in intraperitoneal rat tumors after intraperitoneal chemotherapy: a comparison with systemic chemotherapy[END_REF][START_REF] Van De Vaart | Intraperitoneal cisplatin with regional hyperthermia in advanced ovarian cancer: pharmacokinetics and cisplatin-DNA adduct formation in patients and ovarian cancer cell lines[END_REF]. Hyperthermia, in addition to intraperitoneal chemotherapy, has clearly demonstrated its ability to potentiate the penetration and activity of local chemotherapy in cancer cells in vitro, and this role was confirmed in vivo in several studies [START_REF] Koga | Treatment of implanted peritoneal cancer in rats by continuous hyperthermic peritoneal perfusion in combination with an anticancer drug[END_REF][START_REF] Elias | Treatment of peritoneal carcinomatosis by intraperitoneal chemohyperthermia: reliable and unreliable concepts[END_REF].

Finally, HIPEC must be performed immediately after surgery to avoid peritoneal adhesions in which cancer cells become trapped and could constitute a tumor sanctuary [START_REF] Zoetmulder | Cancer cell seeding during abdominal surgery: experimental studies[END_REF][START_REF] Jacquet | Tumor implantation in cicatrization sites following surgery for digestive cancers[END_REF].

HIPEC is becoming widespread

Publications devoted to HIPEC have increased exponentially between 1994 and 2009. To date, approximately five hundred have concerned colorectal PC. At the same time, the number of centers using HIPEC has progressively increased worldwide. In France, it increased from 3 in 1994 to 25 in 2009. This reflects the enhanced interest of physicians in this new therapeutic approach.

2) Validated and nonvalidated aspect of this combined treatment

Global results

This combined treatment (CCRS immediately followed by HIPEC) works, as definitively demonstrated by the randomized study of the Amsterdam group: 105 patients presenting colorectal PC were randomized between surgery + HIPEC (and systemic chemotherapy) versus systemic chemotherapy alone [START_REF] Verwaal | Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer[END_REF]. In that study, 50% of the patients in the experimental arm were ultimately not good candidates for HIPEC because their PC could not be completely surgically resected. In spite of

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this selection bias, the reported median survival was 22 months in the experimental arm versus 13 months in the control group (p=0.032) (figure 1).

A more recent retrospective study compared similar patients with resectable PC treated with CCRS and HIPEC to standard systemic chemotherapy: the median survival rate was 63 months in the CCRS + HIPEC group versus 24 months in the systemic chemotherapy group (figure 2) [START_REF] Elias | Complete cytoreductive surgery plus intraperitoneal chemohyperthermia with oxaliplatin for peritoneal carcinomatosis of colorectal origin[END_REF].

Complete cytoreductive surgery

The impact of the completeness of cytoreductive surgery is very strong in this combined treatment. This is clearly apparent in all studies from experienced as well as less experienced centers. For example, we report in figure 3 the survival rates according to the radicality of surgery in the 523 patients collected by the AFC (Association Française de Chirurgie) registry [START_REF] Elias | Peritoneal Colorectal Carcinomatosis Treated With Surgery and 15[END_REF]. This study underlined the strong impact of the completeness of cytoreductive surgery on overall survival: 5 years after surgery, no patient was alive if the size of the remaining tumor nodules after surgery was ≥ 2.5 millimeters whereas nearly 30% of the patients were alive if CCRS was possible (p<0.0001). Furthermore, CCRS was identified as an independent prognostic factor for disease-free survival (p=0.05).

Hyperthermic Intraperitoneal Chemotherapy

The exact effect of HIPEC alone in this package is currently unknown in human beings. Its role is to cure the residual microscopic PC after complete cytoreductive surgery. In a randomized trial in rats, those treated with HIPEC survived longer than those treated with intraperitoneal chemotherapy alone or exclusively with intraperitoneal hyperthermia [START_REF] Koga | Treatment of implanted peritoneal cancer in rats by continuous hyperthermic peritoneal perfusion in combination with an anticancer drug[END_REF]. Until now, no comparable trial

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has been proposed to patients, but a French randomized multicentric trial (Prodige 7) is ongoing which is comparing HIPEC versus no HIPEC after complete cytoreductive surgery.

HIPEC techniques are heterogeneous but their elaboration is highly complex.

The combination of drugs can be modified, as can their concentration, but also the composition as well as the volume of the perfusion, the duration, and the temperature. A high number of combinations of these six parameters is possible, and it is not possible to test all of them. Each modification of one of these parameters implies conducting a new pharmacokinetic study. Schematically, there are two main trends worldwide for HIPEC : one uses mitomycin C over 60-90 min at 41°C with a closed-abdomen technique, and the other uses oxaliplatin (± irinotecan) over 30-40 min at 43°C with an opened-abdomen technique.

In the future, there is a rationale for conducting HIPEC with other drugs and new targeted therapy (without hyperthermia, if monoclonal antibodies are used).

3) What indications and what results in 2010 ?

Indications

Indications are based on absolute and relative contraindications. An absolute contraindication for CCRS plus HIPEC is a poor general status, the presence of extra-peritoneal metastases and huge and diffuse PC. Relative contraindications are : a subocclusive syndrome due to more than one digestive stenosis, peritoneal disease progressing under chemotherapy and the presence of more than 3

Oncologic Results

Results obtained with CCRS + HIPEC are interesting and promising. In the AFC study, overall 5-year survival was 27%. This result takes into account all the learning curves of 28 different centers and will be the worst possibly obtained.

The results of experienced centers, concerning patients who underwent CCRS + HIPEC are consistent, with overall 5-year survival rates close to 40% [START_REF] Verwaal | Long-term survival of peritoneal carcinomatosis of colorectal origin[END_REF][START_REF] Da Silva | Analysis of prognostic factors in seventy patients having a complete cytoreduction plus perioperative intraperitoneal chemotherapy for carcinomatosis from colorectal cancer[END_REF][START_REF] Elias | Peritoneal carcinomatosis of colorectal origin[END_REF]. It was 32% for the 70 patients reported on by da Silva et al. [START_REF] Da Silva | Analysis of prognostic factors in seventy patients having a complete cytoreduction plus perioperative intraperitoneal chemotherapy for carcinomatosis from colorectal cancer[END_REF], 43% for the 59 patients reported by Verwaal et al. [START_REF] Verwaal | Long-term survival of peritoneal carcinomatosis of colorectal origin[END_REF], and 48% for the 30 patients in the study by Elias et al. [START_REF] Elias | Peritoneal carcinomatosis of colorectal origin[END_REF]. Such a survival rate has never been published before about PC, even if it concerns only selected patients. It is thus a real therapeutic revolution.

Furthermore, these results are exactly similar to those obtained with hepatectomy for liver metastases [START_REF] Elias | Complete cytoreductive surgery plus intraperitoneal chemohyperthermia with oxaliplatin for peritoneal carcinomatosis of colorectal origin[END_REF]. The message appears to be that selected patients with PC should be treated with this combined therapy in the same way as selected patients with LM should be treated with hepatectomy, given that the same survival rates are obtained [START_REF] Elias | Peritoneal carcinomatosis or liver metastases from colorectal cancer: similar standards for a curative surgery?[END_REF].

Post-operative mortality and morbidity

The first studies concerning CCRS and HIPEC reported high post-operative mortality and morbidity rates, creating a obstacle to its diffusion. However, in the AFC study, the postoperative mortality rate was comparable to that of standard colorectal surgery (3%) and grade 3 or 4 complications (according to the National Cancer Institute Common Toxicity Criteria) occurred in 31% of the patients [START_REF] Elias | Complete cytoreductive surgery plus intraperitoneal chemohyperthermia with oxaliplatin for peritoneal carcinomatosis of colorectal origin[END_REF].

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These acceptable operative results were confirmed in a recent Australian study, which reported a postoperative mortality rate of 3% and a severe morbidity rate of 43% [START_REF] Chua | Morbidity and Mortality Outcomes of Cytoreductive Surgery and Perioperative Intraperitoneal Chemotherapy at a Single Tertiary Institution: Towards a New Perspective of This Treatment[END_REF]. Thus, fear of a severe post-operative course is no longer an acceptable reason for not using CCRS and HIPEC.

