Moug Sj

PhD Mrcs

Smith Frca

MD ‡, C Leen Frcr

PG Roxburgh Mrcs

PhD Horgan Frcs

Evidence for a synchronous operative approach in the treatment of colorectal cancer with hepatic metastases: a case matched study

Background

Traditionally, a staged operative approach has been used for patients with synchronous colorectal cancer and liver metastases in the U.K. With improved outcomes from hepatic resection the role of a synchronous operative approach needs re-evaluated.

Methods

32 consecutive patients with colorectal cancer and hepatic metastases that underwent a synchronous operative approach were individually case matched (according to: age; sex; ASA grade; type of hepatic and colonic resection) with patients that had undergone a staged approach. The following variables were analysed: operative blood loss; in hospital morbidity and mortality; duration of hospital stay; disease free and overall survival.

Results

Operative blood losses were: synchronous group, median 475mL (range 150-850mL) vs median 425mL (range 50-1700mL), (p>0.050). There were no significant differences in morbidity: (34% synchronous group vs 59%, p=0.690) with no recorded mortality.

Synchronous group had a shorter hospital stay (median 12 days [range 8-21] vs 20 [range 7-51], p=0.008). There were no statistical differences between synchronous and staged patients for disease free and overall survival: 10 months (95% CI 5.8 -13.7) versus 14 (95% CI 12.2 -16.3); p=0.487) and 21% versus 24% at 5 years (p=0.838).

Conclusion

This present study provides supporting evidence for synchronous operative procedures in patients with colorectal liver metastases.

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Introduction

Synchronous colon cancer with liver metastases presents a unique opportunity to deal simultaneously with both the primary and secondary disease. With at least 25% of patients with colorectal cancer presenting with liver metastases at time of initial diagnosis, there is potential to perform combined hepatic and colonic resections, as well as local ablative techniques at the same laparotomy [START_REF] Blumgart | Resection and embolization in the management of secondary hepatic tumors[END_REF] . This synchronous operative approach offers the advantage to the patient of a single laparotomy and hospital stay, allowing early instigation of aggressive adjuvant therapy when indicated. In addition, one hospital stay is likely to be more cost effective than the traditional staged approach with up to twelve weeks, the usual interval, between colonic resection and hepatic resection. Despite these potential advantages, the staged approach remains the standard policy in most colorectal units in the United Kingdom. This is primarily based on evidence from earlier studies that suggested a significantly higher morbidity and mortality in patients undergoing synchronous resections compared to a staged approach [START_REF] Schlag | Resection of liver metastases in colorectal cancer-competiive analysis of treatment results in synchronous versus metachronous metastases[END_REF][START_REF] Jenkins | Hepatic resection for metastatic colorectal cancer[END_REF][START_REF] Scheele | Hepatectomy for liver metastases[END_REF][START_REF] Wanebo | Surgical management of patients with primary operable colorectal cancer and synchronous liver metastases[END_REF][START_REF] Jaeck | Surgical treatment of synchronous hepatic metastases of colorectal cancers. Simultaneous or delayed resection?[END_REF] . Indeed, one study reported mortality as high as 17% in patients undergoing synchronous resections [START_REF] Bolton | Survival after resection of multiple bilobar hepatic metastases from colorectal carcinoma[END_REF] .

The quality of hepatic surgery has improved greatly over the last two decades with advances in surgical and anaesthetic techniques, as well as radiological imaging, leading to improved short and long term outcomes [8][START_REF] Melendez | Perioperative outcomes of major hepatic resections under low central venous pressure anesthesia: blood loss, blood transfusion, and the risk of postoperative renal dysfunction[END_REF][START_REF] Fong | Liver resection in the elderly[END_REF][START_REF] Kooby | Influence of transfusions on perioperative and long term outcome in patients following hepatic resection for colorectal metastases[END_REF] . Furthermore, with the introduction of radiofrequency (RF) ablation [START_REF] Solbiati | Percutaneous radiofrequency ablation of hepatic metastases from colorectal cancer: long term results in 117 patients[END_REF][START_REF] De Baere | Adverse events during radiofrequency treatment of 582 hepatic tumors[END_REF][START_REF] Oshowo | Radiofrequency ablation extends the scope of surgery in colorectal liver metastases[END_REF] and other ablative techniques, the traditional exclusion criteria of bilobar disease and multiple hepatic metastases are no longer absolute contraindications to performing partial hepatectomy. As a result, attention has turned

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again to the role of synchronous resections, where caution is still advised especially if major colonic or hepatic surgery is being considered 15,[START_REF] Thelen | Simultaneous versus staged liver resection of synchronous liver metastases from colorectal cancer[END_REF] .

It has been the policy in this small volume surgical department to pursue a synchronous operative approach in the treatment of metastatic colorectal cancer. To determine short and long term patient outcomes, this study cased matched patients undergoing synchronous procedures to patients undergoing staged procedures.

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Methods

Patients

Ethical approval for this study was obtained from the local research and ethics committee. Thirty two consecutive patients with colorectal cancer and hepatic metastases that underwent a synchronous operative approach (synchronous group) were individually case matched with patients that had undergone a staged approach (staged group). The patients in the staged group had their colonic resection performed at another hospital and were subsequently referred to this unit for treatment of their hepatic metastases.

Patients were case matched according to: age; sex; ASA grade (American Society of Anesthesiologists); type of hepatic resection and type of colonic resection. TNM stages were compared to ensure similar pathological staging between the two groups. In addition, the Clinical Risk Scores were calculated for each patient. This prognostic score has been developed for patients with colorectal liver metastases and inclusion in this study allowed further comparison between the synchronous and staged groups.

The criteria for selection for synchronous surgery have been documented previously and included: fitness for anaesthesia; expected margin negative resection (R0) of the primary disease; no unresectable extrahepatic disease and adequate predicted volume of hepatic remnant post resection [START_REF] Schindl | The value of residual liver volume as a predictor of hepatic dysfunction and infection after major liver resection[END_REF][START_REF] Moug | Selective continuous vascular occlusion and perioperative fluid restriction in partial hepatectomy. Outcomes in 101 consecutive patients[END_REF][START_REF] Stewart | The extent of resection influences outcome following hepatectomy for colorectal liver metastases[END_REF][START_REF] Moug | The renal sequelae of a triphasic approach to blood loss reduction during hepatic resection[END_REF] . Preoperative staging included contrast-enhanced CT and/ or MRI with intraoperative unenhanced and contrast enhanced ultrasound routinely performed 21,[START_REF] Leen | Potential value of contrast-enhanced intraoperative ultrasonography during partial hepatectomy for metastases: an essential investigation before resection?[END_REF] . In patients with synchronous disease, all were considered for synchronous resections according to the above mentioned criteria, irrespective of the type of colonic or hepatic resection that would be required.

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Operative approach

All procedures in the synchronous group were performed by a single consultant surgeon (PGH), anaesthetist (DS) and radiologist (EL). The type of hepatic resection was classified as: right lobectomy (Couinaud's segments V, VI, VII and VIII); left lobectomy (segments II, III and IV); bisegmentectomy; monosegmentectomy and non-anatomical subsegmentectomy [START_REF] Couinaud | Lobes et segments hepatiques:note sur l'architecture anatomique et chirurgicale due foie[END_REF] .

Intraoperatively, the large bowel was resected first through an appropriately sited midline incision with closure of the laparotomy wound prior to commencing hepatic resection via a subcostal incision. Often, a right hemicolectomy and hepatectomy could be performed via a single subcostal incision. Partial hepatectomy was performed using a triphasic approach: preoperative active dehydration; intraoperative CVP less than 5 cm H 2 0 and continuous selective vascular occlusion (the half Pringle) [START_REF] Moug | Selective continuous vascular occlusion and perioperative fluid restriction in partial hepatectomy. Outcomes in 101 consecutive patients[END_REF][START_REF] Moug | The renal sequelae of a triphasic approach to blood loss reduction during hepatic resection[END_REF]24,[START_REF] Rmcl | Central venous pressure and its effect on blood loss during liver resection[END_REF] . Intraoperative blood loss (mL) was measured by adding the suction bottle volume to the increase in weight of surgical packs and swabs. In patients undergoing combined hepatic procedures, the hepatic resection was performed first, followed by RF ablation. RF ablation, using a water tip cooled system of 1-3 needles as required, was performed under ultrasound guidance (both unenhanced and enhanced) to both target the metastasis and to assess the ablation necrosis zone intraoperatively.

Follow up of patients

Postoperatively, patients entered the departmental surveillance programme. This consisted of serial examination and contrast-enhanced CT at six months, then at yearly intervals, up until five years after their operation. Colonoscopies were performed at one

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year, three years and five years after colonic resection. Patients that had undergone RF ablation had one additional scan at 6 weeks to allow confirmation of complete necrosis.

Outcome variables

The following variables were analysed in the synchronous group and compared to combined values from both the initial colorectal resection and subsequent hepatic surgery from the staged group: operative blood loss; in hospital morbidity and mortality; duration of hospital stay; time to recurrence and long term survival.

Thirty day morbidity and mortality were standardised using a published grading system [START_REF] Clavien | Proposed classification of complications of surgery with examples of utility in cholecystectomy[END_REF] .

Grade 0 represents no complications. Grade 1 complications resolve spontaneously or with minimal intervention i.e. antibiotics, bowel rest. Grade 2 requires moderate intervention i.e. intravenous medication, chest drain insertion. Grade 3 graded complications require surgical or radiological intervention or readmission to hospital. Grade 4 is scored when patients are left with a long standing disability, organ resection or enteral division. Grade 5 represents death. Overall, minor complications are grouped as grades 1 to 2 and major complications 3 to 5.

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Results

There were no statistical differences found between the synchronous and staged groups for age, sex and ASA grade. In addition, there were no differences in TNM staging and Clinical Risk Score between the two groups with similar numbers of patients having undergone chemotherapy and/ or radiotherapy (Table 1). Seventy-eight percent of colorectal operations were classified at major resections with 22% major hepatic resections performed (Table 2). RF ablation was performed in six patients (five synchronous patients and 1 staged patient), with only one liver metastasis ablated in each case.

Intraoperative blood losses

The median operative blood loss in the synchronous group was 475mL [mean 488mL (range 150-850mL)] versus median loss of 425mL [mean 574mL (range 50-1700mL)] for staged group (p>0.050). No patient returned to theatre with postoperative bleeding.

Postoperative outcomes

There were no significant differences in morbidity: n=11 synchronous group versus n=19 in the staged group (34% vs 59%, p=0.690). There was no recorded mortality. Table 3 shows the morbidity recorded within the synchronous group, 10 out of the 11 complications were classified as minor. The synchronous group also had a significantly shorter hospital duration (median 12 days [range 8-21] vs 20 days [range 7-51], p=0.008).

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Long term outcomes

There were no statistical differences in disease free and overall survival. The median time to cancer recurrence in the synchronous group was 10 months (95% CI 5.8 -13.7) versus 14 months (95% CI 12.2 -16.3); p=0.487) in the staged patients. The overall median survival of the synchronous versus the staged patients was 39 months versus 42 months and 21% versus 24% at 5 years (log rank p=0.838).

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Discussion

The evidence for performing staged colonic and hepatic resections comes from several earlier studies that suggested an associated greater blood loss, higher morbidity and higher mortality with synchronous surgery [START_REF] Schlag | Resection of liver metastases in colorectal cancer-competiive analysis of treatment results in synchronous versus metachronous metastases[END_REF][START_REF] Jenkins | Hepatic resection for metastatic colorectal cancer[END_REF][START_REF] Scheele | Hepatectomy for liver metastases[END_REF][START_REF] Jaeck | Surgical treatment of synchronous hepatic metastases of colorectal cancers. Simultaneous or delayed resection?[END_REF] . However, the majority of these studies were performed before the time frame of significant improvements in patient outcomes with hepatic resection. In addition, it is difficult to evaluate these early studies as there was no accepted definition of the term synchronous resection. For some authors, this was classified as hepatic resection at the time of laparotomy for the colonic primary. For others, the term synchronous referred to resection of the hepatic metastases up to three months after the primary bowel surgery.

Evidence supporting synchronous resections

Recent studies have been published that overcome some of the limitations of the earlier studies. Chua et al (2004) retrospectively analysed 96 patients that presented with colorectal cancer and liver metastases 15 . These patients underwent either synchronous (n=64) or staged bowel and hepatic resections (n=32) within the same surgical unit. For analysis of outcomes in the staged group, variables from both the primary and secondary surgery were added together and compared with the synchronous resections group. The results showed a trend towards lower volume liver resections (p=0.09) with an increased blood transfusion rate after synchronous resections (mean 326mL vs 185mL, p=0.08).

Postoperative complication rates were similar between groups (53% synchronous vs 41% staged, p=0.25) with no operative mortality. The synchronous group experienced a significantly shorter hospital stay (mean 11 vs 22 days; p=0.001). In relation to long term outcomes, no significant differences between groups (synchronous vs staged) in disease

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free survival or overall survival were found (median 13 vs 13 months, p=0.53; median 27 vs 34 months, p=0.52).

Martin and colleagues from the Memorial Sloan-Kettering Cancer Centre performed a similar analysis from a prospective database over a 17 year period [START_REF] Martin | Simultaneous liver and colorectal resections are safe for synchronous colorectal liver metastases[END_REF] . One hundred and thirty four patients (group I) underwent synchronous resections, whilst 106 patients underwent staged resections (group II). Again, the extent of hepatic disease was less in the synchronous resections group (fewer number of tumours, p=0.001; smaller tumours, p=0.009) resulting in significantly lesser hepatic resections being performed (major resections 34% group I vs 72% group II, p=0.001). In addition, right hemicolectomy was performed in 40% of synchronous resections compared to only 14% in staged resections.

Although the blood loss was significantly greater in group II, there was no difference in transfusion rates between groups. Regarding postoperative complications, the synchronous resections had significantly less (49% vs 67%, p<0.003) than group II, which on further analysis appeared to be a direct result of a second laparotomy in the staged group. This reduced complication rate also contributed to the significantly shorter hospital stay (median 10 vs 18 days, p=0.001). Perioperative mortality was exactly the same in both groups (n=3). Unfortunately this study did not analyse long term outcomes.

A retrospective multi-institutional analysis of 610 patients with colorectal liver metastases (n=135 synchronous resections, n=475 staged resections) is the largest study to date 28 . Again, they found that there were greater major colonic resections performed with larger hepatic resections in the staged group. In addition, staged patients were more likely to undergo local ablation with the hepatic resection. Hospital stay was significantly shorter in the synchronous group (median 9 vs 14 days) with morbidity and mortality not

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statistically different between the two groups (overall morbidity 36.3% vs 38.6% for simultaneous vs staged respectively, with 14.1% vs 12.5% classified as severe; mortality 1.0% vs 0.5%). This study divided the groups into major and minor hepatic resections, documenting higher rates of severe morbidity when compared to the staged group, leading the authors to state that caution should be exercised before performing synchronous colonic with major hepatic resections.

Current study supports synchronous resections

This present study provides further supporting evidence for the application of synchronous procedures in patients with colorectal liver metastases. This study overcomes some of the limitations of the studies referred to previously. Patients had no significant differences in age, sex and ASA. With no statistical differences in TNM staging and Clinical Risk Score we have compared groups with similar disease burdens. Furthermore, matching each synchronous patient according to the hepatic and colonic resection with a patient in the staged group removed any bias for performing lower volume hepatic resections and/or minor colonic resections in one group. In fact, 6 patients underwent combined major colorectal and major hepatic resections.

In agreement with Martin et al's results there were no significant differences in blood losses between the two groups [START_REF] Martin | Simultaneous liver and colorectal resections are safe for synchronous colorectal liver metastases[END_REF] . Indeed the overall blood loss was low reflecting the advances in hepatic surgery and anaesthesia. In this study, there were no patients that had documented cirrhosis. Greater blood losses have been documented in cirrhotic patients undergoing partial hepatectomy and greater losses would be expected if they were to undergo synchronous operative procedures. As a consequence, it has been suggested that extreme caution should be applied before allowing these patients to undergo a

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synchronous approach, with some authors stating that cirrhotic patients should be excluded 24 . In relation to patients that have undergone staged procedures to allow administration of chemotherapy, it has been shown that steatosis, steatohepatitis, and sinusoidal dilatation and congestion can result, leading to increased blood losses and increased morbidity after hepatic resection, although this was not clearly demonstrated in this study 29,30 . This study did not find a significant difference in complication rates between the two groups (34% synchronous vs 59% staged). Indeed, all complications in the synchronous group, excluding one, were minor that resolved during the same hospital admission. It is worth highlighting that no patient developed an anastomotic leak which has been previously cited as a reason not to perform synchronous procedures. This study has also shown that major colonic resections can be performed safely as part of a synchronous approach and that they can be combined with major hepatic resections. In particular, rectal surgery which has been previously documented as a contraindication to synchronous surgery was performed in almost half the cases in this study [START_REF] Thelen | Simultaneous versus staged liver resection of synchronous liver metastases from colorectal cancer[END_REF] .

Long term outcomes not compromised by synchronous resections

In relation to long term outcomes, no significant differences between groups in number of recurrences, disease free survival or overall survival were found. Although the study numbers were small, these results suggest that synchronous resections are safe and performing effective oncological surgery. One other area that needs further clarification is the long term outcomes after RF ablation. There are many studies stating that RF ablation is an effective and safe procedure for colorectal liver metastases, but many have focused on the technological aspects and short term outcomes only [START_REF] Solbiati | Percutaneous radiofrequency ablation of hepatic metastases from colorectal cancer: long term results in 117 patients[END_REF][START_REF] De Baere | Adverse events during radiofrequency treatment of 582 hepatic tumors[END_REF][START_REF] Oshowo | Radiofrequency ablation extends the scope of surgery in colorectal liver metastases[END_REF] . In this unit, we

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find RF ablation a useful adjunct to surgical resection. It allows metastases that lie adjacent to major vessels to be ablated safely under ultrasound guidance.