Prognostic factors

Some studies recently underlined the prognostic impact of the extent of the peritoneal disease (measured with the peritoneal cancer index : PCI) [START_REF] Elias | Peritoneal Colorectal Carcinomatosis Treated With Surgery and 15[END_REF][START_REF] Da Silva | Analysis of prognostic factors in seventy patients having a complete cytoreduction plus perioperative intraperitoneal chemotherapy for carcinomatosis from colorectal cancer[END_REF]. This index ranges from 1 to 39 (a score from 0 to 3 is given for each of the 13 intraabdominal areas) [START_REF] Sugarbaker | Intraperitoneal chemotherapy and cytoreductive surgery for the prevention and treatment of peritoneal carcinomatosis and sarcomatosis[END_REF]. Among the 523 patients in the AFC registry, a peritoneal index > 20 appeared as one of the main prognostic factors for survival in the multivariate analysis [START_REF] Elias | Peritoneal Colorectal Carcinomatosis Treated With Surgery and 15[END_REF]. The results of the AFC registry are reported in figure 4.

Five-year overall survival is directly correlated with the PCI, ranging from 44% with a very low PCI (less than 6) to 7% with the highest PCI (more than 19). We currently believe that a PCI exceeding 20 should be considered as a relative contraindication for CCRS with HIPEC.

The main prognostic factors for survival selected by various studies through multivariate analysis are as follows : the completeness of cytoreductive surgery, a PCI score > 20, the presence of positive lymph nodes and the delivery of adjuvant chemotherapy [START_REF] Elias | Complete cytoreductive surgery plus intraperitoneal chemohyperthermia with oxaliplatin for peritoneal carcinomatosis of colorectal origin[END_REF][START_REF] Da Silva | Analysis of prognostic factors in seventy patients having a complete cytoreduction plus perioperative intraperitoneal chemotherapy for carcinomatosis from colorectal cancer[END_REF]. When they are resectable simultaneously with HIPEC, associated liver metastases merely exert a borderline non-significant impact [START_REF] Elias | Complete cytoreductive surgery plus intraperitoneal chemohyperthermia with oxaliplatin for peritoneal carcinomatosis of colorectal origin[END_REF].

Until now, no CCRS plus HIPEC technique has demonstrated clear superiority over

another. The technique commonly used in our department has been extensively described elsewhere [START_REF] Sugarbaker | Peritonectomy procedures[END_REF][START_REF] Elias | Traitement chirurgical a vise e curatrice des carcinoses pe ritone ales[END_REF]. In addition, the intraperitoneal use of new targeted drugs ought to be explored.

b) Progress with new targeting molecules.

If new and more efficient molecules capable of treating colorectal cancers become available, then the place of HIPEC will be re-analyzed. A prospective multicentric trial will be necessary to compare CCRS and HIPEC to a non-surgical treatment using these new drugs.

c) Cost-efficiency of CCRS-HIPEC.

This combined treatment is complex and costly (approximately 35,000 Euros per patient). It cures only 20% of the patients with PC, but significantly increases median survival. Its cost-efficiency can be measured with the QALY method which measures the price of one year of survival gained with the treatment [START_REF] Bonastre | Cost of radiofrequency ablation in the treatment of hepatic malignancies[END_REF]. After that, each country will have to decide if it is rich enough to pay the price and whether treating this advanced disease is a priority or not. Also, The results of

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such treatment will have to be weighed against the cost of new systemic chemotherapy molecules (close to 5,000 Euros per month). d) A surgical procedure reserved for specialized centers.

CCRS and HIPEC are technically challenging, with a rather long learning curve [START_REF] Elias | Complete cytoreductive surgery plus intraperitoneal chemohyperthermia with oxaliplatin for peritoneal carcinomatosis of colorectal origin[END_REF]. Moreover, as mentioned above, it is an expensive treatment. High volume and experienced centers obtain better results than others [START_REF] Elias | Complete cytoreductive surgery plus intraperitoneal chemohyperthermia with oxaliplatin for peritoneal carcinomatosis of colorectal origin[END_REF] and quality control measurement does not currently exist. Controlling the quality of surgery is currently difficult to implement and apply to gastric and rectal cancers. It will be even more difficult for this complex technique. This is why there is a strong rationale for authorizing this activity exclusively in a few specialized centers in the future.

Prophylactic HIPEC for high-risk patients

All the series concerning the treatment of established macroscopic PC conclude that survival results are far better when peritoneal disease is less bulky [START_REF] Elias | Complete cytoreductive surgery plus intraperitoneal chemohyperthermia with oxaliplatin for peritoneal carcinomatosis of colorectal origin[END_REF][START_REF] Verwaal | Long-term survival of peritoneal carcinomatosis of colorectal origin[END_REF][START_REF] Da Silva | Analysis of prognostic factors in seventy patients having a complete cytoreduction plus perioperative intraperitoneal chemotherapy for carcinomatosis from colorectal cancer[END_REF]. Also postoperative morbidity and mortality are significantly lower when the peritoneal index is lower, because surgery is less extensive [START_REF] Elias | Peritoneal Colorectal Carcinomatosis Treated With Surgery and 15[END_REF]15]. These two points are strong arguments in favor of operating patients with the lowest peritoneal index. However, early PC is currently not detectable clinically, biologically or with imaging. Early PC is only detectable by a second-look laparotomy. Second-look laparoscopy is not recommended because it does not allow the surgeon to "re-expose" all the dissection planes of the first surgery, and because palpation cannot be used. The aim of this second-look procedure is to detect the beginning of PC early and to treat it with cytoreductive surgery plus HIPEC. As this a rather aggressive and expensive treatment, it should be proposed exclusively to patients presenting a high risk of developing PC after resection of the primary. A major proportion of the at-risk population has recently be defined by Elias et al [START_REF] Elias | Results of systematic second-look surgery in patients at high risk of developing colorectal peritoneal carcinomatosis[END_REF] and concerns: 1) patients presenting a few nodules of synchronous PC which are completely resected with the primary tumor, 2) patients with ovarian metastasis, and 3) patients with a perforated primary tumor (spontaneous or iatrogenic). A second-look procedure performed one year after the first surgery and 6 months after the end of systemic adjuvant chemotherapy, in asymptomatic patients with a completely negative work-up, was able to detect macroscopic PC in respectively 63%, 75% and 33% of these sub-groups. Patients with macroscopic PC were treated with cytoreductive surgery plus HIPEC, with no mortality, low morbidity and a promising survival rate (2-year disease-free survival exceeding 50%). Patients without macroscopic PC were treated prophylactically with or without HIPEC. The subgroup receiving HIPEC presented far fewer peritoneal recurrences than those who did not receive HIPEC (17% versus 43%, respectively).

Based on this preliminary study, a multicentric randomized trial was designed which will begin in France in 2010. All high-risk patients (see definition above) will receive the standard adjuvant systemic chemotherapy with FOLFOX over 6 months. Afterwards, a complete work-up will be performed. If it is negative, patients will be randomized between a simple survey (control group) and a second-look with in principle HIPEC. The main evaluation criterion will be the rate of peritoneal recurrences at 3 years.

Conclusion

In conclusion, comparable to the rise in the use of hepatectomy for colorectal LM observed fifteen years ago, CCRS and HIPEC is becoming the standard treatment for colorectal PC. This combined treatment is a complex and costly therapeutic package that is slowly being adopted by surgical teams. However, it is associated with promising long-term survival and is currently the only treatment able to cure patients with PC. Its future evolution may lead to even better oncologic and surgical results.

The authors thank Ms lorna Saint-Ange for editing.

  M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT Titre 6 resectable liver metastases (LM are not contraindicated if there are < 4 and they are easily resectable )[15].

4 )

 4 New trends for HIPEC in the future Established macroscopic PC: a) Standardization of the techniques. A comparative study of the main techniques is desirable, but difficult and to perform and time-consuming. While awaiting the results of such a study, treatment decision-making is based on a consensus among experts. Ongoing multicentric studies are a way of standardizing these techniques. The relation between the duration and the temperature of HIPEC should be carefully explored.

  To date, the risk of developing PC has not been clearly established for patients with a pT4 lesion of the colon or an occlusive tumor. Data in the M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT Titre 11 literature are discordant and a new prospective study on this issue would be useful.

Figure 1 : 13 Figure 2 : 14 Figure 3 :Figure 4 : 4 M

 113214344 Figure 1: Overall survival after surgery + HIPEC or standard systemic


The effect of immediate breast reconstruction with Becker-25 prosthesis on the preservation of proper body posture in patients after mastectomy

Keywords: body posture, immediate breast reconstruction, mastectomy, Moire conturography

Purpose: This was a prospective study comparing coronal, sagittal and transverse plane body posture parameters in women after radical mastectomy and women after radical mastectomy with immediate breast reconstruction (IBR) for stage I and II breast cancer.

Methods: The three studied groups were one that underwent Madden's radical mastectomy (n=38), a second with skin sparing mastectomy with IBR with expander-prosthesis Becker-25 (n=38), and the control (n=38). All the women were examined to determine their body posture in the coronal, sagittal and transverse planes using threedimensional (3D) body surface analysis before and 6, 12, 18 and 24 months after surgery.

Results: There is a significant difference body posture in the coronal, sagittal and transverse planes between groups of patients after mastectomy with IBR comparing with patients after mastectomy alone. The women after radical mastectomy demonstrated the greatest postural changes in particular parameters of body posture in postsurgical months 18 and 24. The IBR group only demonstrated significant postural changes in one parameter, though as time after surgery increased, these changes decreased.

Conclusions: IBR after mastectomy has an impact on proper body posture. Photogrammetric examination revealed important body posture disturbances only in the radical mastectomy group. It gives useful information on body posture parameters in the evaluation of quality of life in breast cancer survivors. It appears that immediate breast reconstruction helps to preserve proper body posture after mastectomy.

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Introduction:

Breast cancer remains the most frequent malignant neoplasm in women. Surgical options include radical mastectomy (RM), breast conservative treatment (BCT), and immediate breast reconstruction (IBR). Treatment of breast malignancies is currently centered on minimalizing surgical intervention while still eradicating the neoplasm. Despite an increasing proportion of indications for surgical intervention with breast conservation in early breast cancer stages, as many as 10% of stage I and 30% of stage II patients do not qualify for BCT [START_REF] Morrow | Factors Influencing the use of Breast Reconstruction Postmastectomy: A national Cancer Database Study[END_REF]. In addition to difficulties in offering each patient a 5-week course of radiotherapy, the number of unwilling patients and difficulties in staging the disease before surgery, there are many women who still undergo RM in early stages of the disease [START_REF] Parker | Short-term and long-term psychosocial adjustment and quality of life in women undergoing different surgical procedures for breast cancer[END_REF][START_REF] Janni | Quality of life influenced by primary surgical treatment for stage I-III breast cancer-Long term follow up of a matched pair analysis[END_REF]. In these patients, a good solution to minimalize scarring is IBR [START_REF] Cordeiro | Breast reconstruction after surgery for breast cancer[END_REF]. To date, the value of IBR has been mainly in the return or improvement of quality of life and maintenance of a natural appearance, both factors leading to better self-esteem and emotional well-being in this group of women [START_REF] Elder | Quality of life and patient satisfaction in breast cancer patients after immediate breast reconstruction: a prospective study[END_REF][START_REF] Sk | Comparison of psychological aspects and patient satisfaction following breast conserving surgery, simple mastectomy and breast reconstruction[END_REF][START_REF] Cordeiro | A single surgeon's 12-year experience with tissue expander/implant breast reconstruction: II. A prospective analysis of long-term complications, aesthetic outcomes and patients satisfaction[END_REF].

There have been almost no attempts to determine the effect of mastectomy and breast reconstruction on the maintenance of proper body posture after surgery. A large number of women after mastectomy complain of increased back pain a few months to years after mastectomy [START_REF] Rietman | Late morbidity after treatment of breast cancer in relation to daily activities and quality of life: a systemic review[END_REF][START_REF] Kopański | Influence of some anthropometric parameters on the risk of development of distal complications after mastectomy carried out because of breast carcinoma[END_REF]. The studies by Rostkowska et al. have shown a statistically significant disturbance of proper body posture in women after mastectomy [START_REF] Rostkowska | Body posture in women after mastectomy and its changes as a result of rehabilitation[END_REF]. These disturbances have even been demonstrated in women who underwent intensive rehabilitation. It has also been noted that these disturbances in body posture are decreased in women who used an external prosthesis not only during the day but also at night, while sleeping [START_REF] Bak | The influence of using breast prosthesis during the night on the changes of body posture among woman after mastectomy[END_REF]. This leads to the assumption that IBR may have a positive effect in maintenance of proper body posture in women after mastectomy.

The purpose of this study was to compare the changes in body posture of women after RM and women who underwent IBR with expander-prosthesis Becker-25.

Patients and methods:

Prospective studies were performed in a group of women with stage I and II breast cancer,operated in 2000-2005 at the General Surgery Department of the State Regional Hospital in Leszno, Poland.

Group A (n=38) underwent RM using Madden's method. Group B (n=38) underwent skin sparing mastectomy (SSM) with single-stage IBR using a subpectorally placed expander-prosthesis Becker-25. The control group,

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ACCEPTED MANUSCRIPT 4 group C (n=38), were healthy women who have not had surgery. Groups A and B were comparable in terms of age, body mass, height, the degree of cancer advancement, and comorbidities (Table 1). The study continued until all dimensional parameters had been obtained for each group's 38 women.

All the women were examined to determine their body posture using three-dimensional (3D) analysis of the body surface with photogrammetry. This method involves objective anthropometric measurements based on computer analysis of the 3D image constructed of the spine of each examined woman. The theoretical basis of the measurements is Moire conturography, described in optics. A ray of while light hitting an uneven surface leads to this light reflecting at various degrees. The reflected image was registered by a camera and digitally configured and saved by a special computer program. This system allowed for real-time registration and comparison of the resultant changes in the body posture of the examined women (Photograph 1). This non-invasive and non-burdening manner of obtaining measurements allowed for multiple measurements in each woman post-operatively. Before taking a measurement, characteristic bony structures were marked on the patient's back: the C7 to S1 spinous processes, the lower borders of the scapulae, and the superior posterior iliac spines. The static measurements were taken in specific, reproducible conditions, accounting for the same parameters of the visual apparatus, at a constant distance of 3.2 m between the camera and the patient, who was standing in a relaxed position. This examination allowed for the measurement of 54 parameters in the coronal, sagittal, and transverse planes, which made it possible to objectively evaluate the body posture of the patients.

For the purposes of this study, only a few parameters that best demonstrated differences in the coronal, sagittal and transverse planes were used, and were selected before the first examination:

• MDL -the maximal deviation of the line of the superior posterior iliac spines from C7-S1,

• DHSh -the difference in the height of the shoulders,

• DHS -the difference in the height of the lower border of the scapulae (angling of the body),

• API -the angle of pelvic inclination,

• APR -the angle of pelvic rotation in the sagittal plane, and

• RS -the difference in the depth of the lower border of the scapulae (rotation).

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Five measurements were taken for each patient: before the surgery (after final diagnosis and determining the best method of treatment), and 6, 12, 18, and 24 months after surgery.

Statistical analysis:

To compare the measurable parameters at each interval that met the initial criteria for one-way ANOVA were analyzed with the post hoc Newman-Keuls test with the assumption of Gaussian distribution and homogeneity of variance at the p < 0.05 level. When the parameters did not meet the above criteria, the nonparametric Kruskal-Wallis test was used with Dunn's multiple comparisons test, also at p < 0.05. To compare groups of examinated women univariate assessment for nominal data was made using Fisher exact test or Chi-square test.

Analysis was performed using STATISTICA (data analysis software system), v 8.0 In this prospectively planned photometric study of body posture, it was possible to obtain full data on the measurements in 38 women of each group. As result analysis included only those women whose measurements were taken preoperatively and at the four postoperative times designated, these measurements took two postoperative years to be completed. Women whose complete measurements could not be obtained, for any reason, for the five time periods, were excluded from the study. In this manner, two groups of women of similar age, body mass, height, mass of breast tissue removed, degree of disease advancement, and type of postoperative treatments were obtained.

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The photogrammetric results obtained for these women demonstrate a significant difference in body posture between the patients who underwent IBR and those with RM who never had reconstruction. The measurements taken preoperatively, but after clinical diagnosis and qualification to surgical treatment, did not differ significantly in the women who were treated with IBR or RM, either between each other or in comparison to the control group (Table 2).

Examination of the patients 6 months postoperatively demonstrated a considerable increase in body posture divergence in the patients who had RM without breast reconstruction.

Twelve months postoperatively, this body posture divergence is even more obvious in the group of patients without reconstruction after RM, and is significantly different from the results obtained from the IBR and control groups.

In the eighteenth postoperative month, the difference between the RM and IBR groups reached its peak, with the RM group showing even more divergence in body posture. Two years after surgery, there is no further increase in divergence demonstrated by the parameters of body posture in the coronal plane in the patients with RM. We can therefore presume that adaptation of the body stabilizes approximately 18 months after surgery and does not progress further (Photograph 2).