The main limitation in this study was the small patient numbers, which is a reflection of the hospital involved being a small volume centre and not a specialist hepatobiliary centre. Both colonic and hepatic resections were performed by the same surgeon, demonstrating that the synchronous approach should be considered in all hospital settings. Ideally, a randomised trial in which the two groups were matched as in this study would provide definite answers about long term outcomes in this patient group, which continues to be the outstanding unanswered question.

Conclusion

In conclusion, this study provides supporting evidence for the role of synchronous procedures in patients with colorectal liver metastases confirming that major colorectal resections can be safely performed in tandem with hepatic resections to provide effective oncological surgery.

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  SK, Pawlik TM, Zorzi D, et al. Simultaneous resections of colorectal cancer and synchronous liver metastases: a multi-institutional analysis. Annals of Surgery Oncology 2007; 14: 3481-3491. 29. Vauthey JN, Pawlik TM, Ribero D, et al. Chemotherapy regimen predicts steatohepatitis and an increase in 90-day mortality after surgery for hepatic colorectal metastases. J Clin Oncol 2006; 24:2065-2072. 30. Karoui M, Penna C, Amin-Hashem M, et al. Influence of chemotherapy on the risk of major hepatectomy for colorectal liver metastases. Ann Surg 2006; 243:1-7.

22 Table 3 :*

 223 areas represent major colorectal resections (n=25) and major hepatic resections (n=7).RF ablation -N=3 sub/monsegmentectomy and anterior resection N=1 monsegmentectomy and left/ sigmoidectomy N=1 bisegmentectomy and anterior resection N=1 bisegmentectomy and left/sigmoidectomy Type and grade of postoperative complications recorded by synchronous and staged groups. Secondary to chest infection• UTI -urinary tract infection• Clostridium difficile• Acute renal failure.

Table 1 :

 1 Comparison of patient demographics, type of operation, pathological stage and chemotherapy/radiotherapy for synchronous and staged groups.

	synchronous	staged	P value
	(n=32)	(n=32)

* denotes any type of neo-adjuvant and/or adjuvant chemotherapy and/ or radiotherapy.

Table 2 :

 2 Summary of operative procedures in synchronous group.


Haldar K Mrcog

MD Martinek Ie
email: igor.martinek@bluewin.ch

Aggressive angiomyxoma: A case series and literature review

Background: Aggressive angiomyxoma was identified as a distinct clinicopathologic entity in 1983 and since then fewer than 250 cases of these rare tumours have been reported in world literature. These tumours usually arise in the pelvis and perineal regions, most often in women of the reproductive age group; however a few cases of its occurrence outside the pelvis have also been reported.

Patients and methods:

We report a series of 7 women treated in our institute in the last 8 years. Relevant literature on aggressive angiomyxoma was looked at and various management options reviewed.

Conclusion:

Aggressive angiomyxomas are locally aggressive, notorious for local recurrence and extremely rare to metastasize. While surgery remains the mainstay of treatment, there has been a definite shift towards less radical forms of excision, over the years. Various adjuvant treatment modalities have also been tried to reduce tumour recurrence.

Introduction

Aggressive angiomyxoma (AA) is a rare, locally aggressive myxoid mesenchymal neoplasm preferentially arising in the pelvic and perineal regions of young adult females, most commonly in the reproductive age group [START_REF] Fetsch | Aggressive angiomyxoma: a clinicopathologic study of 29 female patients[END_REF]. In men, the tumour involves analogous sites including the scrotum and inguinal area and usually appears at an older age [START_REF] Idrees | Aggressive angiomyxoma of male genital region. Report of 4 cases with immunohistochemical evaluation including hormone receptor status[END_REF]. AA was first described in 1983 [START_REF] Steeper | Aggressive angiomyxoma of the female pelvis and perineum. Report of 9 cases of a distinctive type of gynecologic soft tissue neoplasm[END_REF] and since then less than 250 cases have been reported in literature, mostly in the form of small case series or isolated case reports. Though most of these tumours are locally aggressive occasional distant metastasis has also been reported [START_REF] Siassi | Metastasizing aggressive angiomyxoma[END_REF][START_REF] Blandamura | Cruz J aggressive angiomyxoma: a second case of metastasis with patient's death[END_REF].

Diagnosis, more often than not, is at histological examination following surgical resection. Pre-operative diagnosis is difficult because of rarity of these tumours and lack of typical presenting signs and symptoms. The tumour is characterised by a soft, nonencapsulated mass with finger like projections into the adjacent soft tissue.

Surgery is usually the first line of treatment. Incomplete excision is common because of the infiltrating nature of the neoplasm and absence of a definite capsule. Local recurrence is common even after complete excision. Non-surgical interventions like hormonal manipulation, radiotherapy, arterial embolization etc. have been tried with variable success rates.

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Patients and methods

From 2002 -2009, 11 women with aggressive angiomyxoma were managed in our institution. Seven of these cases were directly managed in our centre while the others were for referred for expert opinion only. Among the seven, one interesting case of AA in a pregnant woman (case 1-table 1) has previously been reported separately [START_REF] Aye | A case of multi-modal managed vulval aggressive angiomyxoma diagnosed before conception and monitored during pregnancy[END_REF]. We also performed a MEDLINE search from 1983 to July 2009 with the key words "aggressive" and "angiomyxoma" and reviewed relevant literature.

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Results

Table 1 summarizes the most relevant details for the 7 patients managed in our institution. In all but one case (case no 2), the diagnosis of AA was made only after initial surgery. The average age at diagnosis in our group of patients was just under 45 years (range 22 to 58 years), with an average disease free interval (DFI) of over 25 months. In 6 out of 7 cases histopathology confirmed involved resection margins. Five women had no recurrence following initial surgery. AA did not recur in the patient with clear margin.

Case no 1 did respond well to GnRH-agonist therapy each time however recurred after discontinuation. Case no 2 was given GnRH-agonist as a neo-adjuvant treatment with the aim of tumour reduction but the treatment was unsatisfactory and the patient had to undergo surgery.

The MEDLINE search yielded 93 single case reports of this rare neoplasm in women if limited to the perineum and pelvis, and thirty-four of them in men. Ten cases of AA are reported in other parts of the body as well as two rare cases of lung metastases. A further 98 patients including both sexes are reported in series (n= 2 to 29 cases) bringing the whole number of cases reported in the literature to under 250 since the first description of AA in 1983.

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Discussion

Aggressive angiomyxomas are locally invasive connective tissue tumours presenting in about 90% of cases in women of reproductive age group with a peak incidence in the fourth decade of life [START_REF] Chan | aggressive angiomyxoma in females: is radical resection the only option?[END_REF]. The initial presentation varies from an asymptomatic perineal or vulval nodule/polyp or perineal hernia to a pelvic mass diagnosed on imaging studies.

Occasionally, the tumour can be cystic and mistaken for a Bartholin's, labial or Gartner's duct cyst. They can exhibit a slow and insidious growth pattern and hence patients may be asymptomatic for long time until they become conscious of the significant size of the tumour. Tumour recurrences, like the primary ones, are often asymptomatic.

Pre-operative diagnosis is often a problem because of the rarity of these neoplasms and lack of typical features and most cases are diagnosed on histology after primary surgical excision. Accurate diagnosis before surgical excision is important in planning extent of excision and patient counseling.

Imaging characteristics of angiomyxomas

Ultrasound is helpful in this regard and usually demonstrates a hypo echoic soft tissue mass that may even appear cystic. CT appearances are variable and include a welldefined homogenous mass hypo dense relative to muscle, a hypo attenuating solid mass with swirling internal pattern with contrast or a predominantly cystic appearing mass with solid components [START_REF] Jayadevan | Imaging features of aggressive angiomyxoma[END_REF]. With MRI imaging an iso intense or less commonly hypo intense mass (compared to muscle) on T1 and hyper intense on T2 weighted images is characteristic. MRI imaging is accurate in detecting trans-levator spread and also is helpful in surgical planning by defining relation of the mass with anal sphincter, urethra, bladder and pelvic side-wall [START_REF] Jayadevan | Imaging features of aggressive angiomyxoma[END_REF]. Recurrent tumor is also detected consistently in MRI scans and recurrent lesions have similar signal characteristics as that of primary tumor.

Histopathological findings

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Macroscopically these tumors often have a smooth surface, partially or completely encapsulated and cut surface gives a glistening, gelatinous appearance, bluish grey in color, with areas of hemorrhage and congestion. They are usually homogenous in consistency with no obvious nodularity [START_REF] Steeper | Aggressive angiomyxoma of the female pelvis and perineum. Report of 9 cases of a distinctive type of gynecologic soft tissue neoplasm[END_REF].

Histologically they reveal a hypo cellular mesenchymal lesion consisting of a sparse population of bland spindled and stellate cells scattered in a background of loose myxoid stroma (Fig 1) composed of wavy collagen fibrils. The cells have abundant wispy pink cytoplasm with bland nuclei. There is no cytologic atypia, no atypical mitotic features or discernible mitotic activity and no evidence of coagulative tumor cell necrosis either. The lesion often also shows numerous blood vessels of varying caliber [START_REF] Steeper | Aggressive angiomyxoma of the female pelvis and perineum. Report of 9 cases of a distinctive type of gynecologic soft tissue neoplasm[END_REF]. The stromal cells can show immunoreactivity to different combinations of vimentin, desmin, smooth muscle actin, muscle specific actin, CD 34, estrogen and progesterone receptors [START_REF] Smith | Aggressive angiomyxoma of the female pelvis and perineum: review of the literature[END_REF].