There is no difference between IBR patients and healthy controls in MDL, regardless of when the measurements are taken postoperatively. This indicates that the changes in MDL in women after mastectomy increase over time, and therefore women who underwent RM without reconstruction demonstrate increasing divergence of body posture from healthy controls and patients with IBR (Figure 1a).

Analysis of DHSh also demonstrates significant changes just 6 months after surgery. Thegreatest differences between patient groups are seen 18 months after surgery (Figure 1b).

Similarly, analysis of DHS shows a significant difference in the RM and IBR groups just 6 months after surgery, and this difference increases over time between these groups (Figure 1c).

Analysis of API also shows a significant difference in the RM and IBR groups just 6 months after surgery, and this difference increases over time between these groups (Figure 1d).

The measurements of APR demonstrate an obvious increase in the angle of pelvic rotation in women 12 months after radical mastectomy. This trend continues over the 24 months that measurements were taken (Figure 1e).

The values of RS are statistically significant from 6 months after surgery only in the IBR and RM groups. This difference is also present between the RM and control groups over all postoperative months. There is no significant difference between the IBR and control groups at any time (Figure 1f).

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Changes in proper body posture occurring in patients after RM involved raising of and moving anteromedially the shoulder on the operated side, with a simultaneous rotation of that scapula in the sagittal plane.

Discussion:

Breast size and body posture:

It is well known that back pain is common in women with large breasts. The weight of the breasts is responsible for a change in the center of gravity of these women, and also leads to a change in body posture [START_REF] Rostkowska | Body posture in women after mastectomy and its changes as a result of rehabilitation[END_REF][START_REF] Findikcioglu | The impact of breast size on the vertebral column: a radiologic study[END_REF]. This can cause frequent neck pain, back pain, shoulder pain, a feeling of neck stiffness, painful ras serie strap grooving, and persistent intertrigo in the inflammatory folds. As explained by Findikcioglu et al. [START_REF] Findikcioglu | The impact of breast size on the vertebral column: a radiologic study[END_REF], there are statistical differences in the angle of thoracic kyphosis and lumbar lordosis between women of breast cup A and cup D.

Patients of breast cup B and D were also compared, and demonstrated a significant difference in the angle of lumbar lordosis [START_REF] Rostkowska | Body posture in women after mastectomy and its changes as a result of rehabilitation[END_REF][START_REF] Findikcioglu | The impact of breast size on the vertebral column: a radiologic study[END_REF]. No differences were noted in the sacral inclination angle. This demonstrates that the vertebral column changes dynamically, and disturbances of one part of the spine are compensated by changes in another part of the spine. In the 38 IBR patients, twenty of the women that underwent conturography had corrective surgery of the healthy breast 5-8 months after IBR. However, in the initial evaluations this corrective surgery did not appear to have an effect on conturography results. It seems that, regardless of how similar symmetrically the breasts were, maintaining the correct body posture is more greatly affected by the presence of a replacement breast. Further studies must be performed to confirm this.

Use of Moire conturography

Moire conturography is used to evaluate body posture divergence in scoliosis [START_REF] Wong | Direct spinal curvature digitization in scoliosis screening -a comparative study with Moire conturography[END_REF][START_REF] Takasaki | Moiré topography[END_REF][START_REF] Meadows | Generation of surface contours by Moiré patterns[END_REF]. Detailed analysis of Moire conturography has demonstrated that it is an adequate tool to diagnose the presence, degree, and direction of scoliotic changes, but cannot precisely evaluate the size of the scoliosis [START_REF] Rostkowska | Body posture in women after mastectomy and its changes as a result of rehabilitation[END_REF][START_REF] Wong | Direct spinal curvature digitization in scoliosis screening -a comparative study with Moire conturography[END_REF]. Body position, buttock rotation, body type, and fat rolls and folds are all involved in the lack of precision in evaluating vertebral curvature using body surface tophography. However, this is a good tool in the evaluation of disturbances of body posture. In studies conducted under reproducible conditions by an experienced physiotherapist Moire conurography is a good tool for the evaluation of changes occurring to the body posture, though radiologic studies are required to evaluate changes in the vertebral column itself. Two positive aspects of conturography are the noninvasive nature of the test and the possibility to perform repeated examinations over time.

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8

Asymmetry of body posture after mastectomy

In the coronal plane, the asymmetry of the buttocks in women after RM was studied by Rostowska et al. [START_REF] Rostkowska | Body posture in women after mastectomy and its changes as a result of rehabilitation[END_REF][START_REF] Bak | The influence of using breast prosthesis during the night on the changes of body posture among woman after mastectomy[END_REF].

The results of these studies indicated that the asymmetry was related to the position of the shoulders and scapulae. In the case of RM without breast reconstruction, an external prosthesis worn as a special bra was a significant factor in the degree of buttock asymmetry. Women who wore such a prosthesis regularly, both during sleep and during the day, demonstrated a lesser degree of body posture disturbances. It is also necessary for the patient to undergo rehabilitation to decrease the changes in body posture [START_REF] Rostkowska | Body posture in women after mastectomy and its changes as a result of rehabilitation[END_REF].

Our study demonstrated that body posture disturbances significantly affect the vertebral column of patients after RM. The study by Bak et al. also showed a change in body posture in women after mastectomy as compared to healthy women, but no correlation was found between the operated side (left or right) and the direction of asymmetry in body posture [START_REF] Bak | The influence of using breast prosthesis during the night on the changes of body posture among woman after mastectomy[END_REF]. This publication also noted a statistical significance in clinical observations.

The scapula on the operated side was higher than the scapula on the unoperated side. Women who were older at the time of surgery more frequently have a right rotation to their buttocks and their pelvis is located more posterior on the right side. The spinous process with the greatest deviation from a vertical line perpendicular to the ground was expressed to a greater degree in women after mastectomy. This deviation was most significant in the lower thoracic spine (Th 7-12) of older women, while in younger women it was at a higher part of the thoracic spine (Th 1-6). Another interesting clinical observation is the change in body posture depending on how much time had passed since surgery. In the early postoperative time, there is a tendency to thrust the buttocks forward, and as more time passes after surgery the buttocks are thrust posteriorly. This is due to the fact that thrusting the buttocks forward in the early postoperative period has an anesthetic and psychological effect, which passes over time [START_REF] Rostkowska | Body posture in women after mastectomy and its changes as a result of rehabilitation[END_REF][START_REF] Bak | The influence of using breast prosthesis during the night on the changes of body posture among woman after mastectomy[END_REF][START_REF] Wong | Direct spinal curvature digitization in scoliosis screening -a comparative study with Moire conturography[END_REF].

The MDL measurement in the women after RM depended on whether they wore their external prosthesis at night or only during the day, with a lesser deviation in women who wore the prosthesis also while sleeping.

Statistic and selection bias:

Certain criteria were used to determine which of the 102 IBR patients would be chosen to participate in the 38women group. One of the criteria used to determine each woman's participation in the study was her compliance in having all of the analysis performed at the set post-operative times. Therefore, women who did not participate in all conturography analyses, patients who had to receive postoperative radiotherapy (n=8), and women with postoperative complications requiring repeat surgery (n=10) were excluded from the study.

M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 9

It should be noted that breast reconstruction surgery has a significant effect on the patient's postoperative body posture. Although the changes in body posture are not completely eliminated, breast reconstruction considerably decreases the amount of divergence from normal body posture, as compared to patients who do not have reconstruction after mastectomy. It is possible that those women who had breast reconstruction may be more body-conscious, be more involved in physical fitness, place greater emphasis on their appearance, be more attentive to their posture, and may be more likely to comply with postoperative rehabilitation.

Future studies should aim at determining the effects of perimammary procedures on body posture, as such procedures can also impact the patient's quality of life.

Conclusions

In prospective studies of women treated operatively for breast cancer, it was demonstrated that RM causes significant changes in body posture. Divergence from proper body posture appeared just 6 months after surgery, with a tendency to further diverge until the 18-24 postoperative month. Similar studies conducted on women who underwent RM with IBR using expander-prosthesis Becker-25 did not show significant changes in proper body posture over the 24-month observation and study period. The parameters used to measure body posture did not differ significantly between the group of women who underwent IBR and the control group. We therefore suggest that simultaneous breast reconstruction leads to a better postoperative outcome, not only in terms of aesthetic results or patient self-esteem, but mainly through preventing complex changes in body posture that can result in permanent changes in the patient's physical equilibrium and related symptoms.