Recurrent tumors usually show similar histological characteristics.

Angiomyxoma genetics

Chromosomal abnormality involving chromosome 12, associated with rearrangement of HMGIC gene, has been reported in cases of AA [START_REF] Nucci | Chromosomal translocation t(8:12) induces aberrant HMGIC expression in angiomyxoma of vulva[END_REF]. On one hand the lack of consistent HMGIC expression in the vascular component and on the other hand very high frequency of HMGIC expression in the spindled stromal cells might suggest that this is the true neoplastic component and that the admixture of blood vessels may be a secondary phenomenon. Localization of HMGIC to neoplastic stromal cells of aggressive angiomyxoma by immunohistochemistry might be applied as a diagnostic tool in assessing margins status, which might be extremely difficult to assess on morphologic grounds alone [START_REF] Nucci | Chromosomal translocation t(8:12) induces aberrant HMGIC expression in angiomyxoma of vulva[END_REF].

Tumour characteristics and surgical management

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Angiomyxomas are locally aggressive tumors and distant metastasis has only been reported in two occasions [START_REF] Siassi | Metastasizing aggressive angiomyxoma[END_REF][START_REF] Blandamura | Cruz J aggressive angiomyxoma: a second case of metastasis with patient's death[END_REF]. In view of the high risk of local recurrence, wide local excision with tumor-free margins was initially thought to be the treatment of choice. Reexcisions, if the initial surgery was deemed incomplete, were also advocated.

Involvement of bladder, gastrointestinal tract and bone has been described with angiomyxomas and in such situations extensive surgical resection, with significant operative morbidity, would be necessary to achieve clear margins. A review of over 100 cases however refuted this belief and showed that patients with clear resection margins were as prone to developing recurrences. The chances of remaining disease free were not statistically different from those who had incomplete resection, 50% vs. 40% in 10 years [START_REF] Chan | aggressive angiomyxoma in females: is radical resection the only option?[END_REF]. Also, excluding one case of metastasizing angiomyxoma, these tumors are not life threatening, even primary and recurrent tumors are often asymptomatic. Fertility is also an important factor as most of these tumors occur in women of the reproductive age group and radical resection in such situations may not be the best option. Thus though complete excision is still the aim, incomplete removals are acceptable when high operative morbidity is anticipated and fertility preservation is an issue [START_REF] Chan | aggressive angiomyxoma in females: is radical resection the only option?[END_REF].

Adjuvant therapies

Most of these tumors show estrogen and progesterone receptor positivity [START_REF] Ca | Aggressive angiomyxoma of the female tract: A clinic-pathologic and immunohistochemical study of 12 cases[END_REF] and are likely to be hormone dependant. Hormonal manipulation is thus thought to be a viable treatment option. GnRH analogues have been used in a few instances in premenopausal women with AA [START_REF] Mccluggagu | Aggressive angiomyxoma of vulva: dramatic response to gonadotropin-releasing hormone agonist therapy[END_REF] but re-growth of tumor can occur, as in one of our patients, once therapy is discontinued. Pre-operative shrinking of tumors using GnRH analogues might increase chances of complete excision and minimize the radicality of surgical procedure [START_REF] Sereda | Aggressive angiomyxoma of the vulva: a case report and review of the literature[END_REF]. One patient treated with tamoxifen however continued to have tumor growth in spite of ongoing treatment [START_REF] Magtibay | Aggressive angiomyxoma of the female pelvis and perineum: A case series[END_REF].

Due to low mitotic activity radiotherapy or chemotherapy is unlikely to be a useful adjunct to primary surgery [START_REF] Fetsch | Aggressive angiomyxoma: A clinic-pathologic study of 29 female patients[END_REF]. We could find no reports of use of chemotherapy in

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treatment of AA. Pre-operative external beam irradiation and intra-operative electron beam radiotherapy was used in one case to reduce risk of recurrence but follow-up data on the same is not available [START_REF] Nyam | Large aggressive angiomyxoma of the perineum and pelvis: An alternative approach[END_REF]. Two cases of successful control of recurrent angiomyxoma with relatively high doses of external radiotherapy have also been reported [START_REF] Rhomberg | Aggressive angiomyxoma: Irradiation for recurrent disease[END_REF][START_REF] Suleiman | Pelvic excision of large angiomyxoma in a woman: Irradiation for recurrent disease[END_REF]. Angiographic embolization has also been attempted to shrink the tumor pre-operatively and thus increase the chances of complete removal [START_REF] Nyam | Large aggressive angiomyxoma of the perineum and pelvis: An alternative approach[END_REF]. The fact that the tumor might derive its blood supply from multiple sources rather than a singular feeding vessel would reduce the success of such procedure [START_REF] Chan | aggressive angiomyxoma in females: is radical resection the only option?[END_REF].

Equally, a trial of watchful waiting in case of asymptomatic patients with recurrent tumors or with large tumors where surgery carries significant morbidity might be a reasonable option [START_REF] Behranwala | Aggressive angiomyxoma: A distinct clinical entity[END_REF].

Recurrence is one of unique characteristics of these otherwise non-malignant tumors.

The usual sites of recurrence reflect the sites of the primary disease i.e. perineum, pelvis, ischio-rectal fossa and retro-peritoneum. No definite relation between patient's age and size of tumor and rate of recurrence has been established so far [START_REF] Chan | aggressive angiomyxoma in females: is radical resection the only option?[END_REF].

Recurrences generally occur in the first 5 years after primary surgery, about 70% in the first 3 years, but late recurrences up to 14 years have been reported. Follow-up should be clinical supplemented by radiological investigations; especially MRI scans [START_REF] Jayadevan | Imaging features of aggressive angiomyxoma[END_REF].

Angiomyxomas and pregnancy

Though angiomyxomas are common in the reproductive age group women, very few reports are available to clearly define their behavior in pregnancy. There is one report of recurrence of previously treated angiomyxoma in a woman during her pregnancy [START_REF] Fishman | Aggressive angiomyxoma of the pelvis and perineum. A case report[END_REF].

One of our patients, while being followed up for recurrent disease became pregnant. The lesion was followed up throughout her pregnancy with MRI scans showing only marginal increase in size. This could be attributable to the hormone dependency of these tumors.

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Conclusion

Aggressive angiomyxomas are rare, locally aggressive tumors, arising mainly in the female pelvis with a high likelihood of recurrence even after complete surgical excision.

Pre operative diagnosis is difficult due to its rarity and lack of characteristic features.

Hence, AA should be considered a possibility in case of atypical mass lesion in the female pelvis or perineum. Few management options are available and multimodal therapy may be a good option. Patient counseling, multi disciplinary approach and individualization of each case and follow-up are essential for adequate management.

Fig 1 -Fig 2 -

 12 Fig 1-Microscopic appearance: The hypo cellular stroma and abundance of blood vessels of varying calibre are evident.Fig 2-Macroscopic appearance: perineal angiomyxoma resected at initial surgery, Case 1 of our series.

Table 1 : Summary of patients with aggressive angiomyxoma (AA):

 1 GnRH analogue : gonadotropin-releasing hormone agonist therapy; DFI: disease Free Interval ; WLE: Wide Local Excision

	ARTICLE IN PRESS

Acknowledgements

We thank Dr. Sunanda Dhar, Consultant Gynaecological Pathologist, for her help.


Kalra S Al

MRCS Mr S Kalra

Abudu Frcs

MD Mr H Murata

Mr Rj

Grimer Frcs

Mr Rm

Tillman Frcs

Mr Sr

Carter Frcs

We present our experience of treating patients with tumours involving the whole femur with excision and total femur endoprostheses over the last 30 years (1975 to 2005). There were 26 consecutive patients (14 men and 12 women). Average age was 40 years (14 -82 years) at the time of surgery and 21 of the patients had primary malignant bone tumours with five having the procedure for metastases. 11 patients were still alive of which nine were free of disease at the time of review at a mean follow-up of 57 months (3 to 348). The overall patient survival at 10 years was 37%. The survival of patients with a primary localised tumour was 50% at 10 years.

Revision of the prostheses was necessary in two patients (at 110 and 274 months) because of recurrent dislocation and aseptic loosening. Amputation was necessary in two patients but long-term limb survival was 92% at 10 years. Nine patients alive with no evidence of disease had a mean MSTS functional score of 72%.

Introduction

Tumours involving the whole femur present a challenge when limb preservation is considered. These tumours are often large and resection involves removal of the whole femur with disruption of the hip abductor mechanism. Extensive soft tissue dissection and reconstruction of the joint above and below are required.