  Results:Between September 20 2000 and June 19 2005, there were 125 women operated for breast cancer at the General Surgery Department of the State Regional Hospital in Leszno, and all of these women underwent breast reconstruction with expander-prosthesis Becker-25. Of these patients, 102 had IBR, while in 23 patients the use of expander-prosthesis Becker-25 was delayed by 6 months to 10 years after mastectomy. During the same time period, 142 patients underwent RM without use of an expander-prosthesis.Patients with stage I and II breast cancer, evaluated clinically prior to surgery, were qualified to IBR assuming no contraindications to this type of surgery. All the women qualified for IBR agreed to radical mastectomy with reconstruction and also declared their intention to participate actively in postoperative breast modeling and rehabilitation. Approximately 5-8 months after IBR, 50 of the 102 patients who had undergone IBR also had corrective surgery of the healthy breast, to correct symmetry, using the McKissock (n=25), Lejour (n=19), or Benelleg (n=6) procedure.

Figure 1

 1 Figure 1Dynamic changes in body posture parameters in the coronal, sagittal and transverse planes for women after radical mastectomy with IBR and women after RM without reconstruction in the 24 months after surgery:

Table 1 :

 1 Characteristics of women in groups A, B, and C, who underwent photogrammetric examination

		IBR n=38	RM n=38	Control n=38	p-value
	age (years)	48,5 ±10,99 (29-65)	51,3 ± 9,2 (36-68)	49,8 ± 11,1 (34-66)	p=0,66 (ANOVA)
	height (cm)	163 ± 14,8 (146-176)	160,7 ± 9,8 (152-169)	158,9 ± 8,9 (145-168)	p=0,8 (ANOVA)
	weight (kg)	61,3 ± 12,4 (48-79) 64,1 ± 11,7 ( 50-82) 62,4 ± 10,2 (51-77)	p=0,57 (ANOVA)
	mass of resected breast tissue (g)	455 ± 156	512 ± 182		p=0,09 (t-Student)
	Hormonal status:
	Menstruating	17	16	19	p=0,9 (Fisher-Freeman-
					Halton)
	Menopausal	21	22	19
	Additional
	treatment:
	Chemotherapy	26	28		p=0,8 (Fisher)
	Hormone therapy	33	31		p=0,75 (Fisher)
	Radiotherapy	0	0

Table 2 :

 2 Results of body posture measurements in the coronal, saggital and transverse planes in women after

	mastectomy with immediate breast reconstruction (IBR), women after radical mastectomy without
	reconstruction (RM), and controls.
	MDL	I	II	III	IV	V
	MDL
	IBR		2,16 ± 1,2	3,18 ± 2,92	3,25 ± 2,89	3,11 ± 2,6	3,11 ± 2,6
	RM		2,58 ± 0,97	3,42 ± 1,12 *	5,18 ± 2,45 *	6,21 ± 2,51 **	5,99 ± 2,49 **
	CONTROL	2,33 ± 0,84
	DHSh
	IBR		4,52 ± 3,69	3,77 ± 3,10	4,01 ± 3,39	4,47 ± 3,61	4,46 ± 3,35
	RM		3,45 ± 1,33	5,69 ± 4,31 *	7,45 ± 4,85 *	8,41 ± 5,82 **	7,97 ± 5,36 **
	CONTROL	2,69 ± 1,35
	DHS
	IBR		3,34 ± 3,22	3,60 ± 3,10	3,58 ± 4,03	3,51 ± 3,79	3,39 ± 3,59
	RM		3,81 ± 2,56	4,96 ± 3,27 *	7,25 ± 4,66 *	7,64 ± 4,02 **	8,01 ± 5,80 **
	CONTROL	2,08 ± 1,24
	API
	IBR		0,78 ± 0,85	0,81 ± 0,88	0,97 ± 0,97	0,99 ± 0,94	0,99 ± 0,88
	RM		1,13 ± 0,91	1,92 ± 1,29 *	2,41 ± 1,9 *	2,62 ± 2,11 **	2,62 ± 1,81 **
	CONTROL	1,1 ± 0,99
	APR
	IBR		2,41 ±0,51	2,72 ±1,1	2,83 ±1,63	2,71 ±1,75	2,85 ±1,86
	RM		2,11 ±0,66	3,41 ±0,99*	4,50 ±1,55 *	4,61 ±1,66*	4,58 ±1,54*
	CONTROL	1,78 ±0,88
	RS
	IBR		2,99 ± 1,56	4,26 ± 2,69	4,18 ± 2,94	4,38 ± 3,24	4,28 ± 3,10
	RM		3,00 ± 1,32	6,26 ± 3,68 *	7,51 ± 5,27 *	8,31 ± 7,11 **	8,27 ± 6,18 **
	CONTROL	2,87 ± 1,16
	*	p-value < 0,05
	** p-value < 0,001
	I	before OP
	II	6 months after OP
	III 12 months after OP
	IV 18 months after OP
	V 24 months after OP


MD Carina Riediger

MD Matthias Maak

MD Bruno Sauter

MD Helmut Friess
email: friess@chir.med.tu-muenchen.de

MD Robert Rosenberg

H Friess

Surgical management of medicamentous uncontrollable biliary reflux after esophagectomy and gastric

Keywords: esophageal cancer, biliary reflux, esophagectomy, gastric pull-up

come

Surgical management of medicamentous uncontrollable biliary reflux after esophagectomy and gastric pull-up

INTRODUCTION

Management of medicamentous uncontrollable biliary reflux after esophagectomy and gastric pull-up is a challenging surgical problem. [1] Although functional disorders after esophagectomy can usually be satisfactorily handled by dietary measures in combination with specific medications, functional disorders persist in rare cases despite extensive conservative treatment procedures. Surgical reintervention is a rarely used, second-choice option. This case report describes successful surgical intervention due to medicamentous, uncontrollable biliary reflux after esophagectomy and gastric pull-up.

DESCRIPTION

We present the case of a 60-year-old male patient with severe, medicamentous, uncontrollable biliary reflux seven years after curative subtotal esophagectomy, which was performed at an external hospital in 2001 due to an infrabifurcal squamous cell carcinoma of the esophagus. Reconstruction of the intestinal passage had been performed with a total gastric pull-up in combination with a pyloroplasty to avoid gastric emptying problems. The postoperative histopathology had revealed a pT1N0M0R0 tumor. including high-dose proton pump inhibitors (PPI), antacids, metoclopramide, domperidone and cholestyramine had been initially effective, but did not maintain a satisfactory state of health as documented by endoscopy and the symptoms had worsened again in the last year before admission. Although the patient had refrained from eating in the evening, he continued to suffer from severe biliary reflux, which worsened during the night and led to coughing due to silent aspiration and vomiting.

Flexible endoscopy at our department confirmed stage II reflux esophagitis. The esophageal anastomosis at 27 cm was wide and without evidence of tumor recurrence. The gastric pull-up showed signs of gastritis and 80 ml of biliary reflux was suctioned from the gastric pull-up. The pylorus was moderately distorted, but passable. The biliary reflux was confirmed by a Bilitec measurement and, in addition, acid reflux was detected by 24-h esophageal pH monitoring. Fraction time with pH < 4.0 was 10.4%. The DeMeester score in the ph channel was 140.4. pH monitoring showed under the PPI, in addition to the biliary reflux, reflux disease, especially in the horizontal position and postprandially. In addition, manometry and barium swallow were performed.

Based on the examinations performed and the long history of worsening symptoms, we decided to operate. We performed a postbulbar exclusion of the duodenum with preservation of the right gastroepiploic artery. The intestinal passage was reconstructed with a postpyloric end-to-side Roux-en-Y duodenojejunostomy and a side-to-side jejuno-jejunostomy (Figure 1). The postoperative course was uneventful.

Immediately after the operation the patient became asymptomatic. He was discharged from our department eight days after operation. The

DISCUSSION

Reflux of duodenal and/or gastric contents after esophagectomy and gastric pull-up is a recognized problem and occurs in 60-80% of patients. [START_REF] Dresner | A human model of duodeno-gastrooesphageal reflux in the development of Barrett's metaplasia[END_REF] Patients often report after esophagectomy clinical signs of gastro-esophageal reflux such as heartburn, regurgitation, and coughing, all of which can alter quality of life. Reflux-particularly at night-causes the risk of aspiration pneumonia. Biliary and/or acid reflux can usually be well managed and controlled conservatively through dietary measures in combination with specific medications such as prokinetics (metoclopramide or erythromycin), antacids, and bile acid binders such as cholestyramine. [1,[START_REF] Aly | Reflux after oesophagectomy[END_REF] Conservative therapeutic approaches to avoid or control functional conduit disorders are usually successful. In addition, eating four to six small meals per day and staying upright for at least one hour after the meal are helpful. If symptoms persist even after all dietary and medical options have been applied, reoperation remains the ultimate therapy.