The options for treating such patients include amputation by hip disarticulation or limb preserving surgery. Limb preserving surgery is better accepted by patients, is more cost effective in the long term, and is associated with significantly lower oxygen consumption and energy requirements per meter walked compared to amputation [START_REF] Grimer | The cost-effectiveness of limb salvage for bone tumours[END_REF][START_REF] Otis | Energy cost during gait in osteosarcoma patients after resection and knee replacement and after above-knee amputation[END_REF] . Moreover, patients' survival is not improved by amputation [START_REF] Gebhardt | Long-term results of limb salvage and amputation in extremity osteosarcoma[END_REF] . The choices available for reconstruction in such patients include the use of endoprostheses, allograft or rotationplasty [START_REF] Buchman | The femur and knee joint replacement with a vitallium endoprosthesis[END_REF][START_REF] Mankin | Long-term results of allograft replacement in the management of bone tumours[END_REF][START_REF] Marcove | Total femur and total knee replacement[END_REF][START_REF] Morris | Modular endoprosthetic replacement after total resection of the femur for malignant tumour[END_REF][START_REF] Nerubay | Total femoral replacement[END_REF][9][START_REF] Steinbrink | The total femoral prosthesis: a preliminary report[END_REF][START_REF] Hardes | Rotationplasty type B1 versus type BIIIa in children under age of ten years. Should the knee be preserved?[END_REF][START_REF] Winkelmann | Type-B-IIIa rotationplasty: an alternative operation for the treatment of malignant tumors of the femur in early childhood[END_REF][START_REF] Horowitz | Prosthetic and extremity survivorship after limb salvage for sarcomas: How long do the reconstructions last ?[END_REF] .

We carried out a retrospective review of patients treated with Total Femur Endoprosthetic Replacement (TFEPR) at our centre over the past 30 years to identify the factors which affect survival, complications and function following TFEPR.

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Kalra S et al 6

Materials and Methods

Data Collection and Ethics:

This was a retrospective analysis of data which had been collected prospectively onto our oncology database with further reference to patient charts and radiographs where necessary. Institutional review board ethical approval was granted prior to the study being undertaken.

Tumour diagnosis, treatment and outcome data was obtained from the database. Functional outcomes were collected on surviving patients using the revised Musculoskeletal Tumour Society (MSTS) system [START_REF] Enneking | A system for the functional evaluation of reconstructive procedures after surgical treatment of tumours of the musculoskeletal system[END_REF] and the Toronto Extremity Scoring System (TESS) scores [START_REF] Davis | Development of a measure of physical function for patients with bone and soft tissue sarcoma[END_REF] .

Patients:

Total femoral replacement was indicated for patients with tumour involving all or most of the femur and in whom no other reconstructive option was deemed feasible. 26 patients (14 men and 12 women; mean age: 40 years, range: 14 -82 years) underwent this procedure over 30 years. The oncological diagnoses in these patients were: Osteosarcoma in 10 patients, Chondrosarcoma in 5, Ewing's sarcoma in 2, Malignant Fibrous Histiocytoma in 1, Leiomyosarcoma in 1, Fibrosarcoma in 2 and Secondary Bone Metastases in 5 patients. Three of the 21 patients with primary bone tumours had lung metastases at the time of diagnosis. These three and the five with secondary bone metastases were considered to be palliative resections whilst the others were treated with curative intent.

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Kalra S et al 7

The operation involved disarticulation of the hip and knee with removal of the entire femur, surrounding muscles involved with the tumour, while preserving the neurovascular bundle in all cases. In four patients who had inadvertent prior intramedullary nailing for the treatment of a pathological fracture of the femur, the nail was removed with the resected bone and the entry portal and tract were also excised (Figures -1a to1c).

Surgical Procedure:

A custom made cemented total femur endoprosthesis (Stanmore Implants ®) was used in 24 patients and a modular cemented total femur endoprosthesis (Stanmore Implants ®) was used in two patients. The modular prostheses only being available more recently and being used for patients with metastatic disease to avoid the delay in manufacturing a custom implant.

The knee joint was reconstructed with a fixed hinge prosthesis in all but two patients and the hip was reconstructed with either a 32mm metal on high molecular weight polyethylene cup or more recently with a unipolar head which allowed the use of larger femoral heads with greater stability.

Adjuvant Treatment:

Patients had chemotherapy and radiotherapy appropriate for their diagnosis.

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Kalra S et al 8

Statistics:

Statistical analysis included descriptive statistics and analytical statistics including Kaplan Meier survival analysis.

Results

Patient survival:

Kaplan Meier survival curves are shown in Figure -2. Survival of the patients was related to their oncologic diagnosis. None of the eight patients with metastases at diagnosis undergoing palliative resection were alive at long followup. However, survival of patients with a primary malignant bone tumour without metastases was 50% at 5 years. Eleven patients were alive with an overall mean follow-up of 105 months (range 9 to 348), nine patients being free of disease.

Local recurrence:

Local recurrence was seen in patients with primary osteosarcoma (one), primary chondrosarcoma (one) and metastatic renal cell carcinoma (one). No local recurrence was seen in the three patients who had a primary malignant bone tumour but had been inadvertently treated with an intramedullary nail. Local recurrence was treated with surgery and adjuvant treatment while amputation was required in one patient.

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Kalra S et al 9

Limb survival:

Complications that led to amputation occurred in patients with deep infection (one) and local recurrence (one). Limb survival using amputation as the end point was 92% at 10 years.

Complications that led to revision of the prosthesis were aseptic loosening of the acetabular cup (one) and recurrent dislocation of the hip (one). The survival of the prosthesis without revision surgery was 100% at 5 years and 80% at 10 years.

Complications:

Complications which did not impact on limb or prosthetic survival were dislocations in the early postoperative period (three) which resolved with appropriate muscle rehabilitation, two wound infections which resolved with appropriate antibiotics and one foot drop which recovered spontaneously. One deep infection required amputation.

Functional outcomes:

The function of the salvaged limbs was assessed using the revised Musculo-Skeletal Tumour Society (MSTS) rating system [START_REF] Enneking | A system for the functional evaluation of reconstructive procedures after surgical treatment of tumours of the musculoskeletal system[END_REF] . This system assesses 6 parameters on a 5 point scale (1 to 5 with 5 being no limitation). Nine patients who had no evidence of disease at last follow-up were assessed at mean follow-up of 125 months (range: 8 -348). The mean functional score was 21.8 (14 -29). The scores for the individual components are summarized in Table-1. Five of the nine patients who were alive with no evidence of disease also had TESS scores. The mean TESS scores were 52.4% (range: 20-86).

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Kalra S et al 10

Discussion

The last few decades have witnessed increased popularity and wider acceptance of endoprosthetic replacement in treating patients with malignant conditions of the bone due to the availability of effective chemotherapy, improved prosthetic design, availability of modular endoprosthesis and increasing experience in the use of these implants.

Total Femur Endoprosthetic Replacement is a major surgical reconstructive procedure for patients with a bone tumour involving the entire femur. The procedure is challenging both for the surgeon and equally for the patient.

The patient needs intensive rehabilitation after the procedure as all muscle attachments of the femur are detached although in selected cases attempts were made to reattach the hip abductors. This has been emphasised in the literature [START_REF] Morris | Modular endoprosthetic replacement after total resection of the femur for malignant tumour[END_REF] .

Limitations:

A major limitation of this study was the length of time over which the data was accrued. This is because total femur replacement is not a common procedure. It is rarely needed, and most patients with a bone tumour can be treated with a less extensive form of reconstruction. We have only been able to evaluate the function in the survivors.

However, we believe that the function would have been similar in those who did not survive their disease.

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Kalra S et al 11

Literature review:

We did an extensive literature review and compared the outcomes in this study with those by other authors for this complex reconstructive procedure (Table-2).

Reported results of total femur endoprosthetic replacement have demonstrated the relative success of the procedure in terms of limb salvage but relatively poor functional outcomes. The main problems reported by most authors are the relative lack of muscles especially the abductors of the hip and quadriceps in the knee. Even so, there are psychological and rehabilitative advantages of limb preserving surgery over amputation [START_REF] Rougraff | Limb salvage compared with amputation of osteosarcoma of the distal femur[END_REF] .

Our results show that in the majority of patients the goal of limb salvage is achievable with good long term prosthetic (80%) and limb survival (92%). However, the oncologic diagnosis is the major determinant of patient survival.

Soft tissue reconstruction:

Morris et al emphasized the importance of maintaining the proximal and distal muscles if good or excellent results are to be achieved. They suggested that reattachment of the abductors to the endoprosthesis often fails and therefore they suture the abductors to the fascia lata. They also emphasised that the rectus femoris should be saved, if possible [START_REF] Morris | Modular endoprosthetic replacement after total resection of the femur for malignant tumour[END_REF] .

In our study patients reported very good psychological acceptance after total femur replacement with a mean score of 4.5 out of 5 despite having poor gait patterns which are primarily due to the lack of good abductor muscle attachment.

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Kalra S et al 12

Hip dislocation:

Hip dislocation is a common complication reported after total femur replacement. This is probably due to the lack of functional abductor musculature and the long lever arm of the total femur replacement. In non-tumour cases this can be as low as 12%. [START_REF] Berend | Total femoral arthroplasty for salvage of end-stage prosthetic disease[END_REF] It was comparably low at 11% in the present series. We believe that a rotating hinge design at the knee should be avoided in patients with total femur replacement since rotation at the knee can lead to hip dislocation and we have seen aseptic loosening of the tibial implant only on one occasion at 22 years. Also, we have noticed a lower dislocation rate since we stopped replacing the acetabulum routinely; we now recommend hemiarthroplasty of the hip whenever possible since this allows the use of a larger femoral head.