The patient presented in our case underwent an unusual reconstruction of the intestinal passage after esophagectomy, which may explain the severity of his

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

ACCEPTED MANUSCRIPT 5 symptoms. We and other large esophageal centers believe that the operation of choice, offering the best functional outcome for infrabifurcal esophageal cancer, is an abdomino-thoracic esophagectomy with gastric tube pull-up and intrathoracic anastomosis [4][START_REF] Crofts | Ivor-Lewis esophagectomy for middle and lower third oesophageal lesions-how we do it[END_REF][START_REF] Muller | Surgical therapy of oesophageal carcinoma[END_REF] (Figure 1). We would not perform a total gastric pull-up or a pyloroplasty. Nevertheless, although several surgical techniques of reconstruction after esophagectomy are described in the literature, no randomized controlled data have been published on the reconstruction of choice. [7][START_REF] Yildirim | Colonic interposition vs. gastric pull-up after total esophagectomy[END_REF] Some centers prefer a gastric pull-up; others prefer a colon interposition. Most groups that prefer the stomach for reconstruction use a gastric tube pull-up, while a few prefer a total stomach pull-up. Advantages and disadvantages have been published for each of these techniques.[7-8] Gastric pull-up for esophageal reconstruction has the advantages of reliable perfusion from the right gastroepiploic artery, the relative simplicity of the operation compared with the colon interposition, the need for only one anastomosis (esophagogastrostomy), and the functional preservation of the gastrointestinal passage. Disadvantages are the loss of gastric reservoir function after tube reconstruction, the danger of anastomotic leakage due to intrathoracic gastric secretion, and early or late reflux complications combined with silent pulmonary aspiration.

Although no randomized controlled data have been published, most high-volume centers favor the stomach and form a gastric tube as reconstruction after esophagectomy.[9-10] For better functionality it seems to be important for the gastric tube to have a diameter of about 5 cm, and the esophago-gastric anastomosis should be located above the azygos vein. In addition, the interposition should be The need for a gastric drainage procedure such as pyloroplasty or mechanical endoluminal dilatation of the pylorus after pull-up of the stomach is also a controversial topic of discussion. No data have been published that have shown any advantages of pylorus dilatation procedures. Donington state that a drainage procedure seems to be helpful, especially when the whole stomach is used as a conduit. [START_REF] Palmes | Effect of pyloric drainage procedures on gastric passage and bile reflux after esophagectomy with gastric conduit reconstruction[END_REF] We occasionally perform an endoluminal dilatation of the pylorus using a clamp, and believe that an operative pyloroplasty intensifies reflux symptoms, as demonstrated in the case presented here, and represents overtreatment to avoid gastric emptying problems.

Palmes et al. analyzed the advantages of pyloric drainage in 198 patients with gastric conduit reconstruction after esophagectomy. They compared pyloroplasty, pylorotomy and no pyloric drainage operation. There was no improvement in delayed gastric emptying problems, which were found in one third of all patients, but there was increased bile reflux and reflux esophagitis in patients undergoing pyloric drainage. [START_REF] Palmes | Effect of pyloric drainage procedures on gastric passage and bile reflux after esophagectomy with gastric conduit reconstruction[END_REF] Another group tried to reduce duodenal and biliary reflux after esophagectomy by performing 360° fundoplication around the anastomos is and the remnant esophagus.

They observed less reflux after this modification of the operation.

  The patient had suffered since the operation from biliary (alkaline) gastro-esophageal reflux, which was classified in 2006 as grade IV according to Savary and Miller, in 2007 as grade II and in 2008 as grade II-III under medicamentous treatment and before admission. At admission, the patient was suffering clinically from heartburn, regurgitation and daily vomiting at night-time. Conservative treatment with medication M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 3

  patient was completely asymptomatic in the 18-month follow-up. Postoperative pH monitoring 18 M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 4 months after the operation revealed no biliary reflux, but the acid component remained in the pH monitoring (without PPI) with a fraction time pH<4.0 of 10.4% and a DeMeester score of 140.4. The patient and his gastroenterologist were contacted postoperatively several times and both reported that the patient was completely asymptomatic under PPI medication. All symptoms (vomiting, cough and inability to eat in the evening), which were caused by the alkaline reflux, were resolved.

  E P T E D located in the posterior mediastinum. The reconstruction with a whole stomach as a conduit leads to more gastric emptying problems.

Figure 1 :

 1 Figure 1: Illustration of reconstruction techniques after esophagectomy. A: normal anatomy. B: total gastric pull-up with endto-side esophagogastrostomy and pyloroplasty. C: exclusion of the duodenum with end-to-side Roux-en-Y duodenojejunostomy and side-to-side jejuno-jejunostomy. D: tube gastric pull-up with end-to-side esophagogastrostomy.

ACCEPTED MANUSCRIPT

Although no evidence-based recommendations are available, we recommend that reconstruction after esophagectomy includes creation of a gastric tube pull-up instead of using the full-sized stomach and the abdication of pyloroplasty to avoid problems with reflux. We present the case of a patient with medicamentous, uncontrollable biliary reflux after esophagectomy, which was successfully managed by the exclusion of the duodenum and a Roux-en-Y reconstruction. We recommend this technique as a potential surgical option in patients with severe gastroesophageal reflux after esophagectomy.

Conflict of interest statement

None to declare.


MD Andreas Muth
email: andreas.muth@vgregion.sefredrik.l.persson@vgregion.sesvante.jansson@vgregion.seviktor.johanson@vgregion.sehakan.ahlman@surgery.gu.sebo.wangberg@surgery.gu.se

F Persson

S Jansson

V Johanson

H Ahlman

B Wängberg

Prognostic factors for survival after surgery for adrenal metastasis

Keywords: Adrenal gland neoplasm/secondary, Adrenal gland neoplasm/surgery, Adrenalectomy, Follow-up studies

Aim To better define the indications for adrenalectomy (adx) for adrenal metastasis we have analysed factors predicting survival in our institutional series.

Methods A consecutive series of 30 patients undergoing adx for metastasis (1996)(1997)(1998)(1999)(2000)(2001)(2002)(2003)(2004)(2005)(2006)(2007), excluding patients with simultaneous ipsilateral renal cell carcinoma (RCC), was studied. Metastases were regarded as synchronous (<6 mo), or metachronous (>6 mo), depending on the interval after primary surgery. Survival was calculated from time of adx and risk factors influencing survival were identified.

Results

The tumour diagnoses were RCC n=9, malignant melanoma n=5, non smallcell lung cancer n=5, colorectal carcinoma n=4, foregut carcinoid n=2, adrenocortical carcinoma, breast cancer, hepatocellular carcinoma, urothelial carcinoma, and liposarcoma (one each); nine adrenal metastases were synchronous and 21 metachronous. Ten patients had undergone previous surgery for extra-adrenal metastases. Out of 30 adx 10 were laparoscopic (LAdx) and 20 open (OAdx) procedures without surgical complications. The local recurrence rate was low: LAdx 1/10, OAdx 1/20, and the median survival was 23 months. Independent prognosticators of favourable survival were adx for potential cure (p=0.01), no previous metastasis surgery (p=0.02), and tumour type (p=0.043), with better prognosis for patients with adrenal metastasis from colorectal carcinoma and RCC and worse prognosis in non small-cell lung cancer and malignant melanoma.

INTRODUCTION

Metastases to the adrenal glands are present in 13-27 percent of disseminated malignancies at autopsy [START_REF] Glomset | The Incidence of Metastasis of Malignant Tumors to the Adrenals[END_REF][START_REF] Abrams | Metastases in carcinoma; analysis of 1000 autopsied cases[END_REF] with the highest figures for patients with pulmonary or renal primary tumours. However, isolated adrenal metastasis only occurs in less than one percent of these cases [START_REF] Lam | Metastatic tumours of the adrenal glands: a 30year experience in a teaching hospital[END_REF]. Adrenalectomy (adx) can render the patient tumourfree in case of isolated lesions, but the procedure can also be part of a staged treatment programme when multiple metastatic sites have been identified.