Infection:

The deep infection rate in this series was 7% and similar to the series of Nerubay et al. 8. Superficial infections were treated with antibiotics and deep infections with two stage revisions if the patients general condition allowed it.

Aseptic loosening:

Aseptic loosening rate of 3.6% in our series was comparable to non-tumour series [START_REF] Berend | Total femoral arthroplasty for salvage of end-stage prosthetic disease[END_REF] .

Loosening occurred in one patient at the acetabular cup which was revised twice and once at the acetabular cup and the tibial stem when the whole prosthesis was revised.

This may be due to decreased muscle forces placed on the implants in patients with malignant bone tumours who have undergone muscle resection as part of their tumour operation.

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Kalra S et al 13

Local recurrence:

Local recurrence is a common problem with tumour resection and total femur endoprosthetic replacement since the patients often have large tumours. In our series this was low (11%) compared to the literature. This is attributable to better adjuvant treatment in the present time. The incidence of local recurrence has been found to be inversely proportional to the effectiveness of chemotherapy [START_REF] Simon | The clinical utility of preoperative therapy for sarcomas[END_REF][START_REF] Grimer | Surgical outcomes in osteosarcoma[END_REF] and effective chemotherapy will decrease its incidence even in marginal excisions. [START_REF] Grimer | Surgical outcomes in osteosarcoma[END_REF]

Conclusion:

We believe that our series presents the results of what can be expected in the long term for patients with malignant bone tumours who require total femur endoprosthetic replacement. This form of reconstruction provides predictable results after excisions of the femur for malignant tumours. The complications are comparable to those for similar procedure performed for non-tumour cases even though those with a tumour have more muscle resection and are immunologically challenged from adjuvant chemotherapy. A long term prosthetic survival of 80% and long term limb survival of 92% in this series would imply that this procedure is an excellent method of limb salvage for massive excisions of the femur for primary bone tumour. In those with secondary metastasis this can be a viable palliative procedure to enhance the quality of life of the patient.

  Figure and Table Legend

Figure- 1a :

 1a Figure-1a: A 31 years old woman presented with a pathological fracture of the proximal

Figure- 1b :

 1b Figure-1b: Proximal femoral fracture was inadvertently nailed. Subsequent histologic

Figure- 1c :

 1c Figure-1c: Treated with complete excision of the femur and total femoral endoprosthetic

Figure- 2 :

 2 Figure-2: Kaplan Meier survival curve for all patients.

Figure- 2 :

 2 Figure-2: Kaplan Meier survival curve for all patients.

Table - 1: MSTS functional scoring Table -2: Outcomes

 - in Total Femoral Endoprosthetic Replacements in the literature and the present study

					ARTICLE IN PRESS ARTICLE IN PRESS
	Study		No. of	Diagnosis Oncologic	Followup	Limb /	Functional	Complications
	Score (Reference)	patients	Mean	Range survival	(years)	Percentage Prosthetic outcome
							survival
	6		19	Tumour	68.4% at	1.5	Score Amputa-	Hip -good	Wound (3), local
					17.5 months		tion (5)	Knee -poor;	recurrence (2),
	Pain			3.7	2 -4		74%	Poor gait -Extremity behaved	Femoral Artery thrombosis (1),
								like a	Infection (3), hip
	M A N U S C R I P T 'weak polio leg' dislocation (1) 66% 68% 74% 62% 90% 72.6% Table-1 Functional scoring: MSTS scoring Function 3.3 3 -5 Walking 3.4 2 -5 Support 3.7 3 -5 Gait 3.1 1 -5 Emotion 4.5 4 -5 Overall 21.8 14 -29 10 28 Mixed 50% at 1-year 3 86% at 3 years Hip-satisfactory Knee-poor Infections (11) 8 19 Tumour 36.8% at 4 years 4 (longest 8 years) 44% at 4 years Excellent (5), Good (9), Fair (3), Poor (2) Amputation due to deep infection (1), wound (9) 24 1 Tumour 35 years 35 32 years Ambulation with walker Possible infection 25 21 Mixed 2 years in survivors 2 (longest 10 years) Hip disarticulati on (3) Good (7), Fair( 9), Poor (3); Younger patients(<60) did better than older ones (>60) Local recurrence (2), Infection (4), hip dislocation (2), internal malrotation (1), 20 6 (children) Tumour 83% at 5 years 5 100% limb survival at 5 years MSTS -77.3% Deep infection (1), Revisions (5) 21 59 Non-tumour -4.8 60% prosthetic survival at 4.8 years Harris Hip Score -33.8 of 44, Knee pain scores -42.8 of 50 Infection (8), Dislocation (7), tibial aseptic loosening (3) 19 6 Mixed -3 53% Not reported for Total Femur Infection, loosening, periprosthetic A N U S C R I P T fracture 26 15 Mixed tumour 38.46% 4 Prosthetic Trendelenburg gait implants (5), less Infection (1), M (All revision (3) in all-metallic No dislocations
	27 28 Present Study	A C C E P T E D except 2) 100 Non-tumour -5 7 Tumour --28 Tumour 37% (overall) and 50% (primary tumour) at 10 years 4.8 (longest 29 years) A C C E P T E D localised	Prosthetic revision (9), Amputation (2). 100% limb survival at 5 and 10 years 92% limb survival and 80% survival at 10 years prosthetic	gait problem in allograft-metallic prosthesis hybrids (10). Enneking Functional Score for hip -3.29 (preop-1.25) and for knee -3.29 (preop-2.09); Trendelenburg gait MSTS -19.5 MSTS -21.8 of 30 (72.6%), TESS -52.4%	Deep infection (12), dislocation (6), Material failure (3), patellar problems (2), Peroneal nerve palsy (1) -Loosening (1), dislocation (3), deep infection (2), foot drop (1), amputation
	Table -2: Outcomes in Total Femoral Endoprosthetic Replacements in the literature and the
	present study


MD Venelin M Gerganov
email: vgerganov@gmail.com

M Giordano
email: giordano@ini-hannover.de

C Herold
email: herold@ini-hannover.de

A Samii
email: asamii@ini-hannover.de

M Samii
email: samii@ini-hannover.de

VM • Gerganov

Giordano

• Herold

A, MD, PhD; • Samii

An electrophysiological study on the safety of the endoscope-assisted microsurgical removal of vestibular schwannomas

Keywords: Vestibular schwannoma, endoscope -assisted microsurgery, retrosigmoid approach, intraoperative electrophysiological monitoring

Endoscopy is being increasingly used in skull base surgery. The issue of its safety, however, has not been definitely solved.

Methods

We evaluated the risk of thermal or mechanical iatrogenic nerve injury related to endoscope application during microsurgical removal of vestibular schwannomas (VS) in a prospective group of 30 patients (Group A). Main analysed parameters were electrophysiological monitoring data (auditory evoked potentials and EMG) during and after endoscopic observation. The structural and functional preservation of facial and cochlear nerves, radicality of tumour removal, and CSF leak rate were evaluated and compared to historical group of 50 patients (Group B), operated consecutively with classical microsurgical technique.

Results

No electrophysiological changes directly related to endoscope were registered. The rate of loss of waves I, II, and V did not depend on application of endoscope and was similar in both groups. The functional and general outcome was also similar. Endoscopic inspection provided early and detailed view of anatomical relations within cerebellopontine angle and internal auditory canal and confirmed completeness of tumour removal. Total tumour removal was achieved in all patients from Group A and in 49/50 from Group B. Useful hearing after the surgery had 17/30 patients in Group A and 26/50 in Group B.

Conclusions

The application of endoscope during microsurgical removal of VS is a safe procedure that does not lead to heat-related or mechanical neural or vascular injuries. The actual significance of this additional endoscopic information, however, is related to the particular operative technique and experience of the surgeon.

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The endoscope is an established component of contemporary brain tumour surgery armamentarium. Its application in various skull base procedures, either as a sole visualizing tool or as an adjunct to the microscope, is constantly expanding [START_REF] Monfared | Cranial base approaches to inaccessible intracranial tumours[END_REF]. The endoscope provides superior illumination and magnification, as well as possibility "to look around the corner", thus allowing for more radical but safe surgeries [START_REF] Perneczky | Endoscope-assisted brain surgery: part 1--evolution, basic concept, and current technique[END_REF]. The endoscope-assisted microsurgery (EAM) combines the advantages of both the classical microneurosurgery and endoscopy. Its application in case of lesions located in cerebellopontine angle (CPA), offers the possibility to identify at an early stage various structures and their relations, as well as to look for hidden tumour parts [START_REF] Wackym | Endoscopy in neuro-otologic surgery[END_REF]. In case of vestibular schwannomas (VS) the whole internal auditory canal (IAC) up to its fundus can be inspected without increasing the risk of violation to the bony labyrinth; thus tumour remnants or opened air cells are readily visualized [START_REF] Goksu | Endoscopy of the posterior fossa and dissection of acoustic neuroma[END_REF][START_REF] Göksu | Evaluation of the results of endoscope-assisted acoustic neuroma surgery through posterior fossa approach[END_REF][START_REF] Mckennan | Endoscopy at the internal auditory canal during hearing conservation acoustic tumour surgery[END_REF][7][START_REF] Wackym | Adjunctive use of endoscopy during acoustic neuroma surgery[END_REF].

The issue of the safety of the endoscopic technique, however, has not been definitely solved. When inserting the endoscope through the complex lattice of nerves and vessels in the CPA, a risk of mechanical injury exists [START_REF] Miyazaki | Neuro-otologic surgery through minimally invasive retrosigmoid approach: endoscope assisted microvascular decompression, vestibular neurotomy, and tumour removal[END_REF]. The close observation of vulnerable structures, such as cranial nerves or tiny vessels, exposes them to a potential risk of thermal injury from the heat generated by the light of the endoscope. Although a general awareness of these risks exists [START_REF] Goksu | Endoscopy of the posterior fossa and dissection of acoustic neuroma[END_REF][START_REF] Wackym | Adjunctive use of endoscopy during acoustic neuroma surgery[END_REF][START_REF] King | Endoscope assisted Surgery for acoustic neuromas (Vestibular Schwannomas): early experience using the rigid hopkins telescope[END_REF][START_REF] Hori | Endoscope-controlled removal of intrameatal vestibular schwannomas[END_REF], their clinical significance has not been addressed systematically. The goal of the current study was to evaluate the safety of the EAM technique and the outcome after its application in a prospective series of patients with VS.

Methods and patients

A prospective study was performed that included 30 patients with VS operated via the retrosigmoid approach with the EAM technique. The inclusion criteria were: presence of unilateral sporadic vestibular schwannomas, age above 20 years, primary surgery, normal facial nerve function, and presence of functional hearing on the involved side preoperatively.

Patients with neurofibromatosis type 2, previous surgical or radiosurgical treatment, previous infectious diseases of the brain, facial palsy and/or severe hearing loss, have been excluded.

The Hannover VS extension classification system was applied [START_REF] Samii | Management of 1000 vestibular schwannomas (acoustic neuromas): surgical management and results with an emphasis on complications and how to avoid them[END_REF]. Facial nerve function was assessed using the House-Brackmann grading system [START_REF] House | Facial nerve grading system[END_REF]. Hearing was graded according to the New Hannover Classification. Hearing Classes H1 to H2 with pure tone average of up to 40 dB and speech discrimination score more than 70%, were accepted as functional hearing levels [START_REF] Samii | Management of 1000 vestibular schwannomas (acoustic neuromas): hearing function in 1000 tumour resections[END_REF].

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The evaluated parameters were: structural and functional preservation of the facial and cochlear nerves, the data from the electrophysiological monitoring, radicality of tumour removal, and CSF leak rate. The results in this group (Group A) have been compared to a historical group of 50 patients, operated consecutively with the classical microsurgical technique, that corresponded to the inclusion criteria of the current study (Group B).

Operative technique: in all cases the retrosigmoid approach was used with the patient in semisitting position. The details of the technique have been discussed in detail previously and only the main steps are highlighted here [START_REF] Samii | Management of 1000 vestibular schwannomas (acoustic neuromas): surgical management and results with an emphasis on complications and how to avoid them[END_REF][START_REF] Samii | Improved preservation of hearing and facial nerve function in vestibular schwannoma surgery via the retrosigmoid approach in a series of 200 patients[END_REF]. The goal of surgery has always been to achieve complete tumour removal but preservation of all neurological functions had a priority. A retrosigmoid craniotomy has been performed exposing the edges of the transverse and sigmoid sinuses. A slightly curved dural incision along the sinuses has been done and the lateral cerebellomedullary cistern was opened to allow sufficient egress of CSF. Thus, a minimal brain retraction was necessary. The intrameatal tumour portion was approached initially by removing the posterior wall of the IAC. The dissection of the tumour from cranial nerves and other neural structures was performed only after sufficient tumour debulking. The tumour was dissected from surrounding neural and vascular structures by gripping the tumour capsule only and dissecting it in the level of the arachnoid plane. After the removal of the tumour, multiple fat pieces have been used to plug the drilled IAC and were sealed with fibrin glue.

Neurophysiological monitoring: continuous electrophysiological monitoring using a commercially available hardware and software (Endeavor CR intraoperative monitor; VIASYS Healthcare, Nicolet Biomedical, Madison, WI) provided feedback regarding the functional integrity of the facial and cochlear nerves [START_REF] Samii | Management of 1000 vestibular schwannomas (acoustic neuromas): hearing function in 1000 tumour resections[END_REF][START_REF] Samii | Improved preservation of hearing and facial nerve function in vestibular schwannoma surgery via the retrosigmoid approach in a series of 200 patients[END_REF]. The cochlear nerve function was assessed with brainstem auditory evoked potentials (BAEP): the needle electrodes were placed anteriorly to the tragus on both sides for registering of the potentials. The acoustic stimulation was done by generating alternate click noises, transferred with tubal insert phones (300-V stimulators) for intraaural stimulation. On the tumour side 100-dB normal hearing level stimulus and a 70-dB normal hearing level noise on the other side were applied (100msec stimulus duration and 0.01-Hz stimulus frequency). Input characteristics for acquiring evoked potentials were: 10,000 amplification rate, 1000 averaged sweeps, 150-Hz to 1.5-kHz filter, 0.2-mV sensitivity, and 10-msec duration of signal acquisition. The BAEP findings were classified according to Nordstadt's ABR typing system, consisting of Types B1 through

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B5,which are determined by the presence of waves I to V, their amplitude and latency [START_REF] Matthies | Management of vestibular schwannomas (acoustic neuromas): The value of neurophysiology for diagnosis and prediction of auditory function in 400 cases[END_REF].

The facial nerve function was monitored with EMG recordings of the orbicularis oris and oculi muscles and the input characteristics for acquiring the EMG signals were: 5000 amplification rate, 10-Hz to 1.5-kHz filter, 50-mV sensitivity, and 2-second duration of signal acquisition.

Endoscopic observation: A rigid rod-lens endoscope with a outer diameter of 2 mm and length of 26 cm with lens degree of 0 and 30° have been used (Karl Storz GmbH, Tuttlingen, Germany). They have been introduced in the CPA at different stages of VS dissection and removal for inspection of the relations of the tumour to surrounding neurovascular structures and for identification of cranial nerves and vessels. The endoscope was introduced freehand under microscopic visual control (Fig. 1). After tumour removal, the lateral end of IAC has been inspected in order to look for residual tumour parts and/or opened mastoid air cells. The effect of this procedure on the facial and cochlear nerves was assessed by observing the EMG and BAEP data during the entire procedure with a special attention during the introduction of the endoscope and the endoscopic observation.

Statistical analysis

The x2 test and Fisher's exact test were used to compare the outcome in both groups and a difference of P< 0.05 was accepted as significant.

Results

The mean age of the patients was 47.4 years (range 21-68 years) in Group A and 45.6 years (range 18-72) in Group B. Both groups had similar clinical presentation that included most frequently hearing loss, tinnitus, vertigo, dizziness, or unstable gait. The mean tumour size in Group A was 2.0 cm and in Group B -2.2 cm. Tumour extension data are presented on Table 1. The mean follow up period for Group A was 28 months (range 12-42 months) and for Group B -32 months (range 8-56 months).

Total tumour removal was achieved in all patients from Group A and in 49/50 patients from Group B. In 1 patient from Group B the lesion was tightly adherent to the nerve, and the

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attempt to dissect the nerve from the tumour capsule led to intense changes of the EMG. In this case a deliberate subtotal tumour removal was performed.

Anatomical preservation of the facial nerve was possible in all patients from Group A and in 49/50 patients from Group B (Table 2). In 1 patient with large VS (Grade 4B) the facial nerve was extremely atrophic and its integrity could not be preserved. Three weeks later a hypoglosso-facial anastomosis was preformed in order to reconstruct the function of the facial nerve. Seventeen patients from Group A had useful hearing after the surgery (56.7%); in Group B 26 patients (52%) had preserved hearing. One patient form Group A and 2 patients from the second group had transient caudal nerve dysfunction (swallowing difficulty) that resolved completely in the early postoperative period and did not cause additional morbidity.

A CSF leak was diagnosed in 1 patient from Group A and 2 patients from Group B. In all these cases it was managed successfully by a lumbar drainage insertion.

The evaluation of the electrophysiological data did not demonstrate any changes directly related to the application of the endoscope. The wave I was lost permanently in one case and temporary in 6 cases in Group A and in 2 and 12 cases, respectively, in Group B. Wave III was lost permanently in 2 and transiently in 7 cases in Group A and in 3 and 13 cases, respectively, in Group B. Wave V was lost in 6 cases of microsurgical actions in Group A and in 11 cases in Group B. The reason for loss of waves was most frequently pulling of the nerves during tumour dissection and drilling of the IAC.

The inspection with the E provided clear and detailed view of the anatomical relations within the CPA and in the IAC, up to its fundus (Fig. 2,3). The inspection after microscopically confirmed complete tumour removal did not detect tumour remnants. Opened air cells in the IAC, not directly visible with the microscope, have been found in 5 patients. There were no mechanical injuries during the introduction of the E, its manipulation close to the neuaral structures or its removal. The application of the endoscope added 15 to 20 minute to the standard operative time.