Laparoscopic adx has been claimed to be a safe alternative in suspected or confirmed malignancy [START_REF] Kebebew | Results of laparoscopic adrenalectomy for suspected and unsuspected malignant adrenal neoplasms[END_REF][START_REF] Moinzadeh | Laparoscopic radical adrenalectomy for malignancy in 31 patients[END_REF]. Only few series reporting on indications and results of surgery for adrenal metastases have so far been published [START_REF] Lo | Adrenalectomy for metastatic disease to the adrenal glands[END_REF][START_REF] Kim | The role of surgery in the treatment of clinically isolated adrenal metastasis[END_REF][START_REF] Porte | Resection of adrenal metastases from non-small cell lung cancer: a multicenter study[END_REF][START_REF] Sarela | Metastasis to the adrenal gland: the emerging role of laparoscopic surgery[END_REF][START_REF] Mercier | Surgical treatment of solitary adrenal metastasis from non-small cell lung cancer[END_REF][START_REF] Sebag | Isolated adrenal metastasis: the role of laparoscopic surgery[END_REF][START_REF] Strong | Laparoscopic adrenalectomy for isolated adrenal metastasis[END_REF]. We have analysed our institutional series to identify prognostic factors for survival and further define the indications for surgical treatment.

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PATIENTS AND METHODS

Patients A consecutive series of patients undergoing adx for metastasis to the adrenal gland (1996)(1997)(1998)(1999)(2000)(2001)(2002)(2003)(2004)(2005)(2006)(2007) was studied, i.e. from the introduction of laparoscopic adx at our centre. Patients with direct extension of a primary tumour into the adrenal gland, or renal cell carcinoma (RCC) with ipsilateral synchronous adrenal metastasis, were not studied. The clinical information was gathered through patient records from our unit and referring hospitals. All histopathological reports were reviewed.

Information on causes of death was retrieved from the Swedish Cause of Death Register. The study was approved by the Regional Ethical Review Board in Gothenburg.

Definitions Metastases were regarded as synchronous if detected within 6 months after primary surgery. Metastases discovered more than 6 months after primary surgery were defined as metachronous. Disease-free interval (DFI) was defined as the period of time the patient was tumour-free prior to detection of the adrenal metastasis. As a consequence, patients with an adrenal metastasis detected more than 6 months after primary surgery, but treated for another tumour manifestation within 6 months, thus have a metachronous adrenal metastasis with DFI less than 6 months. Disease-free and overall survival were calculated from time of adx up to tumour recurrence or death. Adx for potential cure was defined as a local R0 resection with no evidence of residual tumour at other sites.

Statistical analysis

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RESULTS

Patient characteristics

Thirty patients with adrenal metastasis (12 female, 18 male, mean (median) age 60.6 (62.5) years, range 30-79 years) were treated and fulfilled the inclusion criteria at our centre during the study period (Tab. 1). The diagnoses were RCC n=9, malignant melanoma n=5, non-small cell lung cancer (NSCLC) n=5, colorectal carcinoma n=4, foregut carcinoid n=2, adrenocortical carcinoma (metastasis to contralateral adrenal), breast cancer, hepatocellular carcinoma, urothelial carcinoma, and liposarcoma (one each).

Clinical presentation Nine patients had synchronous and 21 had metachronous adrenal metastasis; 10/21 had been subject to previous surgery for metastases. The mean (median) interval between primary surgery and detection of metastasis in the metachronous group was 80 (48) months, range 10-460, and mean (median) DFI was 10 (26) months, range 0-117. Nine patients had a DFI > 12 months. There was no mortality associated with the surgical procedure. Two patients had non-fatal procedure-related complications (stroke and atrial fibrillation/heart failure, respectively). The first patient died four months postoperatively of a myocardial infarction, the other of progressive tumour disease 36 months after adx.

Staging and diagnosis

Follow-up, recurrence and survival Complete follow-up was available in all patients. Overall median survival (95% CI) was 23 (15-31) months with a 5-year actuarial survival rate of 22.5%. Median disease-free survival (95% CI) was 6 (0.9-11) months (Fig. 1A). Three patients are alive with no evidence of disease at 101, 60 and two months of follow-up. Five patients are alive with disease after 120, 52, 34, 24 and 16 months of follow-up. Twenty patients died of their tumour disease, two of other causes (traffic accident and myocardial infarction, respectively).

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Adx for potential cure was associated with prolonged survival both in univariate and multivariate analyses, with a hazard ratio of 4.9 for patients with residual metastases (p=0.01) (Tab. 2, Fig. 1B). Previous metastasis surgery was a significant independent risk factor for worse prognosis with a hazard ratio of 5.8 in multivariate analysis (p=0.02) (Tab. 2, Fig. 1C). The mean interval (95% CI) between primary surgery and adx was 47 (2-93) months in patients without vs. 77 (31-123) months in patients with previous surgery for metastases (p=0.41). Significant differences in survival with regard to tumour type were seen (p=0.043), with longer survival for patients with colorectal carcinoma or renal cell carcinoma and shorter for those with non small-cell lung cancer (NSCLC) or malignant melanoma (Tab. 2, Fig 1D). The hazard ratio for death after metastasis surgery in patients with NSCLC vs. colorectal carcinoma was 37.6 (p=0.008). There was no statistically significant difference in survival between patients with synchronous or metachronous metastasis. However, in the metachronous group DFI > 12 months was associated with a 21 months longer median survival (log-rank test, p=0.03). No correlation between survival and gender, age at surgery, surgical technique (LAdx vs. OAdx) or size of the metastasis (> 45 mm vs. < 45 mm) was demonstrated.

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DISCUSSION

Main findings

In our consecutive 12-year series of 30 patients undergoing surgery for adrenal metastasis the overall median survival was 23 months with a 5-year actuarial survival rate of 22.5 %. This is in agreement with other investigators, e.g. Lo et al. [START_REF] Lo | Adrenalectomy for metastatic disease to the adrenal glands[END_REF] reported a 2-year survival rate of 40% in a series of 52 patients. Strong et al. [START_REF] Strong | Laparoscopic adrenalectomy for isolated adrenal metastasis[END_REF], updating a previously published series [START_REF] Sarela | Metastasis to the adrenal gland: the emerging role of laparoscopic surgery[END_REF], reported an actuarial survival rate of 37% (29/78) at 2 years, and of 17% (6/37) at 8 years; the series consisted of 92 patients. Castillo et al. [START_REF] Castillo | Laparoscopic adrenalectomy for suspected metastasis of adrenal glands: our experience[END_REF] reported a mean survival of 26 months in a series of 22 cases. Sebag et al [START_REF] Sebag | Isolated adrenal metastasis: the role of laparoscopic surgery[END_REF], found a median survival of 23 months in 16 patients; onethird was alive and disease-free at 5 years.

In our study adx for potential cure, previous metastasis surgery and tumour type were all independent prognostic factors for survival (Tab. 2). The significance of adx for potential cure as a prognostic factor has previously been identified by some [START_REF] Lo | Adrenalectomy for metastatic disease to the adrenal glands[END_REF][START_REF] Kim | The role of surgery in the treatment of clinically isolated adrenal metastasis[END_REF],

but not other, authors [START_REF] Sarela | Metastasis to the adrenal gland: the emerging role of laparoscopic surgery[END_REF][START_REF] Strong | Laparoscopic adrenalectomy for isolated adrenal metastasis[END_REF].

Impact of surgery on survival

Whether adx alters the course of disease is not easily assessed in a setting of multiple metastatic sites subject to multimodal treatment. Randomized studies have not been performed. In a small case-control study Luketich & Burt [START_REF] Luketich | Does resection of adrenal metastases from non-small cell lung cancer improve survival?[END_REF] demonstrated a prolonged median survival in patients with NSCLC and synchronous solitary adrenal metastasis undergoing chemotherapy and adx vs. chemotherapy alone (31 vs. 8.5 months). In a review of patients with melanoma metastases, Mittendorf et al. [START_REF] Mittendorf | Melanoma adrenal metastasis: natural history and surgical management[END_REF] found longer survival in surgically treated cases compared to the entire patient group. The bias in the selection of adx

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candidates is obvious. However, our finding that adx for potential cure was an independent factor for good prognosis supports a positive survival effect of adx.

Patient selection

To select patients suited for adx leading to potential cure careful preoperative work-up, and optimal imaging, is necessary. With the refinement of CT diagnostics for adrenal lesions [START_REF] Szolar | Adrenal adenomas and nonadenomas: assessment of washout at delayed contrast-enhanced CT[END_REF], dedicated adrenal CT is our method of choice for characterisation of the tumour. In line with this we no longer routinely use fine-needle aspiration cytology. 18 F-FDG-PET-CT was only performed in three patients in this series, but is now our standard procedure for staging [START_REF] Israel | Early detection of cancer recurrence: 18F-FDG PET/CT can make a difference in diagnosis and patient care[END_REF][START_REF] Czernin | Improvements in cancer staging with PET/CT: literature-based evidence as of September 2006[END_REF].

Surgical methods

No difference in survival was seen with regard to the surgical technique in this series, in line with previous studies [START_REF] Sarela | Metastasis to the adrenal gland: the emerging role of laparoscopic surgery[END_REF][START_REF] Strong | Laparoscopic adrenalectomy for isolated adrenal metastasis[END_REF]. The difference in potential curative adx rate between the LAdx and OAdx probably reflects our preference for open surgery in patients with multi-focal disease. The rate of local recurrence was low in both adx groups. However, LAdx was associated with a much shorter hospital stay than OAdx and for patients with isolated metastasis we now prefer LAdx.

Prognostic factors for survival

Tumour type was early suggested to be a prognostic factor leading to better survival in patients with metastases from adenocarcinoma [START_REF] Lo | Adrenalectomy for metastatic disease to the adrenal glands[END_REF]. In our series tumour type was a significant prognosticator with the most favourable outcome for patients with colorectal carcinoma; the shortest survival was seen in patients with NSCLC (Fig. 1D).

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Previous surgery for metastases was an independent negative prognostic factor in our series, i.e. the adrenal metastasis might represent a late manifestation of tumour disease (Fig 1C). However, the time interval between primary surgery and detection of the adrenal metastasis was not significantly longer in these patients than in those without previous metastasis surgery. Ten out of 30 patients in our series had undergone previous surgery for metastases compared to 22% in the report by Sarela et al. [START_REF] Sarela | Metastasis to the adrenal gland: the emerging role of laparoscopic surgery[END_REF] and 56% reported by Sebag et al. [START_REF] Sebag | Isolated adrenal metastasis: the role of laparoscopic surgery[END_REF].

DFI can be regarded as a surrogate marker for tumour aggressiveness. It seems reasonable to assume that patients with a long disease-free period have a more indolent course and therefore a better prognosis. In a study on adrenal metastases of NSCLC by Mercier et al. [START_REF] Mercier | Surgical treatment of solitary adrenal metastasis from non-small cell lung cancer[END_REF], and in the first two reports from the Memorial Sloan-Kettering Cancer Center [START_REF] Kim | The role of surgery in the treatment of clinically isolated adrenal metastasis[END_REF][START_REF] Sarela | Metastasis to the adrenal gland: the emerging role of laparoscopic surgery[END_REF], metachronous tumours were associated with better prognosis. In the updated MSKCC series this association was no longer evident [START_REF] Strong | Laparoscopic adrenalectomy for isolated adrenal metastasis[END_REF] and has not been confirmed by other authors [START_REF] Lo | Adrenalectomy for metastatic disease to the adrenal glands[END_REF][START_REF] Porte | Resection of adrenal metastases from non-small cell lung cancer: a multicenter study[END_REF][START_REF] Sebag | Isolated adrenal metastasis: the role of laparoscopic surgery[END_REF]. In the literature, DFI has been defined as the time interval between primary surgery and detection of the adrenal metastasis, not taking surgery for other tumour manifestations into account.

We used a strict definition of DFI as the period of time the patient was objectively tumour-free prior to the recognition of adrenal metastasis. With this definition DFI > 12 months was a positive prognostic factor in patients with metachronous metastasis.

In contrast to the present and other reports [START_REF] Kim | The role of surgery in the treatment of clinically isolated adrenal metastasis[END_REF][START_REF] Sarela | Metastasis to the adrenal gland: the emerging role of laparoscopic surgery[END_REF][START_REF] Sebag | Isolated adrenal metastasis: the role of laparoscopic surgery[END_REF] Strong et al. [START_REF] Strong | Laparoscopic adrenalectomy for isolated adrenal metastasis[END_REF] found that adrenal metastases with large diameter (>45 mm) were associated with worse prognosis. Almost half (42%) of their patients had lung cancer and tumour size may Please note that patients with metachronous metastasis and other tumour manifestations after primary surgery may have a disease-free interval (DFI) < 6 months.

  Overall and disease-free survival was calculated according to the Kaplan-Meier method. Patient gender, age at surgery, clinical presentation M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT (synchronous or metachronous tumour, DFI, previous metastasectomy), type of operation (open or laparoscopic), completeness of resection, size and histopathological diagnosis of the metastasis were evaluated using overall survival as the main outcome measure. Univariate comparisons of survival in different groups were performed with the log-rank test. Multiple stepwise Cox-regression [13] was used to construct a model relating survival to risk factors. The results given are from the final model. A p-value < 0.05 was considered statistically significant.

  Preoperative work-up included computerized tomography (CT) of the abdomen (n=28), in 10 patients supplemented with abdominal magnetic resonance imaging (MRI). Three patients were staged with 18 F-fluorodeoxyglucose-PET-CT. Fine-needle aspiration cytology of the adrenal mass was performed in seven patients, confirming the diagnosis in five. Surgical treatment The choice of surgical technique was up to the individual surgeon. Laparoscopic adx (LAdx) was preferred in isolated adrenal metastasis, while open adx (OAdx) was considered in multifocal disease or severe peritoneal M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT adhesions. 20 open adx (OAdx) and 10 LAdx were performed, the latter ones using the lateral transperitoneal approach. Three LAdx were converted to OAdx due to technical difficulties. OAdx was in eight patients combined with other surgical procedures: nephrectomy/renal resection in three, liver resection in two, splenectomy, cholecystectomy or bilateral adx in one patient each. The mean hospital stay after LAdx was four days, after OAdx ten days (p=0.05). The local recurrence rate was low in both groups (OAdx: 1/20, LAdx: 1/10, converted to OAdx) during a mean observation period of 35 and 16 months, respectively. No port-site metastases were observed. Adx for potential cure was achieved in 8/10 patients treated with LAdx and in 11/20 treated with OAdx.

Table 1 :

 1 FIGURE CAPTIONS

Figure 1 :

 1 Figure 1: Survival analysis according to Kaplan and Meier showing overall and

Table 2 :

 2 Univariate and multivariate analysis of overall survival with respect to eight different background variables.

Table 2 :

 2

	Variable	Mean survival	Univariate	Multivariate	Hazard
		in months	Analysis	analysis	ratio
		(95% CI)	(p-value)	(p-value)
	Gender		0.86	n.s.
	male (n=18)	28 (18-39)
	female (n=12)	28 (17-39)
	Tumour type colorectal cancer (n=4) renal cell carcinoma (n=9) malignant melanoma (n=5) non-small cell lung cancer (n=5) other (n=7)	42 (27-58) 56 (26-85) 17 (8-26) 12 (4-19) 26 (14-38)	0.023	0.043 0.10 a 0.13 a 0.008 0.16 a	a	1.0 a 8.5 a a 6.2 37.6 4.7 a	a
	Presentation		0.37	n.s.
	synchronous (n=9)	31 (6-56)
	metachronous (n=21)	40 (23-54)
	Disease-free interval		0.028	n.s.
	metachronous DFI<12 months (n=12)	21 (14-29)
	metachronous DFI>12 months (n=9)	57 (33-82)
	Previous metastasectomy		0.53	0.02		5.8
	no (n=20)	42 (23-60)
	yes (n=10)	24 (14-35)
	Size of metastasis		1.00	n.s.
	< 45 mm (n=12)	40 (16-64)
	> 45 mm (n=18)	36 (19-52)
	Surgical technique (OA/LA)		0.14	n.s.
	LA (n=10)	20 (12-28)
	OA (n=20)	46 (26-66)
	Adrenalectomy for potential cure		0.02	0.01		4.9
	achieved (n=19)	51 (31-72)
	not achieved (n=11)	14 (9-19)

b a Versus colorectal carcinoma. b Adx for potential cure.not achieved vs. achieved

ACKNOWLEDGEMENTS

This study was funded in part by a generous unrestricted research grant from the Region of West Sweden.

The expert assistance of Kjell Pettersson, Department of Economics, School of Business, Economics and Law, University of Gothenburg, is greatly appreciated for statistical advice and calculations.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflict of interest.

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