Discussion

Application of endoscopy during VS surgery

The first reported use of an endoscope for the inspection of the CPA was done by Doyen in 1917 [START_REF] Doyen | Surgical Therapeutics and Operative Techniques[END_REF]. Later on, Prott and Opel described in detail the endoscopy of the CPA [START_REF] Nakamura | Intraoperative auditory brainstem responses in patients with cerebellopontine angle meningiomas involving the inner auditory canal: analysis of the predictive value of the responses[END_REF][START_REF] Oppel | Endoscopy of the cerebello-pontine angle: its diagnostic and therapeutic possibilities[END_REF]. In the last two decades the endoscope became an integral part of the skull base surgery

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armamentarium. It increases the light intensity while approaching an object, permits a clear depiction of details in close-up positions and extends the viewing angle [START_REF] Fries | Endoscope-assisted brain surgery: Part 2-Analysis of 380 procedures[END_REF]. In CPA surgery, it is used to identify important anatomic structures and their relations to the tumour. The early identification of the brainstem and neurovascular structures in case of large tumours may be important in order to plan the subsequent surgical steps [START_REF] Gerganov | Endoscope-assisted microsurgery of large vestibular schwannomas[END_REF]. In case of smaller VS, the relationship between the tumour and facial and cochlear nerves within the IAC can be assessed [START_REF] Goksu | Endoscopy of the posterior fossa and dissection of acoustic neuroma[END_REF][START_REF] Mckennan | Endoscopy at the internal auditory canal during hearing conservation acoustic tumour surgery[END_REF][START_REF] Miyazaki | Neuro-otologic surgery through minimally invasive retrosigmoid approach: endoscope assisted microvascular decompression, vestibular neurotomy, and tumour removal[END_REF]. The safe opening of the posterior wall of the IAC may be limited by the posterior semicircular canal and the inner ear. In such cases the endoscopic inspection allows for assessment of the completeness of tumour removal, especially the existence of tumour remnants in the most lateral part of the IAC [22]. The remnant could be removed under endoscopic or microscopic control [START_REF] Wackym | Endoscopy in neuro-otologic surgery[END_REF][START_REF] Göksu | Evaluation of the results of endoscope-assisted acoustic neuroma surgery through posterior fossa approach[END_REF][START_REF] Miyazaki | Neuro-otologic surgery through minimally invasive retrosigmoid approach: endoscope assisted microvascular decompression, vestibular neurotomy, and tumour removal[END_REF]. Although in our series we did not find such remnants, some authors report a rate of up to 17.6% [START_REF] Wackym | Endoscopy in neuro-otologic surgery[END_REF][START_REF] Wackym | Adjunctive use of endoscopy during acoustic neuroma surgery[END_REF]. The endoscopic inspection after tumour removal allows for identification of opened air cells that have to be occluded in order to prevent CSF leaks. Some authors report that thus the risk of CSF leakage has been lowered or even completely avoided [START_REF] Wackym | Endoscopy in neuro-otologic surgery[END_REF][START_REF] Wackym | Adjunctive use of endoscopy during acoustic neuroma surgery[END_REF][START_REF] King | Endoscope assisted Surgery for acoustic neuromas (Vestibular Schwannomas): early experience using the rigid hopkins telescope[END_REF] Our technique for occlusion of the opened IAC is to plug the IAC with multiple small fat pieces, sealed with fibrin glue. It is preformed in all cases and does not rely on the visualization of opened air cells.

The published data showed that the endoscopic inspection during the removal of VS may help reduce the complication rates and avoid remnants. The actual significance of this additional information, however, is related to the particular operative technique and experience of the surgeon. In our series, applying the technical nuances described above, it is of relative value and is used as a method to confirm the completeness of tumor removal.

The application of endoscope, however, is related to some risk of iatrogenic neural or vascular injuries. The introduction and manipulation of the endoscope in the anatomically highly complex CPA is difficult and may lead to mechanical injury [START_REF] Miyazaki | Neuro-otologic surgery through minimally invasive retrosigmoid approach: endoscope assisted microvascular decompression, vestibular neurotomy, and tumour removal[END_REF]. The lack of threedimensional vision does not allow estimating accurately the real distance between the tip of the endoscope and the visualized structures. Further, the surgeon does not have an overview of the entire CPA -only the area at the tip of the endoscope is seen. In one case, reported by Hori et al [START_REF] Hori | Endoscope-controlled removal of intrameatal vestibular schwannomas[END_REF], the facial nerve was mechanically damaged by the endoscope itself, which necessitated its direct suturing. In order to avoid such complications, we always introduce the endoscope under microscopic control. Only when the endoscope is placed in the planned position, is the microscope withdrawn. With this technique we did not register any mechanical endoscope-related complications.

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The issue of potential thermal injury caused by the heat generated by the light source of endoscopes has been mentioned by several authors [START_REF] Wackym | Endoscopy in neuro-otologic surgery[END_REF][START_REF] Göksu | Evaluation of the results of endoscope-assisted acoustic neuroma surgery through posterior fossa approach[END_REF][START_REF] King | Endoscope assisted Surgery for acoustic neuromas (Vestibular Schwannomas): early experience using the rigid hopkins telescope[END_REF]. This effect in laboratory settings has been studies by Hori et al, who performed a thermographic study [START_REF] Hori | Endoscope-controlled removal of intrameatal vestibular schwannomas[END_REF]. The authors found that the endoscopic observation in the CPA did not lead to significant changes of the local temperature. Contrary to that, during drilling of the IAC a prominent increase of the local temperature was registered.

Intraoperative electrophysiological monitoring

The intraoperative monitoring of facial and cochlear nerves function is an essential part of each VS removal and has contributed significantly to the improved functional outcome of such surgeries. The intraoperative monitoring of BAEP, first description by Sohmer in 1967

[23], is a highly sensitive method for evaluation of the cochlear nerve and provides a continuous, almost real-time, feedback information on its functional status [START_REF] Matthies | Management of vestibular schwannomas (acoustic neuromas): The value of neurophysiology for diagnosis and prediction of auditory function in 400 cases[END_REF][START_REF] Nakamura | Intraoperative auditory brainstem responses in patients with cerebellopontine angle meningiomas involving the inner auditory canal: analysis of the predictive value of the responses[END_REF]. Further, a loss of a component may predict the risk of hearing loss, e.g. the loss of wave V is the sign most often associated with a following deafness. It has been shown that the presence of waves I, III and V, their amplitude and latency, correlate to certain miscrosurgical actions, which directly (such as pulling of the nerves during the tumour dissection) or indirectly (such as drilling of the IAC) affect the nerve. Therefore, in the current study we used this technique for assessment of the effect of the heat generated by the light source of the endoscope. Our hypothesis was that if such deleterious influence existed, it should lead to changes of the BAEP trace. Importantly, the groups of patients operated with or without E control, were highly homogeneous in regard to the characteristics of the VS. They have been all operated by a single neurosurgeon (MS) and the operative technique, applied in all cases, was identical.

Further, patients with neurofibromatosis type 2, previous surgical or radiosurgical treatment, previous infectious diseases of the brain, facial palsy and/or severe hearing loss, have been excluded. These inclusion criteria allowed us to exclude other variables that could affect the electrophysiological data or influence the outcome.

Electrophysiological monitoring during endoscope application

The evaluation of our data demonstrated that the risk for loss of waves I, II, and V, both transiently or permanently, did not depend on the application of E and was similar in both patient groups. These rates were not higher than the reported in a previous series of 201

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patients, operated by the same surgeon [START_REF] Matthies | Management of vestibular schwannomas (acoustic neuromas): The value of neurophysiology for diagnosis and prediction of auditory function in 400 cases[END_REF]. Contrary to our findings, King et al [START_REF] King | Endoscope assisted Surgery for acoustic neuromas (Vestibular Schwannomas): early experience using the rigid hopkins telescope[END_REF] observed reversible intraoperative changes of the BAEP during endoscopic observation. However, in those cases it is difficult to exclude the influence of other coexisting factors. The application of endoscopic did not influence the rate of useful hearing preservation: it was preserved in 17/30 patients from Group A and in 26/50 of those from Group B. Further, it did not lead to any EMG abnormalities and influence the facial nerve function after the surgery.

Conclusion

The application of endoscope during microsurgical removal of VS is a safe procedure that does not lead to heat-related or mechanical neural or vascular injuries. It allows for early identification of neural structures and confirms the completeness of tumour resection. The actual significance of this additional information in regards to functional outcome, radicality of surgery and complication avoidance, however, is related to the particular operative technique and experience of the surgeon.

Grade T3b 8 11

Grade T4a 4 7

Grade T4b 3 6

Table 1. Distribution of the VS according to the Hannover VS extension classification. • HB V

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• HB VI

• 16

• 5

• 3

• 3

• 2

• 1

• 26

• 7

• 7

• 6

• 3

• 1

Hearing level:

• useful hearing

• not useful hearing

• 17

• 13

• 26

• 24

Caudal cranial nerves dysfunction 1* 1* * the caudal cranial nerve dysfunction was temporary in these cases and resolved completely in the early postoperative period.

Table 2. Functional outcome and complication rate in both patient groups. No statistically significant differences in the values were found.